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REVIEW
DCLK1 in gastrointestinal cancer: A driver of tumor
progression and a promising therapeutic target
Ahmad Ghorbani Vanan
1
| Soheil Vesal
2
| Parmida Seraj
3
|
Mohammad Amin Ghezel
4
| Pooya Eini
5
| Maryam talebileili
6
| Zeynab Asgari
7
|
Safa Tahmasebi
1
| Mehrdad Hashemi
8,9
| Afshin Taheriazam
8,10
1
Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2
Department of Molecular Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
3
Department of Medicine, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
4
Student Research Committee, Babol University of Medical Sciences, Babol, Iran
5
Toxicological Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
6
Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
7
Department of Immunology, School of Medicine Kerman University of Medical Sciences, Kerman, Iran
8
Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
9
Faculty of Advanced Science and Technology, Department of Genetics, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
10
Faculty of Medicine, Department of Orthopedics, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Correspondence
Safa Tahmasebi, Student Research Committee,
Department of Immunology, School of
Medicine, Shahid Beheshti University of
Medical Sciences, Tehran, Iran.
Email: safa.tahmasebi@sbmu.ac.ir
Mehrdad Hashemi and Afshin Taheriazam,
Farhikhtegan Medical Convergence Sciences
Research Center, Farhikhtegan Hospital
Tehran Medical Sciences, Islamic Azad
University, Tehran, Iran.
Email: mhashemi@iautmu.ac.ir and
a.taheriazam@iautmu.ac.ir
Abstract
Cancers of the gastrointestinal (GI) tract, including colorectal, pancreatic, and hepato-
cellular carcinomas, represent a significant global health burden due to their high inci-
dence and mortality rates. Doublecortin-like kinase 1 (DCLK1), initially identified for
its role in neurogenesis, has emerged as a crucial player in GI cancer progression. This
review comprehensively examines the multifaceted roles of DCLK1 in GI cancers,
focusing on its structural isoforms, functions in normal and inflammatory states, and
contributions to cancer progression and metastasis. DCLK1 is overexpressed in vari-
ous GI cancers and is associated with poor prognosis, enhanced tumorigenic poten-
tial, and increased metastatic capacity. The review discusses the molecular
mechanisms through which DCLK1 influences cancer stem cell maintenance,
epithelial-mesenchymal transition (EMT), and cell survival pathways, as well as its
interactions with key signaling pathways such as Notch, WNT/β-catenin, and NF-κB.
The potential of DCLK1 as a therapeutic target is also explored, highlighting preclini-
cal and early clinical efforts to inhibit its function using small molecule inhibitors or
monoclonal antibodies. Despite significant advancements, further research is needed
to fully elucidate DCLK1's role in GI cancers and to develop effective therapeutic
strategies targeting this protein.
Ahmad Ghorbani Vanan and Soheil Vesal are considered as co-first authors.
Parmida Seraj, Mohammad Amin Ghezel, and Pooya Eini have contributed equally to this study.
Received: 24 October 2024 Revised: 12 January 2025 Accepted: 29 January 2025
DOI: 10.1002/ijc.35365
Int. J. Cancer. 2025;1–19. wileyonlinelibrary.com/journal/ijc ©2025 UICC. 1
KEYWORDS
cancer progression, DCLK1, gastrointestinal cancer, metastasis
1|INTRODUCTION
Gastrointestinal (GI) cancers cause nearly one-third of worldwide
cancer-related mortality, representing a significant global health bur-
den.
1
In 2021, 5.26 million people were diagnosed with GI cancer and
3.70 million died from it. Colorectal cancer takes the largest toll, fol-
lowed by gastric, esophageal, pancreatic, liver, and biliary tract can-
cer.
1,2
In controlling the onset of GI cancers, public policies are
crucially inclusive of reducing alcohol intake, immunizing against hepa-
titis B, and addressing various metabolic disorders.
1
All of these can-
cers share some risk factors, but they differ primarily in terms of
causes and epidemiological features.
2,3
Several modifiable risk factors
contribute to over half of GI cancer cases. These include alcohol and
tobacco use, infections, and obesity, as well as dietary factors like
high-fat diets and excessive consumption of processed foods contain-
ing nitrates, which are recognized as potent risk factors for GI can-
cers.
4
The incidence rate of major GI cancers has fluctuated over time
due to changing frequencies of these risk elements.
5
Early detection
of the disease and prediction of clinical outcomes ultimately correlate
with effectiveness in reducing the mortality rate from GI cancer by
identifying correct prognostic and diagnostic biomarkers.
6
In recent
years, doublecortin-like kinase 1 (DCLK1) (Homo sapiens) is becoming
a molecule that generates a lot of interest regarding GI cancer pro-
gression, making it possible to offer new insights into disease mecha-
nisms and treatment options.
7
DCLK1, the protein originally identified
only in the brain, acts at two main levels: one involving neuron posi-
tions and another involving neurogenesis.
8
The unique composition
consists of doublecortin domains integrated with a serine/threonine
kinase domain.
9
It has been noted that DCLK1 is overexpressed in
various GI cancers, which is associated with poor prognosis and
increased metastatic potential. Interestingly, DCLK1 plays a significant
role in key processes such as cancer stem cell maintenance, regulating
epithelial-mesenchymal transition (EMT), modulating cell cycle pro-
gression, and influencing cell survival pathways, all contributing to GI
cancer progression.
10
Investigations have also shown that DCLK1 sig-
nificantly influences cell signaling through pathways like Notch,
WNT/β-catenin, and NF-κB, which are important for disease treat-
ment strategies.
11
Accordingly, it is positioned as a likely focus for
therapeutic options. In specific GI malignancies, recent studies have
illuminated the part played by DCLK1.
12
It is known that DCLK1 is a
putative cancer stem cell marker in colorectal cancer whose levels
correlate with tumor stage and metastasis.
13
Through different mech-
anisms like regulating pluripotency-associated factors and microRNAs,
DCLK1 promotes tumor growth, drug resistance, and metastasis in
pancreatic cancer.
7
Consequently, there seems to be a relationship
between increased levels of DCLK1 and more advanced tumor stages
with poor clinical outcomes in hepatocellular carcinoma, suggesting
that it might be useful as a marker of poor prognosis.
14
New research
on DCLK1 in GI cancers has generated a lot of interest since it could
be a potential therapeutic target.
15
Several models of GI cancer have
shown that inhibition or knockdown of DCLK1 can suppress tumor
growth, enhance chemosensitivity, and decrease metastatic poten-
tial.
11
In light of this, researchers are currently investigating small
inhibitors and monoclonal antibodies during the initial phases of pre-
clinical and clinical trials to develop novel therapeutic approaches that
specifically target DCLK1.
16
Despite significant progress in under-
standing DCLK1's role in GI cancers, numerous aspects remain
unclear. For instance, the precise mechanism by which DCLK1 sus-
tains cancer stem cells and enables their metastasis or drug resistance
remains unclear.
7
Besides, further research is necessary to explore the
potential connections between DCLK1 and other cancer-related sig-
naling pathways, as well as its interactions with the tumor setting.
17
With a focus on colorectal, pancreatic, and hepatic cancers among
others, this review aims to gather the information currently available
regarding the crucial role of DCLK1 in the pathogenesis of GI malig-
nancies. In light of this, by looking at how DCLK1 affects each of
these GI cancers in particular, we discuss current findings from
research studies, possible mechanisms of action of DLCK1. In this
study, we shed light on the broader role of DCLK beyond its previous
roles as a marker or treatment option, while also highlighting the
existing gaps that require further attention in the future. The ultimate
aim is to contribute towards better diagnoses, prognosis, and thera-
pies for GI tumors, thereby reducing health burdens worldwide.
2|DCLK1 STRUCTURE AND ISOFORMS
DCLK1 is a microtubule-associated protein kinase that plays crucial
roles in neurogenesis, cellular migration, and cancer progression.
18
It
is important to understand the structure and isoforms of DCLK1 in
order to explain its functions and chances of being a target for curing
GI cancers.
19
DCLK1 belongs to the doublecortin protein family, char-
acterized by the presence of doublecortin (DCX) domains.
20
On chro-
mosome 13q13.3, the human DCLK1 gene spans approximately
110 kb in length.
11
The gene undergoes complex alternative splicing,
resulting in multiple isoforms with varying structures and potentially
distinct functions.
21
The complete DCLK1 protein has a length of
740 amino acids and a molecular weight of around 82 kD.
22
It has
two domains at its very beginning (N-terminal), which are of the DCX
kind, one end (C-terminal) that has a serine/threonine protein kinase
inherent in it, and lastly, a portion that is rich in serine/proline in
between them both.
23
DCX's domains allow it to bind to and stabilize
microtubules, and its kinase domain phosphorylates different sub-
strates, such as itself and other proteins that are linked to
2VANAN ET AL.
microtubules.
24
The structure of DCLK1 consists of two distinct
domains (DCX1 and DCX2), which play a crucial role in enabling this
protein to associate with microtubules.
25
The N-terminal doublecortin domain in DCLK1 binds to
microtubules and regulates their polymerization.
26
DCLK1 is a
microtubule-associated protein kinase that plays crucial roles in neu-
rogenesis, cellular migration, and cancer progression.
18
Studies have
shown the expression of this protein in the radial glial cells and neuro-
nal precursors.
