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Exploring the interplay of natural products and long non-coding RNAs in colorectal cancer: pathogenesis, diagnosis, and overcoming drug resistance

Authors:
Hanan Elimam at University of Sadat City
Hanan Elimam
Mahmoud Eldeib at Al-Azhar University
Mahmoud Eldeib
Esma Zeynep Kizilaslan at Heinrich Heine University Düsseldorf
Esma Zeynep Kizilaslan
Nora A. A. Alhamshry
Nora A. A. Alhamshry
Nora A. A. Alhamshry
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Abstract and Figures

Colorectal cancer (CRC) is recognized as one of the most prevalent malignancies, both in terms of incidence and mortality rates. Current research into CRC has shed light on the molecular mechanisms driving its development. Several factors, including lifestyle, environmental influences, genetics, and diet, play significant roles in its pathogenesis. Natural compounds such as curcumin, tanshinone, lycorine, sinomenine, kaempferol, verbascoside, quercetin, berberine, and fisetin have shown great promise in the prevention and treatment of CRC. Research has also highlighted the significance of non-coding RNAs (ncRNAs) as biomarkers and therapeutic targets in CRC. Among these, long non-coding RNAs (lncRNAs) have been found to regulate the transcription of genes involved in cancer. LncRNAs contribute to cancer stem cell (CSC) proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), and chemoresistance. Specific lncRNAs, including GAS5, LNC00337, HOTAIR, TPT1-AS1, cCSC1, BCAR4, TUG1, and Solh2, play crucial roles in these processes. They hold potential as novel biomarkers, detectable in bodily fluids and tissues, and could serve as therapeutic targets due to their involvement in drug resistance and sensitivity. These insights could improve CRC treatment strategies, addressing resistance to chemotherapy and radiotherapy. This review article aims to provide a comprehensive analysis of the current knowledge regarding the effectiveness of natural anti-cancer agents in CRC treatment. Additionally, it offers an in-depth evaluation of lncRNAs in CRC, their role in the disease’s progression, and their potential applications in its management. Graphical Abstract
Biosynthesis, intranuclear, and cytoplasmic functions of lncRNA. a Intranuclear functions: Within the cell nucleus, lncRNAs are transcribed by RNA polymerase II from various genomic elements. b Cytoplasmic functions: To carry out regulatory functions, certain lncRNAs must be transported from the nucleus to the cytoplasm
Biosynthesis, intranuclear, and cytoplasmic functions of lncRNA. a Intranuclear functions: Within the cell nucleus, lncRNAs are transcribed by RNA polymerase II from various genomic elements. b Cytoplasmic functions: To carry out regulatory functions, certain lncRNAs must be transported from the nucleus to the cytoplasm
… 
Molecular regulation of EMT in colorectal metastasis by lncRNAs. Epithelial-mesenchymal transition plays a pivotal role in the pathophysiology of colorectal metastasis
Molecular regulation of EMT in colorectal metastasis by lncRNAs. Epithelial-mesenchymal transition plays a pivotal role in the pathophysiology of colorectal metastasis
… 
Mechanisms of tumor angiogenesis in colorectal carcinoma involving lncRNAs. Tumor angiogenesis plays a pivotal role in enabling the metastasis of colorectal carcinoma. lncRNA GAS5 normally decreases the activation of the ß-catenin pathway. LncRNA LINC00337 recruits DNA methyltransferases. Elevated levels of lncRNA TPT1-AS1 lead to an increase in the activity of NF90
Mechanisms of tumor angiogenesis in colorectal carcinoma involving lncRNAs. Tumor angiogenesis plays a pivotal role in enabling the metastasis of colorectal carcinoma. lncRNA GAS5 normally decreases the activation of the ß-catenin pathway. LncRNA LINC00337 recruits DNA methyltransferases. Elevated levels of lncRNA TPT1-AS1 lead to an increase in the activity of NF90
… 
Molecular mechanisms of drug resistance to 5-fluorouracil (5-fu) in colorectal carcinoma. 5-FU effectively inhibits thymidylate synthase (TS) and disrupts thymidine synthesis. a Low concentration of the coenzyme 5,10-tetrahydrofolate (Ch2THF) may reduce the effectiveness of treatment. b A slowdown in the G1/S phase can result in reduced uptake of 5-FU derivatives into the DNA, diminishing the drug’s efficacy in inhibiting DNA replication. c With high levels of intracellular TS, the conversion of dUMP molecules into dTMP may still be possible
