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Roles of TGF‑β signalling pathway‑related lncRNAs in cancer (Review)



Long non-coding RNAs (lncRNAs) are a class of RNAs that are >200 nucleotides in length that do not have the ability to be translated into protein but are associated with numerous diseases, including cancer. The involvement of lncRNAs in the signalling of certain signalling pathways can promote tumour progression; these pathways include the transforming growth factor (TGF)-β signalling pathway, which is related to tumour development. The expression of lncRNAs in various tumour tissues is specific, and their interaction with the TGF-β signalling pathway indicates that they may serve as new tumour markers and therapeutic targets. The present review summarized the role of TGF-β pathway-associated lncRNAs in regulating tumorigenesis in different types of cancer and their effects on the TGF-β signalling pathway.
ONCOLOGY LETTERS 25: 107, 2023
Abstract. Long non‑coding RNAs (lncRNAs) are a class of
RNAs that are >200 nucleotides in length that do not have the
ability to be translated into protein but are associated with
numerous diseases, including cancer. The involvement of
lncRNAs in the signalling of certain signalling pathways can
promote tumour progression; these pathways include the trans‑
forming growth factor (TGF)‑β signalling pathway, which is
related to tumour development. The expression of lncRNAs
in various tumour tissues is specic, and their interaction with
the TGF‑β signalling pathway indicates that they may serve
as new tumour markers and therapeutic targets. The present
review summarized the role of TGF‑β pathway‑associated
lncRNAs in regulating tumorigenesis in different types of
cancer and their effects on the TGF‑β signalling pathway.
1. Introduction
2. Role of lncRNAs in cancer
3. TGF‑β signalling pathway
4. TGF‑β pathway‑related lncRNAs and CRC
5. TGFβ pathway‑related lncRNAs and hepatocellular
carcinoma (HCC)
6. TGF‑β pathway‑related lncRNAs and GC
7. T G F β pathway‑related lncRNAs and breast cancer
8. TGF‑β pathway‑related lncRNAs and lung cancer
9. T GFβ pathway‑related lncRNAs and other cancer types
10. Conclusions and future perspectives
1. Introduction
Long non‑coding RNAs (lncRNAs) are newly discovered
RNAs that are >200 nucleotides in length and are involved
in a variety of molecular regulatory processes, including
transcriptional and posttranscriptional regulation, protein
localisation and RNA interference (1‑3). Although the full
function of a number of lncRNAs is unknown, their role in
cancer is becoming increasingly clear (4,5).
The transforming growth factor (TGF)‑β signalling
pathway consists of multiple signalling proteins that control
a variety of cell functions, including proliferation, differen
tiation, apoptosis and survival (6). Its inactivation leads to a
variety of pathological states, including malignancy, immune
system disorder and inammatory responses (7). However, the
role of the TGF‑β pathway in carcinogenesis is complex, and it
exerts either tumour‑suppressive or tumour‑promoting effects
depending on the cellular environment (8). The complex
regulatory mechanisms of the TGF‑β pathway in cancer are
cur rently unknown.
There is growing evidence of the interaction between
the TGF‑β signalling pathway and lncRNAs in tumours and
several members of the TGF‑β signalling pathway have been
identied as targets of lncRNAs (9‑11). The present review
summarizes knowledge of crosstalk between the TGF‑β
signalling pathway and lncRNAs in cancer.
2. Role of lncRNAs in cancer
LncRNAs that participate in chromatin remodelling, tran
scriptional control, posttranscriptional processing, protein
modification and RNA degradation (12‑14). After the
discovery of the rst lncRNAs in 1990 (15), lncRNAs have
received increasing attention. Numerous lncRNAs participate
in the pathogenesis of different diseases (16); these include
lncRNA CDC6 in breast cancer (17), lncRNA OIN1 in
ovarian cancer (18) and lncRNA RP11‑567G11.1 in pancre
atic cancer (19). Owing to the development of sequencing
Roles of TGF‑β signalling pathway‑related
lncRNAs in cancer (Review)
Cancer Research Institute, Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
Received September 19, 2022; Accepted January 13, 2023
DOI: 10.3892/ol.2023.13693
Correspondence to: Dr Yang Zhang or Dr Chengkun Wang,
Cancer Research Institute, Medical School, University of South
China, 28 Chang Sheng Xi Avenue, Hengyang, Hunan 421001,
P. R . C hi na
*Contributed equally
Abbreviations: lncRNA, long non‑coding RNA; TGF‑β,
transforming growth factor β; EMT, epithelial‑mesenchymal
transition; TNF, tumour necrosis factor; TRAF, receptor‑associated
factor; ERK, extracellular signal‑regulated kinase; CRC, colorectal
cancer; HCC, hepatocellular carcinoma; GC, gastric cancer;
NSCLC, non‑small cell lung cancer
Key wo rds: cancer, lncRNA, TGF‑β signalling pathway
technology, lncRNAs have been found to serve an important
role in tumour cell proliferation, apoptosis, differentiation and
invasion (11,20).
lncRNAs are considered to be an important component of
cancer, but they play different roles in different types of cancer.
For instance, lncRNA FGD5‑AS1 accelerates cell proliferation
in pancreatic cancer by regulating the microRNA (miRNA
or miR)‑520a‑3p/KIAA1522 axis (21), high expression levels
of lncRNA PCAT1 are associated with drug resistance in
colorectal cancer (CRC) (22) and lncRNA LNMICC promotes
cervical cancer lymph node metastasis by reprogramming
fatty acid metabolism (23). High or low expression of lncRNAs
in tumours contributes to disease via multiple molecular
mechanisms and they have a variety of unique functions and
characteristics. Guide lncRNAs bind enzymatically active
protein complexes and direct them to target gene promoter
regions or genome‑specic loci (24). Scaffold lncRNAs build
a central platform to which multiple protein complexes attach,
thus guiding them to their designated locations (24). Decoy
lncRNAs activate or silence downstream target genes by
binding and interacting with transcription factors or repres
sors (25). In addition, lncRNAs are associated with a number
of key signalling pathways. Regardless of the position of
these lncRNAs in the signalling pathway, they serve different
functions. For example, Wei et al (26) found that lncRNA
MEG3 inhibits proliferation and metastasis of gastric cancer
(GC) cells via the TP53 (a tumour suppressor gene) signal
ling pathway. High levels of lncRNA p21 in thoracic aortic
aneurysms may be associated with regulating vascular smooth
muscle cell proliferation and apoptosis by activating the
TGF‑β signalling pathway (27).
lncRNAs are known to be involved in cellular physiological
and pathological processes (28). Therefore, lncRNAs are also
relevant for diagnosis, treatment and prognosis evaluation (29).
3. TGF‑β signalling pathway
The TGF‑β superfamily has numerous members, including
TGF‑β isoforms, bone morphogenetic protein, growth differ
entiation factors, activators, inhibitors and nodulins (30,31).
TGF has three receptor ligands, TGF‑β1, 2, and 3, which have
similar, but not identical, biological activities in vitro (32). The
TGF‑β signalling pathway consists of two distinct intracellular
pathways: SMAD‑dependent (known as the classical TGF‑β
pathway) and non‑SMAD‑dependent pathway (known as the
non‑classical TGF‑β pathway; Fig. 1) (32). By contrast with
other signalling pathways, the classical TGF‑β pathway is
widely evolved and distributed in a variety of organisms (from
drosophila and nematodes to mice and humans). Activated
TGF‑β is altered by binding to TGF‑β type II receptor
(TGFβR‑II), which affects its structure, then TGFβR‑II
phosphorylates TGFβR‑I on specific serine and threonine
residues (33). In the classical pathway, the activated receptor
complex phosphorylates receptor‑SMADs (R‑SMADs;
including SMAD2 and SMAD3), which are primarily respon‑
sible for the activation of downstream signalling pathways (34).