27
DCLK1 has two isoforms of different lengths
because of the epithelial changes. The shorter isoform (DCLK1-S)
induces colorectal cancer (CRC). As a result, DCLK1-S can be an
important target for inhibiting colon cancer.
28
The C-terminal region
of the kinase domain bears a significant resemblance to the calcium/
calmodulin-dependent protein kinase (CaMK) family.
29
Consequently,
DCLK1 can act as a structural (microtubule stabilization) and signaling
(kinase activity) element of the cell.
11
Several other DCLK1 isoforms
have been identified, each with unique structural characteristics.
DCLK1-short (DCLK1-S), which lacks the appendix region of
N-terminal DCX domains but retains the serine/proline-rich area and
the kinase domain.
30
Its molecular mass is about 50 kDa and is
expressed in both embryonic and adult tissues. This isoform is
expressed primarily in neuronal tissues, where it plays a critical role in
neuronal migration and neurogenesis. The lack of an extra N-terminal
sequence in DCLK1-S affects its affinity for microtubules as well as
stability.
9
DCLK1-long (DCLK1-L), which has extra amino acids at the
N-terminus that improve its binding to microtubules, thereby possibly
changing its regulatory pathways.
31
DCLK1-L is expressed in various
tissues, such as GI tract epithelial cells, indicating its significant role in
stem cell regulation and cancer development.
32
Because DCLK1-L has
an extended N-terminal domain, its regulatory actions may be impor-
tant for tissues other than neurons.
31,33
In various tissues and devel-
opmental stages, the isoform expressions show discrepancies; hence,
they may have different physiological functions.
34
The role of DCLK1
in cancer, especially gastrointestinal cancers, hinges on its structural
features and diversity of isoforms.
35
DCLK1 is crucial for cellular pro-
cesses like proliferation, differentiation, and migration which are char-
acteristic features of cancer progression because of its kinase activity
and microtubule stabilization ability.
36
Overexpression of DCLK1,
especially the long isoform, has been associated with enhanced
tumorigenic potential, contributing to the maintenance and prolifera-
tion of cancer stem cells in GI cancers.
21
Differential expression pat-
terns of DCLK1 isoforms in GI cancers might have a role in tumor
progression and metastasis.
37
The crystal structures of DCX domains,
solved by X-ray crystallography and cryo-electron microscopy, reveal
that they generate a novel ubiquitin-like fold. They cooperatively bind
to the microtubule lattice, and stabilize microtubules, thereby promot-
ing their polymerization—a process critical for cell migration and mito-
sis.
38,39
The structure of the DCLK1 kinase domain is like that of
proteins in the calcium/calmodulin-dependent protein kinase group. It
differs from most CAMK family members, and there is no evidence
that its kinase activity is regulated by calcium. The crystal structure of
the DCLK1 kinase domain exposed possible locations for substrate
binding and catalysis, thus providing a basis for the development of
specific inhibitors.
34,40
Understanding the structural nuances of
DCLK1 isoforms is paramount for developing targeted therapies for
gastrointestinal tumors. There is evidence to support that DCLK1
overexpression is associated with adverse outcomes in colorectal,
pancreatic, and hepatocellular cancers.
13
The differential expression
of DCLK1 isoforms in these cancers indicates that some unique iso-
forms may participate in different oncogenic pathways, affecting
tumor metastatic traits and treatment.
14
3|UPSTREAM AND DOWNSTREAM
SIGNALING PATHWAYS OF DCLK1
DCLK1 has emerged as a pivotal player in cancer progression and
metastasis, with significant implications across various cancer types,
particularly gastrointestinal (GI) cancers. In esophageal squamous cell
carcinoma, the DCLK1-S isoform has been shown to promote tumor
growth and metastasis via the MAPK/ERK/MMP2 pathway, facilitat-
ing epithelial-mesenchymal transition (EMT).
22
Moreover, DCLK1
functions as a cancer stem cell (CSC) marker in several malignancies,
participating in critical oncogenic signaling pathways, including Notch,
Wnt/β-catenin, and RAS.
41
Recent studies have highlighted the role
of DCLK1 in cancer progression, particularly through its interaction
with the PI3K/AKT/mTOR signaling pathway. DCLK1 overexpression
has been associated with poor prognosis in cholangiocarcinoma
42
and
pancreatic cancer,
43
promoting tumor cell invasion, migration,
and proliferation. In colorectal cancer, DCLK1 has been shown to
induce epithelial-mesenchymal transition (EMT) via the PI3K/Akt/NF-
κB pathway.
44
DCLK1 has emerged as a biomarker for cancer stem
cells in various cancer types and regulates tumorigenesis through mul-
tiple pathways, including Notch, Wnt/β-catenin, and RAS.
41
Inhibition
of the PI3K/AKT/mTOR pathway has demonstrated potential as a
therapeutic strategy in DCLK1-overexpressing cancers, suggesting
that targeting DCLK1 or its associated pathways could be a promising
approach for cancer treatment.
In intestinal tumors, DCLK1 enhances pro-survival signaling and
supports tumor growth and self-renewal capabilities.
45
Additionally, in
head and neck squamous cell carcinoma (HNSCC), DCLK1 regulates
the NOTCH signaling pathway, and its inhibition has been shown to
reduce the proliferation, invasion, and migration of cancer cells.
22
Suppressing DCLK1 expression in colorectal cancer models reduces
the formation of adenomas and adenocarcinomas, disrupts survival
signaling, and diminishes the self-renewal capacity of cancer cells. Ele-
vated DCLK1 expression correlates with poor clinical outcomes in
several cancers, including colorectal and HNSCC, underscoring its
potential as a therapeutic target for both inflammatory conditions and
cancer treatment.
45
In colorectal cancer (CRC), DCLK1 correlates with
the activation of pro-survival signaling pathways. Studies utilizing the
ApcMin/mouse model, characterized by a mutation in the APC gene,
reveal that intestinal epithelial cells exhibit heightened expression of
pro-survival signaling, pluripotency, and self-renewal capabilities.
Knockdown of DCLK1 in these mice significantly reduces the forma-
tion of intestinal adenomas and adenocarcinomas, alongside
VANAN ET AL.3
decreased pro-survival signaling and self-renewal potential of tumor
cells. These findings underscore DCLK1's role as a critical regulator of
tumor initiation and progression in CRC.
14
DCLK1-positive pancreatic cancer stem cells emerge at a precan-
cerous stage, driven by dysfunctional epidermal growth factor recep-
tor (EGFR) signaling and oxidative stress-induced protein kinase D1
(PKD1) signaling. Despite the presence of oncogenic KRAS and ele-
vated EGFR activity, EGFR signaling in DCLK1-positive pancreatic
intraepithelial neoplasia (PanIN) cells fails to propagate effectively to
the nucleus. Inhibition of EGFR results in increased hydrogen peroxide
levels, activating PKD1, which in turn drives the formation and expan-
sion of DCLK1-positive pancreatic CSCs. This mechanism contributes
to poor therapeutic outcomes in pancreatic cancer, highlighting
DCLK1's involvement in disease progression and resistance.
45
4|DCLK1FUNCTIONINNORMAL
VS. INFLAMMATORY STATES
DCLK1 was first discovered in the developing rodent brain as a brain-
specific protein.
46
As regards the spatial expression pattern of double-
cortin, it is very similar to DCLK1. It is probable that this kinase is
involved in brain development, axon transport, and neuronal migra-
tion.
47
DCLK1 is also expressed in non-neuronal tissues. At first,
DCLK1 was considered a marker of quiescent gastrointestinal stem
cells.
48
It has been shown that the deletion of DCLK1 in mouse tuft
cells impairs tissue repair.
49
Few studies have explained the correla-
tion between DCLK1 and inflammation. It has been proven that over-
expression of DCLK1-S can induce TNF-αand IL-6 secretion in
Huh7-RFP-DCLK1 cells.
50
The high serum level of IL-6 has been
observed in several types of cancers, including lung, breast, and ovar-
ian cancer.
51
It has been reported that DCLK1, Regulates NF-κB sig-
naling pathway.
52
The NF-κB signaling pathway plays an important
role in various cellular processes such as metastasis, DNA damage,
apoptosis, tumorigenesis, and immune response against cancer.
53
There have been numerous investigations into the role of inflamma-
tion in cancer progression. NF-κB can bind to the promoters of genes,
such as IL-1β, TNF-α, and IL-6. These inflammatory genes have
diverse roles in proliferation, invasion, angiogenesis, and metastasis.
54
There are two types of NF-κB signaling pathways: the canonical and
the noncanonical pathways. In the canonical pathway, the vital step of
activation of the canonical NF-κB is the phosphorylation of IkB sub-
units in NF-κB/IκB complexes. IKK phosphorylates IκB subunits
(IKKβ), triggering ubiquitin-dependent degradation of IκB and activa-
tion of NF-κB. The canonical NF-κB pathway is involved in cancer
metastasis, angiogenesis, and tumor cell epithelial to mesenchymal
transformation. Evidence has shown that DCLK1 interacts with IKKβ
for NF-κB activation.
52
It was shown that DCLK1 mediates the liver
inflammation caused by hepatitis.
55
The inflammatory microenviron-
ment is a cancer trait that induces cancer progression. Cancer-induced
inflammation significantly contributes to the creation of an inflamma-
tory tumor microenvironment (TME), especially in solid tumors.
