Regulatory role of non-coding RNAs in 5-Fluorouracil resistance in gastrointestinal cancers

Abstract

Gastrointestinal (GI) cancers are becoming a growing cause of morbidity and mortality globally, posing a significant risk to human life and health. The main treatment for this kind of cancer is chemotherapy based on 5-fluorouracil (5-FU). However, the issue of 5-FU resistance is becoming increasingly prominent, which greatly limits its effectiveness in clinical treatment. Recently, numerous studies have disclosed that some non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), exert remarkable physiological functions within cells. In addition, these ncRNAs can also serve as important information communication molecules in the tumor microenvironment and regulate tumor chemotherapy resistance. In particular, they have been shown to play multiple roles in regulating 5-FU resistance in GI cancers. Herein, we summarize the targets, pathways, and mechanisms involved in regulating 5-FU resistance by ncRNAs and briefly discuss the application potential of ncRNAs as biomarkers or therapeutic targets for 5-FU resistance in GI cancers, aiming to offer a reference to tackle issues related to 5-FU resistance.

Keywords

Non-coding RNAs / 5-fluorouracil / gastrointestinal cancers / chemoresistance / tumor microenvironment

References

[1] Bijlsma MF,Tan P.Molecular subtypes in cancers of the gastrointestinal tract.Nat Rev Gastroenterol Hepatol2017;14:333-42

[2] Arnold M,Neale RE.Global burden of 5 major types of gastrointestinal cancer.Gastroenterology2020;159:335-49.e15 PMCID:PMC8630546

[3] Huang J,Zhang L.Updated epidemiology of gastrointestinal cancers in East Asia.Nat Rev Gastroenterol Hepatol2023;20:271-87

[4] Ye SP,Huang ZX,Wen XQ.Role of minimally invasive techniques in gastrointestinal surgery: current status and future perspectives.World J Gastrointest Surg2021;13:941-52 PMCID:PMC8462081

[5] Baskar R,Yeo R.Cancer and radiation therapy: current advances and future directions.Int J Med Sci2012;9:193-9 PMCID:PMC3298009

[6] Abdul-Latif M,Dearman C,Khan K.Immunotherapy in gastrointestinal cancer: the current scenario and future perspectives.Cancer Treat Rev2020;88:102030

[7] Yamamoto M.Cancer gene therapy.Technol Cancer Res Treat2005;4:315-30

[8] Heideman DA,Craanen ME.Gene therapy for gastrointestinal tract cancer: a review.Scand J Gastroenterol Suppl2000;232:93-100.

[9] Stem J,Merlino D,Snook AE.Therapeutic targeting of gastrointestinal cancer stem cells.Regen Med2019;14:331-43 PMCID:PMC6886570

[10] Dashti F,Rabiei N.The role of non-coding RNAs in chemotherapy for gastrointestinal cancers.Mol Ther Nucleic Acids2021;26:892-926 PMCID:PMC8551789

[11] Ren C.The drug treatment research of gastrointestinal cancer in China.Eur J Surg Oncol2020;46:e3-6

[12] Grem JL.5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development.Invest New Drugs2000;18:299-313

[13] Zhang N,Xu SJ.5-fluorouracil: mechanisms of resistance and reversal strategies.Molecules2008;13:1551-69 PMCID:PMC6244944

[14] Longley DB,Johnston PG.5-fluorouracil: mechanisms of action and clinical strategies.Nat Rev Cancer2003;3:330-8

[15] Slack FJ.The role of non-coding RNAs in oncology.Cell2019;179:1033-55 PMCID:PMC7347159

[16] Chen Q,Liao Q.Versatile interactions and bioinformatics analysis of noncoding RNAs.Brief Bioinform2019;20:1781-94

[17] Roy B,Mukherjee C.Editorial: role of non-coding RNAs in development and metastasis of solid tumours.Front Cell Dev Biol2023;11:1281200 PMCID:PMC10561194

[18] Wang J,Meng N,Lu R.ncRNA-encoded peptides or proteins and cancer.Mol Ther2019;27:1718-25 PMCID:PMC6822234

[19] Zhang Y,Jiang X.Comprehensive review for non-coding RNAs: from mechanisms to therapeutic applications.Biochem Pharmacol2024;224:116218

[20] Wang WT,Sun YM,Chen YQ.Noncoding RNAs in cancer therapy resistance and targeted drug development.J Hematol Oncol2019;12:55 PMCID:PMC6556047