The receptor‑activated SMAD anchor recruits R‑SMADs into
the activated receptor complex. Finally, the activated receptor
complex binds to SMAD4 (Co‑SMAD4 or common mediator
SMAD4) in a large complex and enters the nucleus, where it
interacts with transcription factors and coactivators to regulate
expression of target genes (34,35).
SMAD6 and SMAD7, also known as inhibitory SMADs
(I‑SMADs), serve an important role in the inhibition of the
TGF‑β signalling pathway through multiple mechanisms.
Firstly, SMAD6/7 competes with R‑SMADs for recruitment
to type I receptors and prevents activation of R‑SMADs by
phosphorylation (36). SMAD7 induces ubiquitination and
degradation of type I receptors by recruiting the E3 ligases
SMURF1 and SMURF2 (37,38). SMAD7 recruits ubiq
uitin‑conjugated E2 enzyme UbcH7 to stimulate SMURF1/2
activity in the R‑SMAD7SM‑URF1/2 complex (39). SMAD7
induces degradation and inactivation of TGFβR‑I by recruiting
two HECT‑type E3 ligases (WWP1/Tiul1 and NEDD4‑2) (40).
This suggests that I‑SMADs are involved in negative feedback
regulation in the TGF‑β/SMAD pathway. Although SMAD
proteins are the basis of TGF‑β regulation of various cellular
signalling pathways, numerous signalling responses are
stimulated by TGF‑β, which is not regulated by SMADs (32).
For example, in the non‑classical pathway, the activated
TGF‑β receptor complex promotes or inhibits downstream
cell biological processes through a number of other trans
duction factors, such as tumour necrosis factor (TNF), TNF
receptor‑associated factor 4 (TRAF4), TRAF6, p38 MAPK,
Ras homology (Rho), phosphoinositide 3 kinase (PI3K)/AKT,
extracellular signal‑regulated kinase (ERK) and NF‑κB, to
promote or inhibit downstream cell biological processes (32).
TGF‑β serves as both an oncogene and an oncogene
promoter. In normal tissue, TGF‑β promotes tissue stabilisa
tion and suppresses inammatory responses. In premalignant
progression, TGF‑β ser ves as an oncogene to promote apoptosis
and cytostasis and inhibit tumorigenesis. However, in cancer
cells, TGF‑β serves as a pro‑oncogene, promoting tumour
growth and metastasis (41,42). TGF‑β signalling promotes
epithelial‑mesenchymal transition (EMT) by increasing
expression of mesenchymal markers, such as N‑cadherin and
vimentin, and decreasing expression of epithelial markers, such
as E‑cadherin (43,44). Since TGF‑β acts extensively in cells,
blocking TGFβ and its downstream signals is a therapeutic
tool. Therefore, anti‑TGFβ signalling therapy is an additional
therapeutic tool along with the currently used CAR‑T (45) and
anti‑PD‑L1 (46) therapy.
4. TGF‑β pathway‑related lncRNAs and CRC
Aberrant lncRNAs in CRC are hypothesized to contribute
to activation or inactivation of the TGF‑β pathway to regu
late tumour development. TGF‑β pathway‑associated CRC
lncRNAs are discussed here, to explore the roles of lncRNAs
in the progression of CRC.
CRC is the third leading cause of cancer‑associated death
worldwide and there are 1.85 million new cases and 850,000
CRC‑associated deaths each year (47). The majority of CRC
tumours arise from precursor lesions, such as adenoma
transforming to adenocarcinoma (48). Therefore, it is key to
identify useful biomarkers to diagnose CRC at the early stages
of disease. Numerous studies have demonstrated the novel
role and therapeutic potential of lncRNAs in CRC (49,50)
(Fig. 2). lncRNA SNHG6 is upregulated in CRC and binds
UPF1 to activate the downstream TGF‑β/SMAD signalling
ONCOLOGY LETTERS 25: 107, 2023 3
pathway to promote proliferation, migration and invasion
of CRC cells (51). Upregulation of lncRNA LOC646329
promotes CRC cell proliferation by competing for binding
to miR‑29b‑1 (52). In addition, knockdown of lnc00858
reduces the proliferative capacity of CRC cells by inducing
production of p53 and blocking the G0/G1 phase of CRC
cells (53). lnc00858 upregulation is negatively correlated
with miR‑25‑3p and SMAD7 is a downstream target of
miR‑25‑3p (53). Similarly, miR‑93‑5p serves as an competing
endogenous RNA (ceRNA) for lncRNA CTBP1‑AS2 and
activates the TGF‑β/SMAD2/3 pathway to promote prolif
eration, invasion and resistance to apoptosis in colon cancer
cells (54). Shen et al (11) demonstrated that TGF‑β promotes
CRC metastasis via the lncRNA TUG1/TWIST1/EMT signal‑
ling pathway. TGF‑β induces metastasis, and knockdown
of TUG1can inhibit metastasis (11). However, expression of
TGF‑β does not increase after TUG1knockdown, suggesting
that TUG1is located downstream of TGF‑β. TUG1 may serve
as a drug target to inhibit CRC development by suppressing
TGF‑β pathway activation (11). Furthermore, Wu et al (49)
found that lnc00941 promotes EMT by directly competing with
β‑transducin repeats‑containing protein to bind to the MH2
structural domain on SMAD4, thereby preventing SMAD4
protein degradation and activating the TGF‑β/SMAD2/3
signalling pathway. lncRNA CASC9 is upregulated in CRC,
and high expression of CASC9 predicts a low prognosis and an
association with TNM stage I (55). Luo et al (55) demonstrated
that CASC9 enhances the function of the telomerase Reverse
Transcriptase (TERT) complex in CRC cells by regulating
expression of TGF‑β2 mRNA and upregulating levels of
TGF‑β2 and TERT, leading to phosphorylation of SMAD3 and
activation of the TGF‑β signalling pathway, thereby enhancing
its Tumorigenic ability.
Since colon cancer only shows symptoms in the advanced
stages of disease, it is necessary to improve the early detection
rate of CRC. An increasing number of studies have found that
TGF‑β/SMAD signalling pathway involvement with lncRNAs
serves an important role in the development of colon cancer,
which provides a new avenue for early diagnosis and treat
ment (49,51,55).
5. TGF‑β pathway‑related lncRNAs and hepatocellular
carcinoma (HCC)
HCC ranks fourth in the world for cancer‑associated
death (56). HCC is a common cancer with a poor prognosis
and high economic cost and disease burden; the 2019 Global
Cancer Report released by the World Health Organization
(WHO) (57) states that about 705 million people worldwide
currently suffer from liver cancer, with about 700,000 new
liver cancer patients each year (57). lncRNAs are involved in
the physiological and pathological processes of HCC cells (28)
(Fig. 2). Certain lncRNAs, such as lnc01278, SBF2‑AS1,
SNAI3‑AS1 and NORAD, have been shown to promote
proliferation, migration and invasion of HCC by partici
pating in the TGF‑β signalling pathway. Huang et al (58)
Figure 1. Classical and non‑classical TGF‑β signaling pathway. TGF‑β ligands bind to TGFβR‑II to modify its conformation and mediate its action. TGFβR‑II
phosphorylates TGFβR‑I on specic serine and threonine residues. In the classical pathway, the activated receptor complex phosphorylates receptor‑SMADs
(SMAD2 or SMAD3), forms a heterogeneous complex with SMAD4 and translocates to the nucleus, where it interacts with tra nscription factors, coactivators
or co‑repressors to regulate expression of target genes. In the non‑classical pathway, TGF‑β activat es MAPKs, N FκB, Ras, TRAF6, TAK1/p38/JNK and PI3Ks,
leading to biological effects. ERK, extracellular signal‑regulated kinase; TAK1, TGF‑β‑activated kinase 1; TF, transcription factor; TGFβR‑I/II, transforming
growth factorβ receptor type I/II; T NK1, tyrosine kinase non‑receptor 1; TRAF6, TNF receptor‑associated factor 4; p, phosphorylated.
found that the lnc01278/miR‑1258/SMAD2/3 axis promotes
HCC metastasis. lnc01278 promotes the expression of the
SMAD2/3 target gene by silencing expression of miR‑1258.