56,57
Kim et al. have shown that DCLK1 is directly involved in the
formation of the invasive phenotype of cancer stem cells in colorectal
cancer. DCLK1 interacts with inflammatory mediators such as PGE2
and contributes to inflammation and cancer progression.
12
The corre-
lation between cancer and inflammation has been proven. Observa-
tions show that cancer originated at chronic inflammation sites.
58
It
has been shown that DCLK1-induced NF-κB signaling increases IL-6
expression. IL-6 is a major driver of the STAT3 pathway, which pro-
motes tumor cell survival, proliferation, and immune evasion.
59
TNF-
α, a multifunctional cytokine, is significantly influenced by NF-κB
activity. While TNF-αcan induce apoptosis at low concentrations, its
chronic overexpression in the TME (partly driven by DCLK1 and NF-
κB) fosters immune suppression, angiogenesis, and tumor growth.
60
By enhancing NF-κB signaling, DCLK1 shifts macrophages from a
tumor-suppressive M1 phenotype to a tumor-promoting M2 pheno-
type. This change reduces anti-tumor immunity and fosters a tumor
microenvironment conducive to cancer progression.
59
NF-κB-driven
cytokines such as IL-6 and TNF-αactivate tumor-associated fibro-
blasts, which contribute to the deposition of extracellular matrix and
the creation of a tumor microenvironment (TME) against anti-cancer
therapies.
60,61
5|DCLK1 ROLE IN CANCER
PROGRESSION AND METASTASIS
Research confirms the upregulation of DCLK1 in diverse cancer types,
including pancreatic cancer,
62
colorectal cancer,
63
hepatocellular
carcinoma,
64
and renal cancer.
65
DCLK1 promotes the expression of
genes associated with DNA damage repair and enhances the prolifera-
tion of cancer cells. this protein contributes to chemotherapy resis-
tance. Also by remodeling the extracellular matrix (ECM), new
pathways are provided for the migration of cancer cells.
66
DCLK1
induces immune tolerance through regulating immune checkpoint PD-
L1 expression on the pancreatic tumor surface.
67
It has been shown
that the initiation of metastasis in cancer progression triggers
epithelial-mesenchymal transition (EMT).
37,68
The short and long
DCLK1 isoforms can activate EMT in pancreatic ductal adenocarci-
noma.
69
The relative proportion of M2 macrophages that suppress
the immune response against cancer was significantly higher in the
mesenchymal group. Thereby, DCLK1 is involved in the formation of
an immunosuppressive microenvironment. Inhibition of DCLK1
restores the T cell function in pancreatic ductal adenocarcinoma.
69
Cancer progression depends on tumor metastasis ability. It has been
proven that DCLK1 serves a role in diverse cancer functions such as
metastasis, cancer recurrence, and drug resistance.
70
Complicated cel-
lular and molecular mechanisms such as NOTCH, WNT, RTK, TGF-β
signaling pathways are involved in metastasis. DCLK1 plays an impor-
tant role in metastasis by controlling these signaling pathways.
71
Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most
important oncogene with the highest mutation rate among all cancers.
Studies have shown that KRAS is associated with some cancers,
including pancreatic ductal adenocarcinoma, non-small-cell lung can-
cer, and colorectal cancer.
72–74
KRAS protein can activate multiple
4VANAN ET AL.
signaling pathways, including mitogen-activated protein kinase (MEK)-
phosphoinositide 3-kinase (PI3K)- mammalian target of rapamycin
(mTOR).
75
DCLK1 is directly associated with increased KRAS expres-
sion via the PI3K and mTOR pathways.
76
DCLK1 can have different
functions among various tumor types. For example, the expression of
DCLK1 in gastric cancer tissues was significantly correlated with lymph
node metastasis and prognosis.
77
A small extracellular vesicle (exo-
some), isolated from a DCLK1-overexpressing human gastric cancer cell
line, promoted the gastric cancer cell metastasis.
78
It was shown that
DCLK1-S induced MMP2 expression via MAPK/ERK signaling to acti-
vate the epithelial-mesenchymal transition in human esophageal squa-
mous cell carcinoma (ESCC).
79
It was revealed that the inhibition of
DCLK1 with a specific monoclonal antibody inhibited tumorigenesis in
ACHN renal cancer xenografts.
80
Also, it has been concluded that
silencing of the DCLK1 gene in breast cancer leads to suppressing the
Wnt/β-catenin pathway proteins like β-catenin and c-Myc. This, in turn,
led to a decrease in the metastasis and migration of malignant cells.
81
6|THE POTENTIAL UTILITY OF DCLK1 AS
A DIAGNOSTIC MARKER IN GI CANCERS
According to recent studies, the cancer stem cell marker DCLK1 regu-
lates the biogenesis and cargo composition of small extracellular vesi-
cles (sEVs) in gastric cancer cells. This study revealed that
DCLK1-reprogrammed sEVs promote recipient cell migration in a
kinase-dependent manner, indicating a critical role of DCLK1 in modu-
lating sEV-mediated processes in gastric cancer. However, while the
study underscores the functional importance of DCLK1 in
tumorigenesis, it does not directly address its diagnostic utility in
exosome-based liquid biopsies.
78
Another study identified a distinct
subpopulation of cells expressing DCLK1 in both preinvasive pancre-
atic neoplasia (PanIN) and invasive pancreatic ductal adenocarcinoma
(PDAC). These cells exhibited cancer stem cell-like properties, posi-
tioning DCLK1 as a marker of tumorigenic potential in preinvasive
pancreatic cancer. Although the study does not evaluate DCLK1 as a
diagnostic marker in exosomes, it highlights its relevance as a stem
cell-associated marker in pancreatic cancer pathogenesis.
82
Further
research into pancreatic cancer demonstrated that DCLK1 levels are
elevated in the serum of early-stage PDAC patients. Moreover,
DCLK1-positive cells constitute a significant fraction of circulating
tumor cells (CTCs) in a PDAC mouse model. These findings suggest a
promising role for DCLK1 as a diagnostic marker in liquid biopsies for
early detection of pancreatic cancer.
83
In hepatocellular carcinoma
(HCC), increased expression of DCLK1 has been observed in both epi-
thelial and stromal compartments of cirrhotic and cancerous tissues.
Notably, plasma levels of DCLK1 were significantly elevated in HCC
patients compared to controls. Furthermore, targeting DCLK1 inhib-
ited tumor xenograft growth via a microRNA-dependent mechanism.
These results establish plasma DCLK1 as a potential diagnostic bio-
marker and therapeutic target for HCC.
84
In colorectal cancer (CRC),
DCLK1 has been extensively studied for its diagnostic and prognostic
significance. A key study confirmed that DCLK1 is both a diagnostic
marker and a therapeutic target in CRC.
18
Another investigation eval-
uated circulating cellular DCLK1 protein (CCDP) in the peripheral
blood of CRC patients using immunoassays. It was found that CCDP
levels were significantly elevated in CRC patients compared to con-
trols and correlated with clinicopathological features. Among the
methods assessed, ELISA emerged as the most suitable for the clinical
evaluation of CCDP, further supporting its potential as a liquid
biopsy-based diagnostic marker for CRC.
85
Recent studies emphasize
DCLK1's promise as a diagnostic marker in liquid biopsies for the early
detection of gastrointestinal cancers. Its detection in circulating tumor
cells, blood serum, and small extracellular vesicles suggests its value as
a minimally invasive biomarker. Nonetheless, additional research is
needed to confirm its clinical reliability and explore its role in
exosome-based diagnostics across various cancer types.
7|DCLK1’S CORRELATION WITH
OVERALL SURVIVAL IN GI CANCER
PATIENTS
Recent evidence suggests that the isoform-specific expression of
DCLK1 plays a pivotal role in determining its prognostic value in GI
cancers. DCLK1-S showed a stronger association with poor prognosis
in CRC patients. Overexpression of DCLK1-S is linked to worse over-
all survival, disease-specific survival, and disease-free survival in
CRC.
13
High levels of DCLK1 have been associated with poor clinical
outcomes and enhanced immune infiltration in colon and gastric can-
cers.
70
A novel 15-miRNA signature, indicative of DCLK1 activity, has
demonstrated predictive value for patient survival across multiple GI
cancer types, and the 15-miRNA signature was able to predict the sur-
vival of patients with these gastrointestinal cancers.
77
Additionally,
DCLK1 appears to influence the tumor microenvironment, as its
expression has been associated with the presence of tumor-
associated macrophages and regulatory T cells. These immune cells
may suppress CD8+T cell activity, contributing to immune evasion
and facilitating tumor progression.
70
8|CURRENT TREATMENTS FOR GI
MALIGNANCIES
Often the first-line treatment for respectable GI tumors (e.g., early-
stage colorectal or pancreatic cancer) is surgery. Common chemother-
apy drugs that are prescribed for patients include fluoropyrimidines
(e.g., 5-FU), oxaliplatin, and irinotecan for colorectal cancer, or gemci-
tabine and nab-paclitaxel for pancreatic cancer. These drugs aim to kill
rapidly dividing tumor cells but often lack specificity, leading to sys-
temic toxicity. Targeted therapies include EGFR inhibitors (cetuximab
or panitumumab) for colorectal cancers with wild-type RAS genes,
VEGF inhibitors (bevacizumab) targeting angiogenesis, and HER2
inhibitors (trastuzumab) for HER2-positive gastric cancers. Also,
immune checkpoint inhibitors include pembrolizumab or nivolumab,
primarily used in MSI-H/dMMR tumors. Radiotherapy is often used in
VANAN ET AL.5
combination with chemotherapy or as adjuvant therapy, particularly in
rectal or esophageal cancers.