[21] Chen B,Yang C,Horst D.Targeting non-coding RNAs to overcome cancer therapy resistance.Signal Transduct Target Ther2022;7:121 PMCID:PMC9008121

[22] Szymanowska A,Lopez-Berestein G.Non-coding RNAs: foes or friends for targeting tumor microenvironment.Noncoding RNA2023;9:52 PMCID:PMC10514839

[23] Labani-Motlagh A,Loskog A.The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses.Front Immunol2020;11:940 PMCID:PMC7243284

[24] Senthebane DA,Thomford NE.The role of tumor microenvironment in chemoresistance: to survive, keep your enemies closer.Int J Mol Sci2017;18:1586 PMCID:PMC5536073

[25] Guo C,Zhou Q.Exosomal noncoding RNAs and tumor drug resistance.Cancer Res2020;80:4307-13

[26] Anastasiadou E,Slack FJ.Non-coding RNA networks in cancer.Nat Rev Cancer2018;18:5-18 PMCID:PMC6337726

[27] Wei L,Lv L.The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma.Mol Cancer2019;18:147 PMCID:PMC6814027

[28] Lin Z,Xie X,Huang H.Noncoding RNAs in drug-resistant pancreatic cancer: a review.Biomed Pharmacother2020;131:110768

[29] Wei L,Zhang N.Noncoding RNAs in gastric cancer: implications for drug resistance.Mol Cancer2020;19:62 PMCID:PMC7081551

[30] Micallef I.The mechanistic roles of ncRNAs in promoting and supporting chemoresistance of colorectal cancer.Noncoding RNA2021;7:24 PMCID:PMC8103280

[31] Yang Z,Li J.Noncoding RNAs in esophageal cancer: a glimpse into implications for therapy resistance.Pharmacol Res2023;188:106678

[32] Vodenkova S,Cervena K,Vodicka P.5-fluorouracil and other fluoropyrimidines in colorectal cancer: past, present and future.Pharmacol Ther2020;206:107447

[33] Wagner AD,Moehler M.Chemotherapy for advanced gastric cancer.Cochrane Database Syst Rev2017;8:CD004064 PMCID:PMC6483552

[34] Tang JC,Liang X.Autophagy in 5-fluorouracil therapy in gastrointestinal cancer: trends and challenges.Chin Med J2016;129:456-63 PMCID:PMC4800847

[35] Mader RM,Steger GG.Resistance to 5-fluorouracil.Gen Pharmacol1998;31:661-6

[36] Blondy S,Verdier M,Perraud A.5-fluorouracil resistance mechanisms in colorectal cancer: from classical pathways to promising processes.Cancer Sci2020;111:3142-54 PMCID:PMC7469786

[37] Gmeiner WH.Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-target effects.Cancer Drug Resist2023;6:257-72 PMCID:PMC10344727

[38] Sethy C.5-fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: implication of DNA repair inhibition..Biomed Pharmacother2021;137:111285

[39] O'Brien J,Zayed Y.Overview of microRNA biogenesis, mechanisms of actions, and circulation.Front Endocrinol2018;9:402 PMCID:PMC6085463

[40] Yan H.Non-coding RNA in cancer.Essays Biochem2021;65:625-39 PMCID:PMC8564738

[41] Chen L,Sun H.The bioinformatics toolbox for circRNA discovery and analysis.Brief Bioinform2021;22:1706-28 PMCID:PMC7986655

[42] Losurdo P,Palmisano S.Potential application of small interfering RNA in gastro-intestinal tumors.Pharmaceuticals2022;15:1295 PMCID:PMC9612316

[43] Mojarad M, Ameli Mojarad M, Shojaee B, Nazemalhosseini-Mojarad E. piRNA: a promising biomarker in early detection of gastrointestinal cancer.Pathol Res Pract2022;230:153757

[44] Ashrafizadeh M,Rangappa S.Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: roles in cancer progression and therapeutic response.Med Res Rev2023;43:1263-321

[45] Xu K,Xia A,Wang S.Non-coding RNAs in radiotherapy resistance: roles and therapeutic implications in gastrointestinal cancer.Biomed Pharmacother2023;161:114485

[46] Weng M,Yang C.Noncoding RNAs in the development, diagnosis, and prognosis of colorectal cancer.Transl Res2017;181:108-20

[47] Xie S,Jin H.Non-coding RNAs in gastric cancer.Cancer Lett2020;493:55-70

[48] El-Aziz MKA,Kiriacos CJ,Hamdy NM.Decoding hepatocarcinogenesis from a noncoding RNAs perspective.J Cell Physiol2023;238:1982-2009