Similarly, downregulation of lncRNA SBF2‑AS1 inhibits
proliferation and migration of HCC by regulating the
miR‑361‑5p/TG Fβ1 signalling pathway (59). SBF2‑AS1
promotes the expression of TGFβR‑I via sponge adsorption of
miR‑140‑5p and in turn promotes the migration and invasion
of HCC cells (60). In addition, SNAI3‑AS1 promotes prolif
eration and metastasis of HCC cells by regulating UPF1 and
activating the TGF‑β/SMAD pathway (61). Yang et al (62)
found that lncRNA NORAD is upregulated in HCC tissue
and that lncRNA NORAD may serve as a ceRNA to regulate
miR‑202‑5p, which promotes HCC progression by targeting
TGFβRs. TGF‑β1 is a positive upstream regulator of UCA1,
while UCA1 is a positive upstream regulator of HXK2, which
forms the TGF‑β1/UCA1/HXK2 axis to promote prolifera
tion of HCC cells (63). In addition, Dong et al (64) found that
downregulation of lncRNA MEG3 promotes HCC prolif
eration, migration and invasion through the upregulation of
SMAD3 (an R‑SMAD) and SMAD4 (a co‑SMAD)
are key proteins involved in the classical TGF‑β signal
ling pathway. Chen et al (65) found that lnc00261 inhibits
SMAD3 expression and phosphorylation and that SMAD3
may be involved in transcriptional regulation in TGF‑β1
signalling. lnc00261 inhibits EMT in HCC cells by inacti
vating the TGFβ1/SMAD3 signalling pathway. In addition,
lncRNAs also participate in the TGF‑β pathway through
epigenetic modifications. Zhang et al (66) found that
lncRNA 34a recruits DNA methyltransferase 3α through
prohibitin‑2 to methylate promoters of miR‑34a and histone
deacetylase 1 to influence histone modification, thereby
inhibiting miR‑34a expression. miR‑34a targets SMAD4 and
downregulation the expression of downstream genes. In the
immune system, activation of TGF‑β signalling suppresses
recruitment of tumour‑inltrating lymphocytes, leading to
tumour immune escape. Wang et al (67) found that rela
tively high levels of lncRNA NNT‑AS1 are associated with
a decrease in the number of inltrating CD4+ lymphocytes
and that knockdown of lncRNA NNT‑AS1 decreases expres
sion of TGF‑β and TGFβR‑I in HCC cells. In conclusion,
lncRNA NNT‑AS1 impairs CD4+ T cell inltration in HCC
by activating the TGF‑β signalling pathway through a novel
Biomarkers useful for early HCC diagnosis are still
lacking and available serum biomarkers show low sensitivity
and specicity, such as α‑fetoprotein and des‑gamma‑carboxy
Figure 2. Molecula r mechanisms of TGF‑β signalling pathway involved in lncRNAs in hepatocellula r carcinoma, colorectal, gastric and breast cancer.
Oncogenic lncRNAs in hepatocellular carcinoma and colorectal, gastric and breast cancer activate the TGF‑β signalling pathway primarily by degrading and
activating the t hree major targets of the complex, SMAD2, SMAD3, and SMAD7, while cer tain lncRNAs may dir ectly regulate TGF‑β as well as T GFβR‑II and
TGFβR‑II, thereby affecting tumorigenesis. lncRNA, long non‑coding RNA; miR, microRNA; TGFβR‑I/II, transforming growth factor‑β receptor type I/II.
ONCOLOGY LETTERS 25: 107, 2023 5
prothrombin (68). TGF‑β signalling pathway‑associated
lncRNAs are typically upregulated in HCC and may be a novel
target for early screening.
6. TGF‑β pathway‑related lncRNAs and GC
GC is the fth most deadly cancer in the world (69). Globally,
1 million new cases of stomach cancer are diagnosed each
year (70). Oncogenic lncRNAs serve an important role in
regulating TGF‑β and are regulated in multiple ways (Fig. 2).
lnc00665 promotes cell proliferation, invasion and metas
tasis by activating the TGF‑β pathway in GC and silencing
Lnc00665 inhibits EMT and decreases the expression levels
of TGF‑β1, SMAD2 and α‑smooth muscle actin (SMA) (71).
Similarly, knockdown of Lnc00978 inhibits activation of the
TGF‑β/SMAD2 signalling pathway and thus inhibits cell cycle
progression, migration, invasion and proliferation and induces
apoptosis in GC cells (72). The differentiation of regulatory
T cells is associated with the TGF‑β signaling pathway (73).
Xiong et al (74) found that lncRNA POU3F3 activates the
TGF‑β signalling pathway by increasing phosphorylation of
SMAD2/3, thus increasing the number of regulatory T cells in
peripheral blood and leading to the proliferation of GC cells.
Huang et al (75) found that SGO1‑AS1 inhibits EMT and
metastasis by competitively binding TGF‑β1 and TGF‑β2 with
polypyrimidine tract binding protein, leading to a decrease in
TGF‑β. In addition, TGF‑β inhibits SGO1‑AS1 transcription
by forming a negative feedback loop to induce ZEB1 produc‑
tion. This SGO1‑AS1/TGF‑β/ZEB1 axis may provide a novel
means for cancer treatment. LncRNAs can also act as cofac
tors for SMAD. Sakai et al (76) identied the EMT‑associated
lncRNA ELIT1, which enhances SMAD promoter activity
via TGF‑β induction and recruiting SMAD3 to the promoter
region of its target gene. In addition, lncRNA MBNL2‑AS1
forms a ceRNA network with miR‑424‑5p and SMAD7,
inactivating the TGF‑β/EMT pathway and inhibiting GC cell
proliferation, migration and invasion (77).
lncRNAs regulate gene expression at genomic, transcrip
tomic and posttranscriptional levels and are recognized as
biomarkers and therapeutic targets for GC (Fig. 2) (77,78).
The TGF‑β signalling pathway is an important pathway that
promotes development of GC and studying the effect of the
interaction of this pathway with lncRNAs in the development
of GC may provide an important target for early diagnosis (71).
7. TG Fβ pathway‑related lncRNAs and breast cancer
Globally, breast cancer is the most frequently diagnosed cancer
in women and ranks second among causes of cancer‑related
deaths in women (79). Although breast cancer can be diag
nosed early and there are numerous treatments available, it is
typically lethal once it metastasises (80). Therefore, it is key to
nd clinically useful biomarkers present in the early stages of
breast cancer. Certain lncR NAs have been shown to promote the
development of breast cancer via the TGF‑β signalling pathway
(Fig. 2). For example, CASC2 (81) and CCAT2 (82) have been
shown to be tumour therapeutic targets by participating in
TGF‑β/SMAD2 signalling and thus promoting proliferation
and metastasis of breast cancer cells. lncRNA ROR knockdown
inhibits SMAD2 and α‑SMA expression and thus inactivates
the TGF‑β signalling pathway to inhibit tumour growth (83).