86
As previously mentioned, DCLK1 is a
marker for cancer stem cells (CSCs). Unlike conventional chemother-
apy, DCLK1 inhibitors specifically target cancer stem cells, which are
often resistant to standard treatments and drive relapse and metasta-
sis. DCLK1 regulates EMT (epithelial-mesenchymal transition), a key
process in chemoresistance and metastasis. Inhibiting DCLK1 can
reverse EMT, sensitizing tumors to traditional therapies and reducing
metastatic potential.
87
DCLK1 influences cytokine profiles and hyp-
oxia within the TME, which play critical roles in tumor progression
and immune evasion.
88
Studies suggest that DCLK1 inhibition may
downregulate PD-L1 expression in cancer cells, enhancing the efficacy
of immune checkpoint inhibitors like anti-PD-1/PD-L1 therapies. Rui
Yan et al. showed that inhibition of DCLK1 down-regulates PD-L1
expression through the Hippo pathway in human pancreatic cancer.
67
This presents an opportunity for combination therapies targeting both
DCLK1 and immune checkpoints. Besides, there are several biological
approaches for targeting DCLK1 in gastrointestinal cancers, including
small molecule inhibitors and monoclonal antibodies. Weygant et al.
and May et al., demonstrated that using LRRK2-IN-1, a small molecule
inhibitor, causes suppression activity of DCLK1 in human pancreatic
and colorectal cancer cell line models and xenograft models in mice.
Inhibition of DCLK1 activity resulted in anti-proliferative, anti-
migratory effects and modulation of EMT activity in these cancers.
Isoform specificity was validated using in vitro kinase assays to mea-
sure the compound's inhibitory effects on DCLK1 kinase activity while
also ensuring minimal cross-reactivity with other kinases. Western
blot analysis and siRNA knockdown experiments were used to con-
firm its selective suppression of DCLK1 isoform expression in colorec-
tal and pancreatic cancer models.
89
Sureban et al. showed that
XMD8–92, which is a DCLK1 kinase inhibitor, inhibits pancreatic
tumor xenograft growth by downregulating DCLK1 and its down-
stream targets responsible for causing cancer. Human pancreatic can-
cer AsPC-1 cells were used in this research. This inhibitor was
validated using cell-based assays and transcriptome analyses to
demonstrate their selective impact on DCLK1-driven downstream sig-
naling pathways, including cancer stem cell (CSC) markers and tumor-
suppressor miRNAs.
71
In addition, several monoclonal antibodies such
as DCLK1-42 and DCLK1-87, have been designed for the identifica-
tion of DCLK1+cells in colorectal cancer tissues. Validation involved
peptide competition assays and immunohistochemistry (IHC) to dem-
onstrate high specificity for DCLK1+cells. These antibodies were
tested on colorectal cancer tissues to distinguish between DCLK1 iso-
forms and unrelated proteins.
90
9|DCLK1 ROLE IN PATHOGENESIS OF
GASTROINTESTINAL CANCERS
9.1 |Colorectal Cancer
Colorectal cancer is a malignancy that arises from the epithelial cells
of the colon or rectum, often due to genetic abnormalities in the
Wnt signaling pathway that enhance signaling activity.
91,92
Unlike
normal stem cells, only cancer stem cells (CSCs) express DCLK1,
according to a preliminary investigation of the gastrointestinal tract.
Therefore, DCLK1 was introduced as a specific marker for CSCs in
CRC.
69
Further studies demonstrated that DCLK1 is predominantly
expressed by tuft cells in the colon and intestine, where these cells
can form stem cell niches and may contribute to inflammation-
associated cancer.
70,93
DCLK1 expression has been shown to be
significantly upregulated in CRC tissue and cell lines compared to
normal cells, with levels progressively increasing from low-grade
adenomas to more severe dysplastic stages.
72
It has two isoforms,
with the shorter isoform (DCLK1-S) mainly implicated in promoting
tumorigenesis in CRC.
73
DCLK1 overexpression is associated with
tumor heterogeneity, poor prognosis, and worse clinicopathological
features in CRC patients. According to studies, increased expression
of DCLK1 promotes tumor proliferation, sphere formation, invasion,
metastasis, angiogenesis, epithelial-mesenchymal transition (EMT),
recurrence, drug resistance, and mortality rate in CRC
10
(Figure 1
and Table 1). Several factors play a critical role in the regulation of
DCLK1 expression, including the elevated expression level of RNA
binding motif 3 (RBM3), AT-rich sequence-binding protein
2 (SATB2), lymphoid enhancer-binding factor 1 (LEF1), miR-15, pro-
lactin, and inflammation.
14
Concerning genetic alteration related to
DCLK1, it was found that a substantial number of DCLK1
+
CRC
cells are associated with an adenomatous polyposis coli (APC) gene
mutation, linked to enhanced tumor cell pluripotency and self-
renewal.
94
There is a growing body of evidence demonstrating that
DCLK1 expression modulates signaling pathways, thereby affecting
various cellular activities in CRC cells. According to a study, DCLK1
stimulates inflammation and enhances CRC cell initiation and devel-
opment by activating the Wnt and Notch1 signaling pathways.
10
A
key point to note is that DCLK1 can promote CRC development
through mechanisms that depend on microRNAs (miRNAs). For the
first time, Sureban et al.
95
revealed that silencing of DCLK1 via
nanoparticles containing DCLK1-siRNA induced the expression of
let-7a, miR-144, and miR-200a as tumor suppressor miRNAs in the
CRC. This suppressed the CRC progression via the Notch1 signaling
pathway. Then, a study conducted by Mohammadi et al. revealed
that the regulatory function of DCLK1 on the expression of miR-
200c mediated the tumor-promoting effects of increased DCLK1 in
CRC cell lines.
63
A study by Gao et al.
74
suggested DCLK1 as a bio-
marker for metastasis in CRC. Another pathway affected by DCLK1
is the TGF-β/Smad signaling pathway. It was found that DCLK1
induces EMT and tumor progression in CRC through the regulation
of tribble homolog 3 (TRIB3) expression and activation of the TGF-
β/Smad pathway.
77
Moreover, Razi et al.
80
demonstrated that
DCLK1 can promote CRC progression, invasion, and tumor growth
by targeting miR-137 and miR-15a. They suggested that DCLK1
may have diagnostic value and serve as a therapeutic target in
CRCs. Recent discoveries reveal that the altered expression of
DCLK1 not only affects tumor cells but also modifies the tumor
microenvironment (TME) and aids in tumor progression. Based on
Kim et al.'s findings,
9
DCLK1 induces the expression of
6VANAN ET AL.
cyclooxygenase-2 (COX2) through the phosphorylation of cross-
complementing 5 (XRCC5), which increases the expression of pros-
taglandin E2 (PGE2) related genes and generates an inflammatory
TME to promote CRC. There is accumulating evidence that DCLK1
plays a role in the resistance or response to chemotherapy and
radiotherapy.
82
Based on Ji et al.'s findings, miR-15b regulates
DCLK1 expression in CRC cells and increases their sensitivity to
chemotherapy and radiotherapy by increasing miR-15b expres-
sion.
83
Another study involving the anticancer drug Niclosamide
demonstrated that suppressing DCLK1 via the LEF-1 transcription
factor increased the effectiveness of chemotherapy and radiother-
apy in CRC cells.
84
In an investigation of radiotherapy alone,
Mohammadi et al.
18
found that radioresistant CRC cells have higher
expression of DCLK1 than normal cells. They also found that silenc-
ing DCLK1 led to an increase in radiosensitivity in CRC cells. The
same findings have also been observed in the case of chemotherapy
alone. The combination of DCLK1 inhibitor (LRRK) with
5-fluorouracil (5-FU) eliminated 5-FU's side effects related to cell
cycle arrest and improved therapeutic outcomes in CRC cells.
85
Afterward, Lin et al. confirmed that DCLK1 is involved in chemo-
therapy resistance in CRC. According to their findings, DCLK1 over-
expression increased resistance to 5-FU by modulating genes
involved in suppressing apoptosis in CRC cells.
13
Moreover, a
recent study found that DCLK1 facilitates resistance to 5-FU in
CRC by activating the cell cycle and apoptosis regulator 1 (CCAR1)/
β-catenin pathway, thereby promoting cancer stem cell characteris-
tics. Importantly, disrupting this pathway by inhibiting DCLK1 effec-
tively suppressed 5-FU-resistant CRC cells in both experimental and
clinical contexts.
86
Additionally, oxaliplatin administration to CRC
cells that were silenced in DCLK1 made them more sensitive to it
and had a combined effect of suppressing the development of
CRC.
77
A study by Sureban et al.