Molecular mechanisms of drug resistance to 5-fluorouracil (5-fu) in colorectal carcinoma. 5-FU effectively inhibits thymidylate synthase (TS) and disrupts thymidine synthesis. a Low concentration of the coenzyme 5,10-tetrahydrofolate (Ch2THF) may reduce the effectiveness of treatment. b A slowdown in the G1/S phase can result in reduced uptake of 5-FU derivatives into the DNA, diminishing the drug’s efficacy in inhibiting DNA replication. c With high levels of intracellular TS, the conversion of dUMP molecules into dTMP may still be possible
… 
Natural compounds targeting lncRNAs in cancer therapy: a comprehensive overview of DIM, gambogic acid, ginsenoside Rg3, quercetin, resveratrol, and berberine
+1
Natural compounds targeting lncRNAs in cancer therapy: a comprehensive overview of DIM, gambogic acid, ginsenoside Rg3, quercetin, resveratrol, and berberine
… 
Figures - available from: Naunyn-Schmiedeberg's Archives of Pharmacology
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Vol.:(0123456789)
Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 398:1243–1263
https://doi.org/10.1007/s00210-024-03425-9
REVIEW
Exploring theinterplay ofnatural products andlong non‑coding RNAs
incolorectal cancer: pathogenesis, diagnosis, andovercoming drug
resistance
HananElimam1 · MahmoudGomaaEldeib2,3· EsmaZ.Kizilaslan4· NoraA.A.Alhamshry1· AbdelkaderE.Ashour5·
NourhanElfar6,7· MaieM.Abdel‑Wahab3· MohamedBakrZaki1· OsamaA.Mohammed8· AbdullahF.Radwan9·
MustafaAhmedAbdel‑Reheim10,11 · RewanMoussa12· AhmedS.Doghish13,14
Received: 8 August 2024 / Accepted: 30 August 2024 / Published online: 17 September 2024
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024
Abstract
Colorectal cancer (CRC) is recognized as one of the most prevalent malignancies, both in terms of incidence and mortal-
ity rates. Current research into CRC has shed light on the molecular mechanisms driving its development. Several factors,
including lifestyle, environmental influences, genetics, and diet, play significant roles in its pathogenesis. Natural compounds
such as curcumin, tanshinone, lycorine, sinomenine, kaempferol, verbascoside, quercetin, berberine, and fisetin have shown
great promise in the prevention and treatment of CRC. Research has also highlighted the significance of non-coding RNAs
(ncRNAs) as biomarkers and therapeutic targets in CRC. Among these, long non-coding RNAs (lncRNAs) have been found
to regulate the transcription of genes involved in cancer. LncRNAs contribute to cancer stem cell (CSC) proliferation, angio-
genesis, epithelial-mesenchymal transition (EMT), and chemoresistance. Specific lncRNAs, including GAS5, LNC00337,
HOTAIR, TPT1-AS1, cCSC1, BCAR4, TUG1, and Solh2, play crucial roles in these processes. They hold potential as novel
biomarkers, detectable in bodily fluids and tissues, and could serve as therapeutic targets due to their involvement in drug
resistance and sensitivity. These insights could improve CRC treatment strategies, addressing resistance to chemotherapy and
radiotherapy. This review article aims to provide a comprehensive analysis of the current knowledge regarding the effective-
ness of natural anti-cancer agents in CRC treatment. Additionally, it offers an in-depth evaluation of lncRNAs in CRC, their
role in the disease’s progression, and their potential applications in its management.
Keywords LncRNA· Colorectal cancer· Drug resistance· Diagnosis· Prognosis
Abbreviations
CRC Colorectal cancer
ncRNA Non-coding RNA
lncRNA Long non-coding RNA
mRNA Messenger RNA
Pol Polymerase
NEAT1 Nuclear enriched abundant transcript 1
MALAT1 Metastasis-associated lung adenocarci-
noma transcript 1
circRNA Circular RNA
ATG12 Autophagy associated 12
HOTAIR HOX transcript antisense RNA
HOTTIP HOXA transcript at the distal tip
HIF-1 α Hypoxia-inducible factor 1 α
PI3K/AKT Phosphoinositide 3-kinase/serine-thio-
nine-protein kinase
STAT3 Signal transducers and activators of tran-
script 3
NF-κβ Nuclear factor-κβ
GOT2 Glutamate-oxaloacetate transaminase 2
INF1 Interferon 1
CSCs Colon cancer stem cells
BCAR4 Breast cancer anti-estrogen resistance 4
Wnt/β-catenin Wingless-related integration site/
beta-catenin
IBD Inflammatory bowel disease
UC Ulcerative colitis
CD Crohn’s disease
MLCK Myosin light chain kinase
PMN-MDSC Polymorphonuclear-myeloid-derived
suppressor cells
ETBF Enterotoxigenic Bacteroides fragilis
Extended author information available on the last page of the article
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... For example, resveratrol, one of the critical polyphenols contained in red wine, inhibits HCC growth by inhibiting the HGF-c-Met path [226]. Quercetin, a flavonol, has anti-tumor properties and reduces the growth of several tumor cells [227], particularly liver cancer. It inhibits HGFand TGF-α-induced HCC progression by blocking the AKT signaling path [228]. ...
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