ARHGAP5‑AS1 induces a decrease in SMAD7 ubiquitination
and degradation by interacting with SMAD7, leading to a
decrease in SMAD7 binding to SMURF1 and SMURF2 (84).
In addition, ARHGAP5‑AS1 may inhibit the TGF‑β signal
ling pathway by stabilising SMAD7. ADAMTS9‑AS2 has
been shown to target downstream ribosomal protein L22 to
inhibit SMAD2 expression, thereby regulating the TGF‑β
signalling pathway, inhibiting cell cycle arrest in breast cancer
cells in vitro and suppressing tumour growth in vivo (85). Loss
of Merlin in breast cancer cells affects functional cellular
metabolism. Mota et al (86) found that the cooperative activity
of TGF‑β transcriptional effectors results in upregulation of
UCA1, which leads to a decrease in Merlin activity against
STAT3. Similarly, Bo et al (87) predicted that lnc00467 may
be involved in signalling pathways involved in peroxisomal
lipid metabolism and immunity via miR‑23b‑5p targeting
TGF‑β2. LncRNAs can also be involved in drug resistance.
Zhang et al (88) found that knockdown of lnc00894‑002 down‑
regulates miR‑200a‑3p and miR‑200b‑3p, upregulates TGF‑β2
and ZEB1 and is involved in the development of tamoxifen
resistance. LncRNA DCST1‑AS1 enhances TGF‑β/SAMD2
signalling in BT‑549 cells by targeting ANXA1 and promoting
EMT (89). Ren et al (90) discovered that SMAD2/3/4 binds to
the promoter site of HOTAIR and is directly transcribed by
HOTAIR, which provides a novel idea for treatment of breast
ca ncer.
Based on the established role of TGF‑β‑associated
lncRNAs in regulating cell proliferation, cell cycle, apoptosis
and other aspects of cell physiology, future studies should
evaluate the potential of these transcripts as therapeutic targets
for breast cancer.
8. TGF‑β pathway‑related lncRNAs and lung cancer
Lung cancer remains the leading cause of cancer‑associated
deaths worldwide (91). One of the reasons for the high
mortality rate of lung cancer is that it often progresses to
an advanced stage before it is diagnosed (92). Therefore,
it is key to determine the molecular mechanisms of lung
tumours and nd new molecular biomarkers for diagnosis
and treatment. Wang et al (93) found that lncRNA ANCR
inhibits non‑small cell lung cancer (NSCLC) cell migration
and invasion via downregulation of TGF‑β1 expression.
Similarly, Su et al (94) found that upregulation of lncRNA
GASL1 may inhibit tumour growth in NSCLC via down
regulation of TGF‑β1. NKILA expression is regulated by
the upstream TGF‑β signalling pathway and interferes with
the NF‑κB/Snail signalling pathway to inhibit migration
and invasion of NSCLC cells (95). Knockdown of SMASR
in lung cancer promotes phosphorylation of SMAD2/3,
thereby inducing EMT via the TGF‑β signalling pathway and
promoting migration and invasion of lung cancer cells (96).
XIST serves as a sponge to directly adsorb miR‑137 and
negatively regulate its expression. miR‑137 overexpres
sion inhibits proliferation and EMT in A549 and H1299
cells (97). In addition, Notch‑1 has been identied as a direct
gene target of miR‑137 (97). Similarly, lncRNA SOX2OT
overexpression serves as a ceRNA to adsorb miR‑104‑5p,
thereby regulating RAC1 expression and activating the
TGF‑β/parathyroid hormone‑associated protein/RANKL
signalling pathway (98).
lncRNAs act as transcribed molecules. Shi et al (99)
demonstrated that E2F1 activates SNHG3 and promotes
NSCLC cell proliferation and migration via the TGF‑β and
IL‑6/JAK2/STAT3 pathways. Similarly, Zhu et al (100) found
that forkhead box P3 protein increases NSCLC cell stem
ness by activating Lnc01232 and thus regulating TGFβR‑I,
activating the TGF‑β signalling pathway and recruiting
IGF2BP2 to stabilise TGFβR‑I. This may provide a theoretical
basis for lncRNA‑based treatment of NSCLC. Furthermore,
upregulation of TBILA enhances RhoA activation by binding
to the SMAD transcription factor complex, which promotes
expression of human hair centre‑associated lymphoma (101).
Jiang et al (102) found that lncRNA HCP5 is induced by
TGF‑β and transcriptionally regulated by SMAD3 to promote
lung adenocarcinoma tumour growth and metastasis. In addi‑
tion, lncRNA LINP1 inhibits EMT in lung cancer cells by
suppressing the TGF‑β pathway (9).
In the aforementioned lung cancer studies, multiple
differentially expressed lncRNAs have been identied, some
of which activate the TGF‑β pathway to drive tumorigenesis,
while others inactivate the TGF‑β pathway to inhibit tumour
progression (Fig. 3). Further study of the role of lncRNAs in
the TGF‑β pathway may help develop molecular markers for
early diagnosis of lung cancer.
9. TGF‑ β pathway‑related lncRNAs and other cancer types
In thyroid cancer, lncRNA FOXD3‑AS1 serves as a sponge
to adsorb miR‑296‑5p and upregulate miR‑296‑5p expres
sion, which inhibits the migration and invasion of thyroid
cancer cells by inactivating the TGF‑β1/SMAD signalling
pathway (103). Zhao et al (104) found that ANRIL may
decrease expression of cyclin‑dependent kinase 4 by inhibiting
the TGF‑β/SMAD signalling pathway and promoting invasion
and metastasis of thyroid cancer cells. Similarly, silencing
SPRY4‑IT1 inhibits TGF‑β1 and phosphorylated SMAD2/3
levels, thereby inhibiting proliferation and migratory capacity
of thyroid cancer cells; knockdown of SPRY4‑IT1‑mediated
functions can be rescued by interference with TGF‑β1 (105).
In cervical cancer, knockdown of lncRNA NEF decreases
the expression of TGF‑β1, which inhibits the migration and
invasion of cervical cancer cells (106). In addition, miR‑665
serves as a ceRNA for lncRNA DANCR and targets TGFβR‑I
through the ERK/SMAD pathway to suppress the malignant
phenotype of cervical cancer cells, which may provide a
novel therapeutic strategy for cervical cancer treatment (107).
Similarly, lncRNA CTS enhances migration and invasive
ability of cervical cancer cells as well as TGF‑β1‑induce d
EMT (108). The expression of lncRNA CTS has a negative
correlation with miR‑505 expression and ZEB2 may act as the
target of miR‑505 (108). lncRNA CTS promotes cervical cell
migration and invasion via the miR‑505/ZEB2/TGF‑β/SMAD
axis (108).
In lymphoma, knockdown of lncRNA ANRIL may inhibit
proliferation and promote apoptosis of Burkitt's lymphoma
cells by regulating the TGF‑β1 signalling pathway (109).
In glioma, UAC1 promotes Slug expression and thus
participates in TGF‑β‑induced EMT by targeting miR‑1
and miR‑203a (110). In addition, p53 inhibits expression of
PVT1and thus inactivates the TGF‑β/SMAD pathway, inhib
iting the proliferation, migration and invasion of glioma cells,
inducing cell apoptosis and inhibiting tumour growth (111).
In endometr ial cancer, lncRNAs promote t umorigenesis and
metastasis via the MIR210HG/miR‑337‑3p/137‑HMGA2 axis,
which activates the TGF‑β/SMAD3 signalling pathway (112).