13
showed that chimeric antigen
receptor (CAR-T) targeting DCLK1 exhibited remarkable anti-
tumoral responses and suppressed CRC cell progression. While sev-
eral studies have demonstrated a negative correlation between
DCLK1 overexpression and overall survival in CRC patients,
14,74
a
contradictory study by Dai et al. revealed a longer survival time for
CRC patients with high DCLK1 expression compared to those with
low expression. However, they did not provide an explanation for
these results or the apparent contradiction.
75
Research on DCLK1's
regulation of EMT (epithelial-to-mesenchymal transition) in colorec-
tal cancer highlights its pivotal role in tumor progression and metas-
tasis. DCLK1 influences EMT primarily through multiple signaling
pathways. DCLK1 interacts with β-catenin, enhancing its nuclear
localization, which drives transcription of EMT-related genes. Also,
DCLK1 promotes EMT through the activation of this pathway,
FIGURE 1 Role of DCLK1 in colorectal cancer stem cells. [Color figure can be viewed at wileyonlinelibrary.com]
VANAN ET AL.7
TABLE 1 Overview of DCLK1s functions and roles in CRC.
Author, year Study model Intervention
Related targets &
pathways Finding(s) Ref.
Sureban et al.
2011
Human ––•Increased expression of DCLK1 71
Xenograft Mouse NPs containing
DCAMKL-1 siRNA
let-7a
miR-144
miR-200a
DCLK1 silencing led to:
•Arrest in tumor growth
•Suppressed EMT
Weygant et al.
2014
Human PC cell line DCLK1 inhibitor
(LRRK2-IN-1)
MEK1/2-MAPK7
cascade/ c-Myc
DCLK1 inhibition led to:
•Suppressed proliferation, migration,
stemness, EMT
Induced apoptosis and cell cycle arrest
72
Gao et al. 2016 Human CRC tissues - - Increased expression of DCLK1
correlated with:
•Metastasis
•Poor prognosis
73
Human CRC cell line DCLK1 vector
transfected
- Increased expression of DCLK1
correlated with:
•Promoted migration, invasion,
and EMT
Dai et al. 2018 Human CRC tissues DCLK1-42 and
DCLK1-87 mAbs
- High DCLK1 expression correlated with:
•longer OS and DFS
74
Mohammadi
et al. 2018
Human CRC tissues - - •Increased expression of DCLK1 70
Human CRC cell lines DCLK1-siRNA
transfected
miR-200c DCLK1 silencing led to:
•Suppressed migration and invasion
•Decreased sphere-forming ability
•Induced apoptosis
Suehiro et al.
2018
Human CRC cell line 5-FU
+
DCLK1
inhibitor
(LRRK2-IN-1)
–DCLK1 inhibition led to:
•Improved response to 5-FU
chemotherapy
75
Jio et al. 2018 Human CRC tissues
& cell lines
–miR-15 as
upstream
target for DCLK1
Increased expression of DCLK1
correlated with:
•Shorter DFS
•Worse prognosis
•Response/resistance to
chemoradiotherapy
76
Li et al. 2019 Human CRC cell line casp-3, casp-4,
and casp-10
Increased DCLK1 expression was
contributed to
•5-FU resistance
77
Makino et al.
2019
Human CRC tissues ––High DCLK1 was correlated with:
•Poor prognosis
•Cancer invasion depth
•Lymph node metastasis
78
Human CRC cell line DCLK1-siRNA
transfected
TRIB3 DCLK1 silencing led to:
•Suppressed the growth, invasion,
and EMT
•Improved response to oxaliplatin
Razi et al. 2020 Human CRC tissues ––DCLK1 overexpression was correlated
with:
•Tumor size
•Poor differentiation
•Lymph node involvement
79
Human CRC cell line ––DCLK1expression has a correlation with
miR-137 and miR-15a
Park et al. 2019 Public databases Niclosamide Wnt/β-catenin
signaling,
LEF1 as upstream
regulator for
DCLK1-B
Increased expression of DCLK1
correlated with:
•Poor prognosis
•Chemoresistance
80
Human CRC cell line
Xenograft Mouse
8VANAN ET AL.
which also contributes to drug resistance and poor prognosis. This
mechanism underscores the role of DCLK1 in sustaining the EMT
state and enhancing tumor aggressiveness.
87
Studies have demon-
strated the potential of DCLK1 as a diagnostic and prognostic bio-
marker, as well as a therapeutic target in CRC.
14,81
9.2 |Pancreatic Cancer
Similar to its role in CRC, DCLK1 serves as a marker for CSCs in pan-
creatic cancer (PC), primarily exhibiting its expression in metastatic
and invasive CSCs.
89
Different types of PC have elevated DCLK1
TABLE 1 (Continued)
Author, year Study model Intervention
Related targets &
pathways Finding(s) Ref.
Sureban et al.
2019
Human CRC tissues ––Increased expression of DCLK1
correlated with:
•Reduced OS and RFS
•Increased EMT related genes
•Increased expression of PD-L1/2
14
Human CRC cell line CAR-T targeting
DCLK1
–Induced CRC cytotoxicity and IFN-γ
secretion
Xenograft Mouse •Reduced tumor growth
Wang et al.
2022
Human CRC tissues ––High DCLK1 was correlated with:
•Poor overall survival
•Resistance to 5-FU
81
Human CRC cell line DCLK1 shRNA &
vector
transfected
DCLK1 was correlated with:
•CRC cell stemness
•Resistance to 5-FU
DCLK1 inhibitor
(DCLK1-IN-1)
CCAR1/β-catenin
pathway
DCLK1 silencing led to:
•Suppressed 5-FU resistance
Xenograft Mouse DCLK1 shRNA &
vector
transfected
DCLK1 was correlated with:
•CRC cell stemness
•Resistance to 5-FU
•Tumor volume
Mohammadi
et al. 2021
Human CRC cell line DCLK1-siRNA
transfected
DCLK1 silencing led to:
•Enhanced the sensitivity to radiation
•Reduced cell survival
•Induced apoptosis rate and cell cycle
arrest
•Reduced CSCs and EMT related
markers
82
Kim et al. 2022 Human CRC tissues XRCC5/COX2/
PGE2 axis
High DCLK1-B expression correlated
with:
•T stage and recurrence
•Shorter OS and RFS
10
Human CRC cell line DCLK1 knockout DCLK1 knockout led to:
•Suppressed survival, proliferation,
migration, and invasion
•Induced apoptosis
Xenograft Mouse DCLK1 vector
transfected
Increased expression of DCLK1
correlated with:
•Improved liver metastasis
•Decreased survival time
DCLK1 inhibitor
(DCLK1-IN-1)
DCLK1 inhibition led to:
•Decreased in tumor growth and size
•Reduced stemness
Abbreviations: 5-FU, 5-fluorouracil; CAR-T, chimeric antigen receptor T-cells; CCAR1, cell division cycle and apoptosis regulator 1; COX2, cyclooxygenase-
2; CRC, colorectal cancer; CSC, cancer stem cell; DCLK1, doublecortin-like kinase 1; DFS, disease-free survival; EMT, epithelial-mesenchymal transition;
IFN-γ, interferon gamma; LEF1, lymphoid enhancer-binding factor 1; MAPK7, mitogen-activated protein kinase 7; mAb, monoclonal antibody; MEK1/2,
mitogen-activated protein kinase 1/2; NPs, nanoparticles; OS, overall survival; shRNA, short hairpin RNA; siRNA, small interfering RNA; PC, pancreatic
cancer; PD-L1/2, programmed death-ligand 1/2; PGE2, prostaglandin E2; RFS, recurrence-free survival; TRIB3, tribbles homolog 3; XRCC5, X-ray repair
cross complementing 5.
VANAN ET AL.9
expression, promoting tumor cell progression. Additionally, high levels
of DCLK1 have been detected in the serum and circulating tumor cells
of pancreatic ductal adenocarcinoma (PDAC) patients.
92
Its increased
expression was also directly correlated with poor survival and high
recurrence rates in PC patients.
93
It has been shown that the dysfunc-
tional epidermal growth factor receptor (EGFR) signaling pathway and
protein kinase D1 (PKD1) activation following oxidative stress are fac-
tors that influence DCLK1 expression in PC cells and can induce the
formation of DCLK1
+
pancreatic CSCs.
63
DCLK1 gene expression has
also been linked to epigenetic alterations in PC, specifically H3K4 and
H3K27 histone modifications.
89
DCLK1 has demonstrated a close
relationship with mutated KRAS during PC progression. The adminis-
tration of CBT-15G, a monoclonal antibody targeting DCLK1, effec-
tively reversed these effects and confirmed the potential of DCLK1 as
a therapeutic target in PC.
96
Researchers have found a close relation-
ship between DCLK1 expression and miRNA expression in terms of
suppressing or promoting PC. A study revealed that downregulation
of DCLK1 expression after the use of the kinase inhibitor XMD8-92
reduced PDAC cell growth by upregulating let-7a, miR-144, miR-
200a-c, and miR-143/145 expressions.
90
Moreover, Zhou et al.
97
showed an inverse relationship between miR-195 expression and
DCLK1 expression in PC, in which miR-195 decreased expression was
associated with increased DCLK1 expression. They also revealed the
relation between increased expression of DCLK1 and TNM stage,
lymph node metastasis, and poor survival in PC patients. There is sub-
stantial evidence that DCLK1 plays a crucial role in PC growth,
migration, invasion, and angiogenesis
70,94
(Figure 2and Table 2). Ito
et al. elucidated the role of DCLK1 in metastasis by showing that
knocking down DCLK1 significantly reduced metastasis of PC cells to
the liver in vivo.