In prostate cancer, SNHG16 promotes proliferation
and migration of prostate cancer cells by targeting the
TGF‑βRII/SMAD axis (113).
In pancreatic cancer, knockdown of PVT1 inhibits cell
survival, adhesion, migration and invasion by suppressing
TGF‑β/SMAD2/3 signalling (114). These ndings reveal that
PVT1 may serve an oncogenic role in pancreatic cancer by
Figure 3. Molecular mechanisms of TGF‑β signalling pathway involved in lncRNAs in lung and other cancer types. Oncogenic lncRNAs in lung cancer
and other types of cancer activate the TGF‑β signa lling pathway primarily by degrading and activating the three major targets of the SMAD2, SMAD3 and
SMAD7, while certa in lncRNAs may directly regulate TGF‑β as well as TGFβR‑I and TGFβR‑II, thereby affecting tumor igenesis. lncRNA, long non‑coding
RNA; miR, microRNA; TGF‑β, transforming growth factor β; TGFβR‑I/I I, TGF‑β receptor type I/ II.
ONCOLOGY LETTERS 25: 107, 2023 7
Table I. lncRNAs associated with the TGF‑β signalling pathway in cancer.
Interaction with
First author, Expression TGF‑β
year lncRNA Cancer type pattern signalling Cancer phenotype Molecular mechanism (Refs.)
Wang et al, SNHG6 CRC Activation Promotes proliferation, invasion lncRNA SNHG6, UPF1 (51)
2019 and migration (protein), SMAD2/3
Javanmard et al, LOC646329 CRC Activation Promotes proliferation lncRNA LOC646329, (52)
2020 miR‑29b‑1, SMAD2/3
Zhan et al, LNC00858 CRC Repression Inhibits proliferation, promotes lnc00858, miR‑25‑3p, (53)
2020 apoptosis SMAD7
Li et al, CTBP1‑AS2 CRC Activation Promotes proliferation and LINCRNA CTBP1‑AS2, miR‑ (54)
2021 invasion, inhibits apoptosis 93‑5p, TGF‑β/SMAD2/3
Shen et al, TUG1 CRC Activation Promotes metastasis TGF‑β, lncRNA TUG1, (11)
2020 TWIST1
Wu et al, LNC00941 CRC Activation Promotes EMT lnc00941, SMAD4, TGF‑β/ (49)
2021 SMAD2/3
Luo et al, CASC9 CRC Activation Promotes proliferation, inhibits LINCRNA CASC9, TGF‑β2/ (55)
2019 apoptosis TERT, SMAD3
Huang et al, LINC01278 HCC Activation Promotes proliferation, LINC01278, miR‑1258, (58)
2020 migration, and invasion SMAD2/3
Wu et al, SBF2‑AS1 HCC Activation Promotes proliferation, LINCRNA SBF2‑AS1, (59,60)
2021; Li et al, migration, and invasion miR‑361‑5p, TGF‑β1,
miR‑140‑5p, TGFβR‑I
Li et al, SNAI3‑AS1 HCC Activation Promotes proliferation, LINCRNA SNAI3‑AS1, (61)
2019 migration, and invasion UPF1, SMAD7
Yang et al, NORAD HCC Activation Promotes proliferation, LINCRNA NORAD, (62)
2019 migration, and invasion miR‑2025p, SMAD2/3
Hu et al, UCA1 HCC Activation Promotes proliferation TGFβ, UCA1, HXK2 (63)
Dong et al, MEG3 HCC Suppression Inhibits proliferation, MEG3, TGFβ1 (64)
2019 migration, and invasion
Chen et al, LNC00261 HCC Suppression Inhibits EMT and stem TGF‑β1, LINC00261, (65)
2022 cell‑like features SMAD3
Zhang et al, LNCRNA HCC Activation Promotes proliferation LNC34a, miR34a, (66)
2019 34a SMAD4
Wang et al, NNT‑AS1 HCC Activation Promotes CD4+ T cell LINCRNA‑NNT‑AS1, (67)
2020 inltration TGF‑β, TGFβR‑I, SMAD5
Table I. Continued.
Interaction with
First author, Expression TGF‑β
year lncRNA Cancer type pattern signalling Cancer phenotype Molecular mechanism (Refs.)
Zhang et al, LNC00665 GC Activation Promotes proliferation, LINC00665, TGF‑β1, (71)
2021 invasion, and metastasis SMAD2, α‑SMA
Fu et al, LNC00978 GC Activation Promotes proliferation, LINC00978, TGFβ/ (72)
2018 invasion and metastasis, SMAD2
induces apoptosis
Xiong et al, POU3F3 GC Activation Promotes proliferation LINCRNA POU3F3, (74)
2015 TGF‐β/SMAD2/3
Huang et al, SGO1‑AS1 GC Suppression Inhibits EMT and LINCRNA SGO1‑AS1, (75)
2021 metastasis PTBP1, TGFβR‑I/II,
Sakai et al, ELIT‑1 GC Activation Promotes EMT progression LINCRNA ELIT‑1, (76)
2019 TGFβ/SMAD3
Su et al, MBNL1‑ GC Suppression Inhibits proliferation, LINCRNA MBNL1‑ (77)
2022 AS1 migration, and invasion AS1, miR‑424‑5p,
Zhang et al, CASC2 Breast Activation Promotes proliferation LINCRNA CASC2, (81)
2019 and metastasis TGFβ/SMAD2
Wu et al, CCAT2 Breast Activation Promotes proliferation LINCRNA CCAT2, (82)
2017 and metastasis TGFβ/SMAD2
Hou et al, ROR Breast Activation Promotes growth, migration, LINCRNA ROR, (83)
2018 and invasion TGFβ/SMAD2
Wang et al, ARHGAP5‑ Breast Suppression Inhibits migration LINCRNA ARHGAP5‑ (84)
2021 AS1 AS1, SMAD7
Ni et al, ADAMTS9‑ Breast Suppression Inhibits tumor growth, LINCRNA ADAMTS9‑ (85)
2021 AS2 promotes apoptosis and AS2, RPL22,
cell cycle arrest SMAD2
Mota et al, UCA1 Breast Activation Promotes aerobic MERLIN, SMAD2/ (86)
2018 glycolysis 3, UCA1
Bo et al, LNC00467 Breast Activation Promotes proliferation LINC00467, miR‑23b‑ (87)
2021 and metastasis 5p, TGF‑β2
Zhang et al, LNC00894‑ Breast Activation Promotes the development lnc00894‑002, miR‑200a/ (88)
2018 002 of tamoxifen resistance b‑3p, TGF‑β, ZEB1
Tang et al, DCST1‑ Breast Activation Promotes EMT and DCST1‑AS1, ANXA1, (89)
2020 AS1 chemoresistance TGF‑β/SMAD2
ONCOLOGY LETTERS 25: 107, 2023 9
Table I. Continued.
Interaction with
First author, Expression TGF‑β
year lncRNA Cancer type pattern signalling Cancer phenotype Molecular mechanism (Refs.)
Ren et al, HOTAIR Breast Activation Inhibits proliferation, HOTAIR, SMAD2/3/4 (90)
2018 migration, and invasion
Wang et al, ANCR Lung Suppression Inhibits migration and LINCRNA ANCR, (93)
2018 invasion TGF‑β1
Su et al, GASL1 Lung Suppression Inhibits tumor growth LINCRNA GASL1, (94)
2018 TGF‑β1
Lu et al, NKILA Lung Suppression Inhibits migration TGF‑β, LINCRNA (95)
2017 and invasion NKILA, NF‑κB
Xu et al, SMASR Lung Suppression Inhibits migration TGF‑β, SMAD2/3, (96)
2021 and invasion SMASR, TGFBR‑I
Wang et al, XIST Lung Suppression Inhibits proliferation LINCRNA XIST, miR‑ (97)
2018 and EMT 137, TGF‑β1
Ni et al, SOX2OT Lung Activation Promotes proliferation LINCRNA SOX2OT, (98)
2021 and metastasis miR‑194‑5p, RAC1,
Shi et al, SNHG3 Lung Activation Promotes proliferation E2F1, LINCRNA (99)
2020 and migration SNHG3, TGF‑β
Zhu et al, LNC01232 Lung Activation Promotes proliferation FOXP3, LINC0123, (100)
2022 and migration IGF2BP2, TGFβR‑I
Lu et al, TBILA Lung Activation Enhances the pro‑ TGFβ, TBILA, (101)
2018 survival pathway HGAL, RhoA
Jiang et al, HCP5 Lung Activation Promotes tumor growth TGF‑β/SMAD3, (102)
2019 and metastasis LINCRNA HCP5,
miR‑203, SNAI
Zhang et al, LINP1 Lung Suppression Inhibits proliferation, TGFβ1, LNCRNA (9)
2018 migration, and invasion LINP1
Chen et al, FOXD3‑ Thyroid Suppression Inhibits proliferation lncRNA FOXD3‑AS1, (103)
2020 AS1 and migration miR‑296‑5p, TGF‑β1/
Zhao et al, ANRIL Thyroid Suppression Promoting invasion lncRNA ANRIL, TGF‑β/ (104)
2016 and metastasis SMADs, p15INK4B
Zhou et al, SPRY4‑ Thyroid Suppression Inhibits proliferation lncRNA SPRY4‑IT1, (105)
2018 IT1 and migration TGF‑β/SMAD
Table I. Continued.
Interaction with
First author, Expression TGF‑β
year lncRNA Cancer type pattern signalling Cancer phenotype Molecular mechanism (Refs.)
Ju et al, NEF Cervical Suppression Inhibits migration LNCRNA NEF, (106)
2019 and invasion TGF‑β1
Cao et al, DANCR Cervical Suppression Inhibits migration LNCRNA DANCR, (107)
2019 and invasion miR‑665, TGFβR‑I,
Feng et al, CTS Cervical Activation Promotes migration LNCRNA CTS, miR‑ (108)
2019 and invasion 505, ZEB2, TGF‑β/
Mao et al, ANRIL Lymphoma Activation Promotes proliferation, lncRNA ANRIL, (109)
2021 inhibits apoptosis TGF‑β1
Li et al, UCA1 Glioma Activation Promotes EMT and UCA1, miR‑1, (110)
2018 stemness miR‑203a, slug
Li et al, PVT1 Glioma Activation Promotes proliferation, P53, LINCRNA PVT1, (111)
2022 migration, invasion TGF‑β/SMAD
Ma et al, MIR210HG Endometrial Activation Promotes proliferation, LINCRNA MIR210HG, (112)
2021 migration, invasion, miR‑337‑3p/137,
and EMT HMGA2, TGF‑β/
Weng et al, SNHG16 Prostate Activation Promotes proliferation lncRNA SNHG16, (113)
2021 and migration miR‑373‑3p,
Zhang et al, PVT1 Pancreatic Activation Promotes survival, adhesion, lncRNA PVT1, TGF‑β/ (114)
2018 migration and invasion SMAD
Papoutsoglou et al, MIR100HG Pancreatic Activation Promotes EMT and stemness TGFβ, MIR100HG (115)
Zhou et al, LNC00462 Pancreatic Activation Promotes proliferation lnc00462, miR‑665, (116)
2018 and migration TGFβR‑I/TGFβR‑II,
Wu et al, PVT1 Ovarian Activation Promotes proliferation, LINCRNA PVT1, (117)
2021 inhibits apoptosis miR‑148a‑3p, AGO1,
Huang et al, DANCR Ovarian Activation Promotes viability, migration, LINCRNA DANCR, (118)
2020 and invasion miR‑214, TGF‑β
ONCOLOGY LETTERS 25: 107, 2023 11
regulating EMT via the TGF‑β/SMAD pathway (114). In addi‑
tion, miR100HG controls the intensity of TGF‑β signalling via
the production of TGFβR‑I in tumours (115). Overexpression
of Lnc00462 increases expression levels of TGFβR‑I a nd
TGFβR‑II, thereby activating the SMAD2/3 pathway in
pancreatic cancer cells (116). miR‑665 is also a target of
lnc00462 (116). Taken together, these ndings indicate that
the lnc00462/miR‑665/TGFβR‑I/II regulatory network may
underlie the mechanism of pancreatic carcinogenesis.
In ovarian cancer, lncRNA PVT1 promotes tumour growth
and proliferation via the PVT1/miR‑148a‑3p/AGO1/TGF‑β
axis (117). In addition, DANCR is a sponge for miR‑214,
while KLF5 is a target of miR‑214 (118). Silencing DANCR
inhibits TGF‑β‑treated ovarian cancer cell viability, migration
and invasion via the miR‑214/KLF5 axis and induces apop
tosis (118).
In bladder cancer, lnc01451 directly targets LIN28 to
activate the TGF‑β/SMAD signalling pathway (119). In
terms of drug resistance, Zhuang et al (120) found that
gemcitabine‑induced aberrant TGF‑β1 regulation of the
LET/NF90/miR‑145 axis promotes urothelial bladder cancer
chemoresistance by enhancing cancer cell stemness.
In osteosarcoma (OS), high levels of lnc00174 form a
ceRNA network with miR‑378a‑3p/SSH2 and activate the
TGF‑β/SMAD pathway to promote OS cell proliferation (121).
The discovery of a large number of TGF‑β‑associated
lncRNAs, their extensive expression patterns in various types
of cancer (thyroid and cervical cancer, lymphoma, glioma and
endometrial, prostate, pancreatic, ovarian and bladder cancer)
and the biological properties that promote tumour cell prolif‑
eration, migration and invasion provides a novel basis for the
development of cancer diagnosis and therapy.
10. Conclusions and future perspectives
lncRNAs are differentially expressed in different tissue and
cells and are highly heterogeneous. They regulate gene expres‑
sion and intracellular homeostasis via multiple mechanisms,
including tumour cell proliferation, survival, migration and
genomic stability (122). The present review conrmed that
lncRNAs play an important role in tumour development,
similar to protein‑coding genes, and are associated with
multiple cellular signalling pathways. Although there are
multiple signalling pathways in tumours by which lncRNAs
may regulate cell proliferation, the TGF‑β signalling pathway
is widely distributed in tumours and serves a key role in the
development of different types of cancer (123). lncRNA tran‑
scription can activate or inhibit the TGF‑β signalling pathway
by interacting with other molecules in the cell, including
DNA, protein and RNA, to provide malignant transforma
tion signals. Thus, lncRNAs affect the pathology of different
cancer types (124,125). Table I lists lncRNAs associated with
the TGF‑β signalling pathway in cancer. In addition, these
lncRNAs may have different methods of targeting the TGF‑β
signalling pathway since they have high tissue and cell speci‑
city. These lncRNAs can also act in different cancer types
through the TGF‑β pathway. For example, lncRNA UCA1
promotes tumour cell proliferation and EMT in breast and
liver cancer and glioma (63,110). lncRNA PVT1 promotes
tumour cell proliferation in pancreatic and ovarian cancer and
Table I. Continued.
Interaction with
First author, Expression TGF‑β
year lncRNA Cancer type pattern signalling Cancer phenotype Molecular mechanism (Refs.)