89
According to a study conducted by Li et al.,
95
DCLK1 overexpression is associated with migration and invasion, as
well as having the potential to serve as a prognostic and metastatic
biomarker in PC. DCLK1 knockdown was found to promote EMT of
PC cells by overexpressing miR-200a.
87
Additionally, DCLK1 silencing
inhibited PC cell EMT via indirect targeting of B cell-specific Moloney
murine leukemia virus insertion site 1 (Bmi-1) and other EMT-related
genes. DCLK1 has been shown to modulate EMT-associated path-
ways and markers in pancreatic cancer. According to studies, DCLK1
is associated with TGF-βsignaling, a central pathway in EMT induc-
tion. This interaction affects mesenchymal markers like N-cadherin
and vimentin, promoting migration, invasion, and metastasis. Blocking
DCLK1-mediated EMT can inhibit these processes and potentially
sensitize tumors to immunotherapies. DCLK1-mediated EMT
enhances the resistance of pancreatic cancer cells to immune
responses, promoting survival and metastasis. This includes interac-
tions with immune checkpoint molecules like PD-L1, which are often
upregulated during EMT.
88
It has been proven that DCLK1 influences
markers such as vimentin (a mesenchymal marker), E-cadherin
(an epithelial marker), and β-catenin. For example, its knockdown
results in the upregulation of E-cadherin, reducing EMT-driven inva-
siveness.
96
DCLK1 promotes the progression, invasion, and migration
of PC cells by activating the Hippo pathway.
71
DCLK1
+
cells were
FIGURE 2 Role of DCLK1 in Pancreatic cancer stem cells. [Color figure can be viewed at wileyonlinelibrary.com]
10 VANAN ET AL.
TABLE 2 Overview of DCLK1s functions and roles in PC.
Author, year Study model Intervention
Related targets
and pathways Finding(s) Ref.
Sureban et al.
2011
Human PC tissues Increased expression of DCLK1 in PC 71
Human PC cell
line
DCAMKL-
1-siRNA
miR-200a
let-7a
miR-144
DCLK1 silencing led to:
•EMT inhibition
•Tumorigenesis suppression
Xenograft Mouse •DCLK1 was introduced as pancreatic stem cell marker
•DCLK1 overexpression was correlated with
mutated KRAS
Sureban et al.
2014
Human PC cell
line
DCLK1 inhibitor
(XMD8-92)
DCLK1 inhibition led to:
•Reduced expression of c-MYC, KRAS and Notch1
84
Xenograft Mouse miR-143/145
Let-7a
miR-200
DCLK1 inhibition led to:
•Tumor growth suppression
•Pluripotency inhibition
•Angiogenesis and EMT inhibition
Weygant et al.
2014
Human PC cell
line
DCLK1 inhibitor
(LRRK2-IN-1)
MEK1/2-MAPK7
cascade/c-Myc
DCLK1 inhibition led to:
•Proliferation, migration, stemness, and EMT
suppression
•Apoptosis and cell cycle arrest
72
Xenograft Mouse DCLK1 inhibition led to:
•Suppression in tumor volume and weight
Ito et al. 2015 Human PC tissues DCLK1 overexpression was correlated with
•Metastasis
18
Human PC cell
line
DCLK1
overexpressing
vector
DCLK1 silencing led to:
•Improved migration
Xenograft Mouse DCLK1-shRNA •Reduced liver metastasis
Westphalen
et al. 2016
Murine •DCLK1
+
cells induced cancer initiation following injury
and inflammation
•DCLK1
+
cells induced KRAS mutant PC tumorigenesis
85
Kawamura et al.
2017
Human PC cell
line
DCLK1-siRNA,
Gemcitabine,
DCLK1 inhibitor
(LRRK2-IN-1)
ATR pathway Silencing DCLK1 along with Gemcitabine led to:
•Increased DNA damage, apoptosis, and cell death
13
Zhou et al.
2017
Human PC tissues DCLK1 overexpression was correlated with:
•TNM
•Lymph node metastasis
•Poor survival
86
Human PC cell
line
miR-195 mimics/
inhibitor
miR-195 as
upstream
regulator for
DCLK1
miR-195 Overexpression via targeting DCLK1 led to:
•Suppression in tumor growth, migration, invasion, and
metastasis
Xenograft Mouse
Li et al. 2018 Human PC tissues DCLK1 overexpression was correlated with:
•Shorter OS
•Clinical stage, pathological stage and distant metastasis
•Mesenchymal phenotype
•Increased proliferation
87
Human PC cell
line
DCLK1-siRNA Bmi-1 DCLK1 silencing led to:
•Tumor growth suppression
•Migration, invasion, and EMT inhibition
Xenograft Mouse DCLK1 silencing led to:
•Decrease in tumor volume and tumor weights
Qu et al. 2019 Bioinformatic
analysis & Human
PC tissues
KRAS and PI3K/
AKT/mTOR-
pathway
•Increased expression of DCLK1 in PC and other
cancers
•DCLK1 overexpression was correlated with poor
prognosis
88
Increased expression of DCLK1 was correlated with:
(Continues)
VANAN ET AL.11
also found to play a key role in pancreatic regeneration in chronic
inflammation and injury. There is evidence showing that increased
expression of DCLK1 following inflammation and mutation could be a
primary step for PC initiation.
91
Additionally, the strong impact of
DCLK1 on stem cell pluripotency in PC is evidenced by the significant
reduction in the expression of stemness-related genes (e.g., MYC,
SOX2, NANOG, and OCT4) following its inhibition.
71
DCLK1
+
cells
contribute to the development of immune responses following injury
and infection within the cell microenvironment.
98
The ability of these
cells to produce IL-17 and PEG2-related products indicates that they
play an important role in modulating the pro-inflammatory
response.
99,100
Moreover, it was discovered that DCKL1 expression
could induce the expression of PD-L1 by regulating the Hippo path-
way, thereby modulating immune responses in PDAC.
101
TABLE 2 (Continued)
Author, year Study model Intervention
Related targets
and pathways Finding(s) Ref.
Human PC cell
line
DCLK1
overexpressing
vector, DCLK1
inhibitor
(XMD8-92), and
Gemcitabine
•Promoted invasion
•RAS activation
•Improved drug resistance
Xenograft Mouse Anti-DCLK1 mAb
(CBT-15X)
DCLK1 inhibition led to:
•Decreased tumor growth, volume, and mass
Yan et al. 2019 Bioinformatic
analysis
Hippo pathway DCLK1 showed a correlation with Hippo pathway 89
Human PC cell
line
DCLK1
overexpressing
vector,
Dclk1 inhibitors
(LRRK2-IN-1 and
XMD8-92)
Hippo pathway Increased expression of DCLK1 was correlated with:
•Induced PD-L1 expression
•Reduced T-cell proliferation
Chandrakesan
et al. 2020
Bioinformatic
analysis
•DCLK1-isoform2 highly increased in PDAC samples
•Correlation between DCLK1-isoform2 and M2 subtype
90
Human PC cell
line
DCLK1
overexpressing
vector and siRNA
•Overexpression of DCLK1 induced M2 polarization
•Induced M2 subtype promoted PC progression
Mouse DCLK1-siRNA Increased expression of DCLK1-isoform2 in PDAC mice
was correlated with:
•Induced M2 polarization
•CD8
+
T cell infiltration, activation and functions
suppression
Ge et al. 2022 Bioinformatic
analysis & PC
tissues
Increased expression of DCLK1 was correlated with:
•Overexpression of EMT related genes
•Induced M2 polarization
•Increased immune checkpoint expression
•Reduced CD8
+
T-cell infiltration
•Reduced ICIs efficacy
91
Human PC cell
line
DCLK1
overexpressing
vector
Increased expression of DCLK1 was correlated with:
•Improved migration and invasion
•Promoted tumor migration and invasion
•Induced immunosuppressive microenvironment
Xenograft Mouse DCLK1
overexpressing
vector
DCLK1 inhibitor
(DCLK1- IN-1)
Increased expression of DCLK1 was correlated with:
•Reduced CD4
+
and CD8
+
T-cell infiltration
•Decrease IFN-γsecretion
•Induced M2 polarization
•Loss of E-cad
•Induced sensitivity to ICIs
Abbreviations: AKT, protein kinase B; ATR, ataxia telangiectasia and Rad3-related; Bmi-1, B lymphoma Mo-MLV insertion region 1; CD8
+
,clusterof
differentiation 8 positive; DCLK1, doublecortin-like kinase 1; ICIs, immune checkpoint inhibitors; IFN-γ, interferon gamma; E-cad, E-cadherin; EMT, epithelial-
mesenchymal transition; Hippo pathway, pathway involved in organ size regulation; KRAS, Kirsten rat sarcoma viral oncogene homolog; mAb, monoclonal
antibody; miR, microRNA; mTOR, mammalian target of rapamycin; OS, overall survival; PC, pancreatic cancer; PD-L1, programmed death-ligand 1; PDAC,
pancreatic ductal adenocarcinoma; PI3K, phosphoinositide 3-kinase; shRNA, short hairpin RNA; siRNA, small interfering RNA; TNM, tumor-node-metastasis.