Shi et al, LINC01451 Bladder Activation Promotes proliferation, LINC01451, LIN28, (119)
2021 invasion, and metastasis TGF‑β/SMAD
Zhuang et al, LET Bladder Activation Promotes chemoresistance TGFβ1, LINCRNA‑LET, (120)
2017 NF90, miR‑145
Zheng et al, LINC00174 Osteosarcoma Activation Promotes proliferation, LINC00174, miR‑378a‑ (121)
2021 invasion, and metastasis 3p, SSH2, TGF‑β/
, downregulation; , upregulation; CRC, colorectal cancer; EMT, epithelial‑mesenchymal transition; GC, gastric cancer; HCC, heptocellular carcinoma; lncRNA, long non‑coding RNA; miR, microRNA;
TGF‑β, transforming growth factor β; TGFβR‑I/II, TGF‑β receptor type I/II.
glioma (111,117). Although the same lncRNAs are involved
in the TGF‑β pathway in different cancer types, they act in
different ways, either directly targeting SMADs or forming a
ceRNA network with miRNAs, which makes clinical targeting
difcult (126). Overall, TGF‑β pathway‑associated lncRNAs
are differentially regulated in different types of cancer and
targeted therapy is a potential way to disrupt key signalling
pathways in tumour cells, such as the Wnt, Notch and TGF‑β
pathways, without compromising their essential functions in
normal tissue (49,126,127). The lncRNA network and TGF‑β
signalling pathway could reveal new cancer diagnosis and
treatment approaches.
Since the TGF‑β signalling pathway is related to tumour
development and metastasis, interfering with this cascade
via inhibitors may be a valuable strategy in tumour treatment
approaches. For example, SD‑208, an inhibitor of TGFβR‑I,
signicantly downregulates expression of miR‑135b, a key
tumour molecule, in SW‑48 colon cells and nude mice
implanted with tumours in situ (128). Han et al (129) found
that dexamethasone inhibits AKT and ERK phosphorylation
in colon cancer cells, leading to a decrease in cy61 expression,
which in turn blocks TGF‑β1‑induced migration. Similarly,
Koelink et al (130) found that 5‑aminosalicylic acid elimi
nates the TGF‑β1 cascade in HCT116 CRC cells and therefore
disrupts phosphorylation of downstream SMAD3. These
inhibitors or drugs act on an important molecular target in the
TGF‑β pathway, which affects the entire pathway. lncRNAs
only indirectly affect expression of certain related proteins in
the TGF‑β pathway and, to the best of our knowledge, little
is known about the potential involvement of lncRNAs in
direct regulation. For TGF‑β‑induced lncRNAs, inhibition of
TGF‑β expression may be a promising therapeutic approach.
Identifying these potential lncRNAs will provide a more
comprehensive understanding of regulation of the TGF‑β
Not applicable.
The present study was supported by the Youth Program
of National Natural Science Foundation of China (grant
no. 81500169), the Hunan Provincial Groundbreaking
Platform Open Fund of University of South China (grant
no. 19K080) and the Student Research Learning and Innovative
Experimental Project of the University of South China (grant
nos. 20155760439 and X2019141).
Availability of data and materials
Not applicable.
Authors' contributions
ZH is responsible for writing the article. YL and ML revised the
manuscript for important intellectual content and constructed
gures. YZ and CW conceived the study. All authors have read and
approved the nal manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
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Studies over the past decades have implicated lncRNAs in promoting the development, migration and invasion of gastric cancer (GC). However, the role and mechanism of lncRNA MBNL1-AS1 in GC promotion are poorly understood. In this research, qRT-PCR showed that MBNL1-AS1 was down-regulated in GC tissues and cells. Cell experiments and the animal study demonstrated that MBNL1-AS1 knockdown accelerated GC cell proliferation, migration, and invasion, thus restraining cell apoptosis. Meanwhile, overexpression of MBNL1-AS1 repressed GC cell promotion. Bioinformatics analysis confirmed that MBNL1-AS1 binds to miR-424-5p via negative modulation. Rescue experiments showed that decreased miR-424-5p level inhibited GC cell promotion by silencing MBNL1-AS1. Furthermore, Smad7 was identified as a target of miR-424-5p that could reverse the promotion of GC cell growth mediated by miR-424-5p. Western blot results proved that MBNL1-AS1 affected TGF-β/SMAD pathways by regulating the miR-424-5p/Smad7 axis. Collectively, MBNL1-AS1 restrained GC growth via the miR-424-5p/Smad7 axis and thus could be a promising target for GC therapy. These findings illustrate that lncRNA MBNL1-AS1, as a tumor suppressor gene, participates in GC progression by regulating miR-424-5p/Smad7 axis, thus activating TGF-β/EMT pathways. The evidence may provide a potential marker for GC patients.
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Glioma is a primary intracranial malignant tumor with poor prognosis, and its pathogenesis is unclear. This study discussed the impact of p53/lncRNA plasmacytoma variant translocation 1 (lncRNA PVT1)/transforming growth factor beta (TGF-β)/Smad axis on the biological characteristics of glioma. Glioma and normal tissues were collected, in which relative lncRNA PVT1 and p53 expression was assessed. Pearson’s analysis was adopted for the correlation analysis between lncRNA PVT1 and p53. Short interfering RNA (siRNA) against lncRNA PVT1 (siRNA-PVT1), siRNA-p53 or both was transfected into the glioma cells to evaluate effects of lncRNA PVT1 and p53 on cell proliferation, migration, invasion, and apoptosis. Mouse xenograft model of glioma was established to verify function of lncRNA PVT1 and p53 in vivo. Relationship among p53, lncRNA PVT1 and TGF-β/Smad was predicted and confirmed. Glioma tissues and cells showed downregulated p53 expression and increased lncRNA PVT1 expression. An adverse relationship was noted between p53 expression and lncRNA PVT1 expression. p53 was shown to be enriched in the lncRNA PVT1 promoter region and resulted in its suppression. p53 inhibited glioma cell proliferation, migration, and invasion, and induced apoptosis as well as arrested tumor growth by downregulating lncRNA PVT1. LncRNA PVT1was found to bind to TGF-β and activate TGF-β/Smad pathway, promoting progression of glioma. Consequently, p53 exerts anti-oncogenic function on glioma development by suppressing lncRNA PVT1 and subsequently inactivating TGF-β/Smad pathway.
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Emerging evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the metastasis and recurrence of hepatocellular carcinoma (HCC). A kinds of lncRNAs were found to be involved in regulating epithelial–mesenchymal transition (EMT) or stem-like traits in human cancers, however, the molecular mechanism and signaling pathways targeting EMT and stemness remains largely unknown. Previously, we found that linc00261 was down-regulated in HCC and associated with multiple worse clinical pathological parameters and poor prognosis. Here, we show that linc00261 was down-regulated in TGF-β1 stimulated cells, and forced expression of linc00261 attenuated EMT and stem-like traits in HCC. Linc00261 also inhibited the tumor sphere forming in vitro and decreased the tumorigenicity in vivo. Furthermore, we revealed that linc00261 suppressed the expression and phosphorylation of SMAD3 (p-SMAD3), which could be core transcriptional modulator in TGF-β1 signaling mediated EMT and the acquisition of stemness traits. A negative correlation between linc00261 and p-SMAD3 was determined in HCC samples. Conclusion: Our study revealed that linc00261 suppressed EMT and stem-like traits in HCC cells by inhibiting TGF-β1/SMAD3 signaling.