12 VANAN ET AL.
Furthermore, DCLK1-isoform2 has been shown to influence macro-
phage polarization toward the M2 subtype (pro-tumoral) and the
development of an immunosuppressive TME, thereby preventing
PDAC cells from migrating, invading, and self-renewing. There is an
interesting finding that DCLK1-isoform2 inhibits CD8
+
T-cell prolifer-
ation and cytotoxic activity, dampening anti-tumor responses.
102
In a
confirmatory study by Ge et al., it was found that DCLK1 overexpres-
sion contributes to the formation of immunosuppressive TME via the
production of immunosuppressive chemokines/cytokines, upregula-
tion of immune checkpoints (e.g., CTLA-4, PD-L1, TIM3, LAG3, and
VISTA), decreased infiltration of CD4
+
and CD8
+
T cells, and IFN-γ
production. It also showed the potential to affect immunotherapy
efficacy. A DCLK1 inhibitor (DCLK1-IN-1) could reverse all these
tumor-promoting effects and promote anti-tumoral T-cell
responses.
103
It is important to note that, unlike CRC, there is a lack
of sufficient studies on the role of DCLK1 in the development of
resistance or response to chemotherapy or radiotherapy in
PC. Kawamura et al.
105
found that LRRK administration with anti-
cancer agent gemcitabine reduced gemcitabine-induced cell cycle
arrest and improved treatment efficacy in PC. LRRK2-IN-1, a first-
introduced DCLK1 inhibitor, showed anti-tumoral effects and con-
firmed the potential of DCLK1 as a therapeutic target in PC.
88
Moreover, a recently introduced DCLK1 inhibitor named Compound
I-5 showed impressive anti-tumoral effects in vitro and in vivo, includ-
ing suppressing PC cell growth, migration, and invasion.
104
9.3 |Hepatocellular carcinoma (HCC)
Liver cancer is the most common cause of cancer-related deaths
worldwide and the fifth most common cause in the United States, and
its annual incidence is increasing.
97,98
Surgery or transplantation
forms the cornerstone of curative treatment for early-stage disease,
and ablative strategies can also treat tumors. However, overall sur-
vival for the disease is poor as only 25% of patients qualify for cura-
tive resection.
99,100
Tissue stem cell mutations can lead to the
formation of tumor stem cells (TSCs) or cancer stem cells
(CSCs).
101,102
In a study in 2011, CD133
+
cells from human HCC tis-
sues underwent epithelial-mesenchymal transition (EMT) and subse-
quently exhibited aggressive tumor growth and metastasis.
103
Tumor
stem cells (CSCs) encompass a subset of cells within a tumor responsi-
ble for initiating the tumor and are often resistant to standard treat-
ments. Identifying CSCs is crucial due to their aggressive nature and
treatment resistance. Current research focuses on targeting CSC path-
ways and their interactions with the tumor microenvironment, leading
to the development of new therapeutic strategies.
104,105
As noted,
DCLK1 has emerged as a potential marker for cancer stem cells and is
believed to play a crucial role in the process of carcinogenesis. It has
been associated with promoting cancer initiation, facilitating tumor
invasion, and supporting metastasis in various solid tumors, including
pancreatic adenocarcinoma, colorectal cancer and hepatocellular can-
cer as well.
80,82
Recent studies have highlighted its critical role in HCC
pathogenesis and its potential as a therapeutic target. Analysis of
DCLK1 expression in HCC tissues has revealed its presence in 81%
of HCC samples and 74% of adjacent non-tumor tissues, suggesting a
pervasive role in liver tumor biology. Notably, DCLK1 expression
independently predicts disease-free survival (DFS), particularly in
patients with portal venous metastasis, intrahepatic metastasis, and
cirrhosis (Figure 3and Table 3). However, it does not serve as a pre-
dictor for overall survival (OS), indicating its specific relevance to dis-
ease progression rather than overall patient survival.
106
DCLK1
influences several key signaling pathways crucial for tumor develop-
ment and progression. Its role in liver inflammation and tumorigenesis
has been established through various methodologies, including immu-
nohistochemistry, Western blotting, ELISA, and analyses of the TCGA
LIHC dataset. DCLK1 overexpression is linked to upregulation of
S100A9, c-Myc, and BRM, proteins associated with inflammation and
cellular transformation.
94
DCLK1 in liver cancer revealed its significant
role in promoting liver inflammation and tumorigenesis according to a
retrospective case–control study. Through immunohistochemistry,
Western blot, ELISA, and TCGA LIHC dataset analysis, researchers
found DCLK1's involvement in S100A9 and NF-κB pathways and
chromatin remodeling. DCLK1 overexpression was linked to increased
S100A9, c-Myc, and BRM levels, while its silencing reduced S100A9
expression and hindered hepatoma cell migration, underscoring its
therapeutic potential.
55
In another retrospective study, DCLK1 level
increased in both tissue and plasma of patients with cirrhosis and
HCC. It clearly shows that targeting DCLK1 with siRNA inhibited
tumor growth and can be used as a potential biomarker and therapeu-
tic target for HCC.
84
Wenyao Wang et al. in 2016, demonstrated that
miR-613 is downregulated in HCC tissues. Their study found
that overexpression of miR-613 in HCC cell lines significantly reduces
cell proliferation and invasion by directly targeting and inhibiting
DCLK1, a key protein involved in tumor growth and progression. This
effect was further confirmed in a xenograft mouse model, where miR-
613 overexpression suppressed tumor growth.
107
Another study con-
firmed that DCLK1 negatively regulates miRNA let-7a, influencing
oncogenic pathways, while its inhibition led to tumor growth arrest
and reduced expression of EMT-related genes through miR-200.
Furthermore, DCLK1 modulates pluripotency factors via
post-transcriptional regulation of miR-143/145, highlighting its poten-
tial as a therapeutic target.
84
DCLK1 plays a significant role in liver
cancer progression, particularly through modulating the β-catenin sig-
naling pathway. Research conducted in cell cultures and animal
models, including DEN/CCl4-induced liver injury models and human-
ized liver mice, has shown that DCLK1 enhances hepatocyte plasticity
and clonogenicity through an atypical β-catenin-dependent mecha-
nism. This is marked by the presence of a 48-kDa active form of
β-catenin, which enhances transcriptional activity and promotes the
expression of cyclin D1, a key player in cell cycle regulation. These
findings were corroborated in a humanized liver mouse model and
confirmed in cirrhotic and HCC patient tissues. In addition to its role
in β-catenin signaling, DCLK1-positive cells have been shown to sup-
press anti-tumor immunity by expressing PD-L1 and inducing macro-
phage polarization, contributing to an immune-suppressive
environment that facilitates tumor progression.
108,109
VANAN ET AL.13
9.4 |Gastric cancer
Gastric cancer (GC) is the fifth most common cancer worldwide and
the third leading cause of cancer-related deaths. It is highly prevalent
in East Asia, particularly in countries like Japan, South Korea, and
China, which account for over 50% of global cases. The high incidence
is linked to risk factors such as Helicobacter pylori infection, dietary
habits, and genetic predisposition. Despite advancements in diagnosis
and treatment, the prognosis for advanced gastric cancer remains
poor due to late-stage detection and therapy resistance.
110
Studies
have shown that DCLK1 is overexpressed in gastric cancer tissues
compared to normal gastric mucosa. This overexpression is associated
with cancer stem cell characteristics, increased tumor growth, and
metastasis. It has been shown that DCLK1+cells in gastric tissue act
as tumor-initiating cells, contributing to tumorigenesis and resistance
to therapies.
70
Feng et al.
111
reported that DCLK1 activates EMT
markers such as Snail and Twist, leading to aggressive phenotypes in
gastric cancer models.
111
Studies on DCLK1 in gastric cancer have demonstrated its critical
role in promoting tumor progression through various mechanisms. It
has been reported that DCLK1 facilitates a pro-invasive and pro-
metastatic phenotype in gastric cancer cells. This involves enhancing
their motility and ability to evade standard therapeutic interven-
tions.
110
High expression of DCLK1 in gastric cancer tissue is linked
with increased immune and stromal cell infiltration, particularly
tumor-associated macrophages (TAMs) and regulatory T cells (Tregs).
It is also associated with elevated levels of immunosuppressive cyto-
kines like TGF-β1 and CXCL12, contributing to an immunosuppressive
microenvironment.
70
The effect of DCLK1 on the biological properties
of gastric cancer stem cells has been investigated. DCLK1 can be a
potential target for gastric cancer stem cells.
112
9.5 |Esophageal cancer
Esophageal cancer is a significant global health concern. In 2020,
there were approximately 604,100 new cases and 544,100 deaths
attributed to this malignancy worldwide. The disease is more preva-
lent in Eastern Asia, as well as Southern and Eastern Africa, where
esophageal squamous cell carcinoma (ESCC) dominates due to risk
factors such as tobacco, alcohol consumption, and indoor air pollution.
Conversely, esophageal adenocarcinoma is more common in North
FIGURE 3 Role of DCLK1 in hepatocellular cancer stem cells. [Color figure can be viewed at wileyonlinelibrary.com]
14 VANAN ET AL.
America and Europe, and is linked to obesity and gastroesophageal
reflux disease (GERD).
113
Esophageal cancer is often diagnosed during
its advanced stages. The general outcome remains very poor for over-
all 5-year survival rates (10%) and 5-year post-esophagectomy sur-
vival rates (15%–40%).
114
Barrett's esophagus is a condition in
which the flat pink lining of the swallowing tube that connects the
mouth to the stomach (esophagus) becomes damaged by acid reflux,
which causes the lining to thicken and become red. The gland cells in
Barrett's esophagus can become more abnormal over time. This is
called dysplasia.
115
Research has shown that DCLK1 expression
TABLE 3 Overview of DCLK1s functions and roles in HCC.
Author, year Study model Intervention
Related targets and
pathways Finding(s) Ref.
Sripathi M et al.
2015
Human PLGA nanoparticles
containing either
DCLK1 siRNA
(NPsiDCLK1) or
scrambled siRNA
(NPsiSCR)
-•DCLK1 expression is increased in
patients with cirrhosis and hepatocellular
carcinoma (HCC) tissues and plasma,
suggesting DCLK1 as a potential
biomarker.
•Targeting DCLK1 with siRNA inhibits
HCC tumor growth by upregulating
tumor suppressor miRNAs and
downregulating oncogenic factors.
100
Sureban SM et al.
2015
Clinical study (HCC
patients)
Measurement of
DCLK1 in tissue and
plasma
DCLK1 in CSC
signaling pathways
•Elevated DCLK1 levels serve as a
potential biomarker for early diagnosis
of HCC
102
Wenyao Wang
2016
Human HCC cell lines
and mice model
–miR-613 •Overexpression of miR-613 suppresses
the proliferation and invasion of HCC
cells by directly targeting and inhibiting
the expression of DCLK1, a protein that
promotes tumor growth and
progression.
•Overexpression of miR-613 inhibits the
growth of HCC xenograft tumors in mice
101
Mengjiao Fan et al.
2017
Mouse model Observational study miR-613 •Overexpression of miR-613 promotes
tumor growth and progression by
inhibiting the expression of DCLK.
105
Mengjiao Fan et al.
2020
NET samples - - DCLK1 is strongly expressed in:
•Gastrointestinal neuroendocrine tumors
•not in neuroendocrine tumors of the
liver, gallbladder, or pancreas.
106
Vik Meadows,
Heather Francis
2021
human cell samples Inhibition of DCLK1
with LRRK2-IN-1
–•Highest serum DCLK1 levels in iCCA
and pCCA patients compared to healthy
control
•DCLK1 upregulation in CCA and CSCs,
absent in healthy cholangiocytes
55
Naushad Ali et al.
2022
Human liver tissues
and Animal model
–β-catenin signaling •DCLK1 overexpression induced
clonogenicity and dedifferentiated
phenotypes in hepatoma cells and
primary human hepatocytes.
104
Dibyashree Chhetri
et al. 2022
Stem cells, Mouse
model
Inhibitors
(LRRK2-IN-1,
XMD8-92,
XMD17-51), siRNA,
shRNA
Wnt, Notch,
Hedgehog, YAP/TAZ
signaling
•High DCLK1 expression correlates with
chemotherapy resistance and poor
survival.
•DCLK1 inhibitors significantly reduce
cancer cell proliferation, migration, and
tumor growth.
12
Dibyashree Chhetri
et al. 2022
Stem cells, Mouse
model
Bioengineered
exosomes targeting
DCLK1
Exosomes, DCLK1,
CSC markers, EMT
factors
Bioengineered exosomes effectively deliver
therapeutic cargo to target cancer cells,
reducing metastasis and tumor growth by
downregulating DCLK1 and associated
pathways.
12
Abbreviations: CCA, cholangiocarcinoma; CSC: cancer stem cell; DCLK1: doublecortin-like kinase 1; EMT: epithelial-mesenchymal transition; HCC:
hepatocellular carcinoma; LRRK2: leucine-rich repeat kinase 2; miR: MicroRNA; PLGA: poly lactic-co-glycolic acid; shRNA: Short Hairpin RNA; siRNA: small
interfering RNA.
VANAN ET AL.15
increases from Barrett's esophagus to dysplasia and then to
esophageal adenocarcinoma.
116
Also In human esophageal squamous
cell carcinoma (ESCC) cells, DCLK1-S induces MMP2 (matrix
metalloproteinase-2) expression via MAPK/ERK signaling to activate
the EMT.
79
Findings suggest that knockdown of DCLK1 may inhibit
the progression of ESCC by regulating proliferation, migration, inva-
sion, and chemosensitivity via suppressing the β-catenin/c-Myc path-
way.
117
Accumulating evidence has shown that the expression of
DCLK1-S isoform is significantly increased in human esophageal squa-
mous cell carcinoma (ESCC) tissues and is associated with malignant
progression and poor prognosis. Molecular analysis in the study by
Yang et al. showed that DCLK1-S was closely related to the EMT pro-
cess in patients with ESCC.
79
Taken together, DCLK1 may serve as a
prognostic biomarker or therapeutic target for patients with ESCC.
10 |CONCLUDING REMARKS AND
FUTURE PERSPECTIVE
It is becoming more well acknowledged that doublecortin-like kinase
1 (DCLK1) is an essential regulator in the pathophysiology of gastroin-
testinal (GI) malignancies, such as colorectal, pancreatic, and hepato-
cellular carcinomas. Because of its participation in important
processes such as metastasis, cancer stem cell (CSC) maintenance,
epithelial-mesenchymal transition (EMT), tumor development, and
treatment resistance, its importance goes beyond that of standard
tumor markers. Due to its distinct role as a mediator and marker of
CSCs, DCLK1 is a promising candidate for therapeutic intervention. It
plays a dual role in carcinogenesis and malignant phenotype mainte-
nance. Overexpression of DCLK1, especially its long isoform, is con-
sistently linked to worse clinical outcomes, such as tumors that are
further along in their development, a higher risk of metastasis, and
resistance to standard treatments like chemotherapy and radiation.
This suggests that DCLK1 may be a viable target for therapy, as well
as a suitable predictive biomarker that may aid in patient classification
and customized treatment plans. DCLK1 affects the growth of cancer
cells by interacting with several key signaling pathways, including
Notch, WNT/β-catenin, and NF-B. These pathways are necessary for
cancer cells to survive, divide, and stay stem-like. Furthermore,
DCLK1 has been connected to the regulation of the tumor microenvi-
ronment, which further encourages the growth and spread of tumors.
This is mainly due to its impact on the immune system and stromal
interactions. Preclinical research has shown that DCLK1 suppression
can result in decreased metastasis, reduced tumor development, and
increased sensitivity to currently available treatments. These results
highlight DCLK1's potential for use as a therapeutic target in gastroin-
testinal malignancies. However, translating these preclinical achieve-
ments into clinical treatments faces several obstacles. These obstacles
include the need for potent and specific DCLK1 inhibitors, the under-
standing of the potential negative effects of targeting a protein also
expressed in normal tissues, and the possibility of tumor resistance
mechanisms emerging. Targeting DCLK1 can be challenging due to its
expression in both normal stem cells and certain neural tissues, raising
concerns about the potential toxicity and side effects of
DCLK1-targeted treatments. So, one important area of future
research is coming up with isoform-specific inhibitors or other ways
to target DCLK1's ability to cause cancer without affecting its normal
physiological functions. Also, the fact that cancer cells have redundant
and compensating systems may make single-agent treatments that
target DCLK1 less effective. Consequently, a combinatorial strategy
that combines DCLK1 inhibitors with other therapies like radiation,
chemotherapy, or immunotherapy may improve the effectiveness of
treatment. For example, combining immune checkpoint inhibitors with
DCLK1 inhibition may offer a two-pronged attack on cancer cells,
focusing on the tumor and the surrounding supporting tissue. In con-
clusion, DCLK1 is a promising target in the battle against GI malignan-
cies, notwithstanding its complexity. Its complex involvement in
cancer biology raises issues that require careful thought and further
investigation, but it also opens up many opportunities for therapeutic
intervention. The future of DCLK1-targeted therapeutics will depend
on how well we can make selective inhibitors, figure out how blocking
DCLK1 affects other parts of the cancer treatment process, and use
these strategies to help patients get better outcomes.
AUTHOR CONTRIBUTIONS
Ahmad Ghorbani Vanan: Conceptualization; investigation;
writing –original draft. Soheil Vesal: Investigation; writing –original draft.
Parmida Seraj: Writing –review and editing; investigation. Mohammad
Amin Ghezel: Investigation; writing –review and editing. Pooya Eini:
Investigation; writing –review and editing. Maryam talebileili: Methodol-
ogy; investigation. Zeynab Asgari: Methodology; investigation. Safa
Tahmasebi: Supervision; writing –review and editing; visualization; vali-
dation; conceptualization. Mehrdad Hashemi: Visualization; validation;
supervision. Afshin Taheriazam: Validation; visualization; supervision.
ACKNOWLEDGEMENTS
We designed our figures with BioRender (https://www.biorender.com).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
ORCID
Safa Tahmasebi https://orcid.org/0000-0002-8598-1922
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How to cite this article: Vanan AG, Vesal S, Seraj P, et al.
DCLK1 in gastrointestinal cancer: A driver of tumor
progression and a promising therapeutic target. Int J Cancer.
2025;1‐19. doi:10.1002/ijc.35365
VANAN ET AL.19
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