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Breast cancer (BRCA) is a malignant tumor with a high incidence and poor prognosis in females. However, its pathogenesis remains unclear. In this study, based on bioinformatic analysis, we found that LINC00467 was highly expressed in BRCA and was associated with tumor metastasis and poor prognosis. The genomic and epigenetic analysis showed that LINC00467 may also be regulated by copy number amplification (CNA), chromatin openness, and DNA methylation. In vitro experiments showed that it could promote the proliferation, migration, and invasion of BRCA cells. Competitive endogenous RNA (ceRNA) regulatory network analysis and weighted gene coexpression network analysis (WGCNA) suggested that LINC00467 may play a role in signaling pathways of peroxisomal lipid metabolism, immunity, and others through microRNAs (miRNAs) targeting transforming growth factor beta 2 (TGFB2). In addition, copy number amplification and high expression of LINC00467 were associated with the low infiltration of CD8+ and CD4+ T cells. In conclusion, we found that LINC00467, driven by copy number amplification and DNA demethylation, may be a potential biomarker for the diagnosis and prognosis of BRCA and a tumor promoter acting as a potential therapeutic target for BRCA as well.
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Background Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a few lncRNAs have been characterized functionally. In this study, we aimed to identify novel lncRNAs involved in the progression of gastric carcinoma (GC) and explore their regulatory mechanisms and clinical significance in GC. Methods A lncRNA expression microarray was used to identify differential lncRNA expression profiles between paired GCs and adjacent normal mucosal tissues. Using the above method, the lncRNA SGO1-AS1 was selected for further study. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) were performed to detect SGO1-AS1 expression in GC tissues. Gain-of-function and loss-of-function analyses were performed to investigate the functions of SGO1-AS1 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Results SGO1-AS1 was downregulated in gastric carcinoma tissues compared to adjacent normal tissues, and its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. The functional experiments revealed that SGO1-AS1 inhibited GC cell invasion and metastasis in vitro and in vivo. Mechanistically, SGO1-AS1 facilitated TGFB1/2 mRNA decay by competitively binding the PTBP1 protein, resulting in reduced TGFβ production and, thus, preventing the epithelial-to-mesenchymal transition (EMT) and metastasis. In addition, in turn, TGFβ inhibited SGO1-AS1 transcription by inducing ZEB1. Thus, SGO1-AS1 and TGFβ form a double-negative feedback loop via ZEB1 to regulate the EMT and metastasis. Conclusions SGO1-AS1 functions as an endogenous inhibitor of the TGFβ pathway and suppresses gastric carcinoma metastasis, indicating a novel potential target for GC treatment.
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Patients with advanced ovarian cancer usually exhibit high mortality rates, thus more efficient therapeutic strategies are expected to be developed. Recent transcriptomic studies revealed that long intergenic noncoding RNAs (lincRNAs) can be a new class of molecular targets for cancer management, because lincRNAs likely exert tissue-specific activities compared with protein-coding genes or other noncoding RNAs. We here show that an unannotated lincRNA originated from chromosome 10q21 and designated as ovarian cancer long intergenic noncoding RNA 1 (OIN1), is often overexpressed in ovarian cancer tissues compared with normal ovaries as analyzed by RNA sequencing. OIN1 silencing by specific siRNAs significantly exerted proliferation inhibition and enhanced apoptosis in ovarian cancer cells. Notably, RNA sequencing showed that OIN1 expression was negatively correlated with the expression of apoptosis-related genes ras association domain family member 5 (RASSF5) and adenosine A1 receptor (ADORA1), which were upregulated by OIN1 knockdown in ovarian cancer cells. OIN1-specifc siRNA injection was effective to suppress in vivo tumor growth of ovarian cancer cells inoculated in immunodeficient mice. Taken together, OIN1 could function as a tumor-promoting lincRNA in ovarian cancer through modulating apoptosis and will be a potential molecular target for ovarian cancer management.
Transforming growth factor–β1 (TGF-β1) is inextricably linked to regulatory T cell (T reg ) biology. However, precisely untangling the role for TGF-β1 in T reg differentiation and function is complicated by the pleiotropic and context-dependent activity of this cytokine and the multifaceted biology of T regs . Among CD4 ⁺ T cells, T regs are the major producers of latent TGF-β1 and are uniquely able to activate this cytokine via expression of cell surface docking receptor glycoprotein A repetitions predominant (GARP) and αv integrins. Although a preponderance of evidence indicates no essential roles for T reg -derived TGF-β1 in T reg immunosuppression, TGF-β1 signaling is crucial for T reg development in the thymus and periphery. Furthermore, active TGF-β1 instructs the differentiation of other T cell subsets, including T H 17 cells. Here, we will review TGF-β1 signaling in T reg development and function and discuss knowledge gaps, future research, and the TGF-β1/T reg axis in the context of cancer immunotherapy and fibrosis.
Background: AFP, AFP L-3 and DCP in combination or in GALAD were tested for HCC surveillance in retrospective cohort and case-control studies. However, there is a paucity of prospective data and no phase 3 biomarker studies from North American populations. Methods: We conducted a prospective-specimen collection, retrospective-blinded-evaluation (PRoBE) cohort study in patients with cirrhosis enrolled in a 6-monthly surveillance with liver imaging and AFP. Blood samples were prospectively collected every 6 months and analyzed in a retrospective blinded fashion. True positive rate (TPR) and false positive rate (FPR) for any or early HCC were calculated within 6, 12 and 24 months of HCC diagnosis based on published thresholds for biomarkers individually, in combination and in GALAD and HES scores. We calculated the area under the receiver operating curve (AUROC) and estimated TPR based on an optimal threshold at a fixed FPR of 10%. Results: The analysis was conducted in a cohort of 534 patients; 50 developed HCC (68% early) and 484 controls with negative imaging. GALAD had the highest TPR (63.6, 73.8, 71.4% for all HCC, and 53.8, 63.3, 61.8 % for early HCC within 6, 12 and 24 months, respectively) but FPR of 21.5-22.9%. However, there were no differences in AUROC among GALAD, HES, AFP-3 or DCP. At a fixed 10% FPR, TPR for GALAD dropped (42.4, 45.2, 46.9%) and was not different from HES (36.4, 40.5, 40.8%) or AFP-3 alone (39.4, 45.2, 44.9%). Conclusions: In a prospective cohort phase 3 biomarker study, GALAD was associated with a considerable improvement in sensitivity for HCC detection but an increase in false positive results. GALAD performance was modest and not different from AFP-3 alone or HES.
Non-small cell lung carcinoma (NSCLC) is one of the most common malignant tumors worldwide with high incidence and mortality. Long non-coding RNAs (lncRNAs) have been reported to affect human cancer progression. The present study aimed to investigate the regulatory role and mechanism of long intergenic non-protein coding RNA 1232 (LINC01232) in NSCLC cells. RT-qPCR results revealed that LINC01232 expression was high in NSCLC cells. Flow cytometry and sphere formation assays indicated that LINC01232 significantly promoted NSCLC cell stemness. Luciferase reporter assay and ChIP assay validated that forkhead box P3 (FOXP3) could bind to LINC01232 promoter and activate LINC01232 transcription. Further, LINC01232 was certified to activate TGF-β signaling pathway through regulating transforming growth factor beta receptor 1 (TGFBR1). After RIP and RNA pull down assays, insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) was proven as the RNA-binding protein (RBP) for LINC01232. LINC01232 promoted TGFBR1 mRNA stability via recruiting IGF2BP2. Subsequently, LINC01232 was verified to accelerate NSCLC cell stemness and induce macrophage M2 polarization via upregulating TGFBR1. Taken together, FOXP3 activated-LINC01232 accelerated NSCLC cell stemness by activating TGF-β signaling pathway and recruiting IGF2BP2 to stabilize TGFBR1, which might offer a rationale for lncRNA-based treatment to NSCLC.