[49] Peng JF,Huang FT.Noncoding RNAs and pancreatic cancer.World J Gastroenterol2016;22:801-14 PMCID:PMC4716078

[50] Feng Q,Yao D,Wang YD.Emerging role of non-coding RNAs in esophageal squamous cell carcinoma.Int J Mol Sci2019;21:258 PMCID:PMC6982002

[51] Deng J,Lei J,Xiong JP.Insights into the involvement of noncoding RNAs in 5-fluorouracil drug resistance.Tumour Biol2017;39:1010428317697553

[52] Benedetti A,Fontemaggi G.Non-coding RNAs in the crosstalk between breast cancer cells and tumor-associated macrophages.Noncoding RNA2022;8:16 PMCID:PMC8874851

[53] Kazemi A,Daneshipour K.Unrevealing the vital role of ncRNAs in gastric cancer chemoresistance.Pathol Res Pract2023;250:154761

[54] Xiong G,Yang G.The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer.Cancer Lett2017;397:94-102

[55] Wu Z,Chen Y.Non-coding RNA and drug resistance in cholangiocarcinoma.Noncoding RNA Res2024;9:194-202 PMCID:PMC10730441

[56] Nishida N,Mimori K.MicroRNA-10b is a prognostic indicator in colorectal cancer and confers resistance to the chemotherapeutic agent 5-fluorouracil in colorectal cancer cells.Ann Surg Oncol2012;19:3065-71

[57] Shang J,Wang Y.MicroRNA-23a antisense enhances 5-fluorouracil chemosensitivity through APAF-1/caspase-9 apoptotic pathway in colorectal cancer cells.J Cell Biochem2014;115:772-84

[58] Li X,Liao D.Elevated microRNA-23a expression enhances the chemoresistance of colorectal cancer cells with microsatellite instability to 5-fluorouracil by directly targeting ABCF1.Curr Protein Pept Sci2015;16:301-9

[59] Gong W,Yuan H.Loss of exosomal miR-200b-3p from hypoxia cancer-associated fibroblasts promotes tumorigenesis and reduces sensitivity to 5-flourouracil in colorectal cancer via upregulation of ZEB1 and E2F3.Cancer Gene Ther2023;30:905-16

[60] Zichittella C,Cordaro A,Alessandro R.Mir-675-5p supports hypoxia-induced drug resistance in colorectal cancer cells.BMC Cancer2022;22:567 PMCID:PMC9123752

[61] Qin Y,Liu Z,Huo Z.miR-106a reduces 5-fluorouracil (5-FU) sensitivity of colorectal cancer by targeting dual-specificity phosphatases 2 (DUSP2).Med Sci Monit2018;24:4944-51 PMCID:PMC6067019

[62] Ren D,Zhang X.Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway.Oncotarget2017;8:49807-23 PMCID:PMC5564809

[63] Kim C,Lee H,Lee EK.MicroRNA-195 desensitizes HCT116 human colon cancer cells to 5-fluorouracil.Cancer Lett2018;412:264-71

[64] Lee H,Kang H.microRNA-200a-3p increases 5-fluorouracil resistance by regulating dual specificity phosphatase 6 expression.Exp Mol Med2017;49:e327 PMCID:PMC5454440

[65] Wang W,Huang da B,Ji CS.Targeting PCDH20 gene by microRNA-122 confers 5-FU resistance in hepatic carcinoma.Am J Cancer Res2016;6:1681-94. PMCID:PMC5004072

[66] Shi L,Chen Z.MiR-141 activates Nrf2-dependent antioxidant pathway via down-regulating the expression of Keap1 conferring the resistance of hepatocellular carcinoma cells to 5-fluorouracil.Cell Physiol Biochem2015;35:2333-48

[67] Lei QY,Zhao B.TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway.Mol Cell Biol2008;28:2426-36 PMCID:PMC2268418

[68] Chen M,Xu S,Jiang J.Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway.Oncotarget2015;6:44466-79 PMCID:PMC4792569

[69] Wang W,Wei X.MicroRNA-320a promotes 5-FU resistance in human pancreatic cancer cells.Sci Rep2016;6:27641 PMCID:PMC4899709

[70] Wei X,Wang L.MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4.Cancer Med2016;5:693-702 PMCID:PMC4831288

[71] Yang X,Zhang X,Cai L.Downregulation of miR-183 inhibits the growth of PANC-1 pancreatic cancer cells in vitro and in vivo, and increases chemosensitivity to 5-fluorouracil and gemcitabine.Exp Ther Med2019;17:1697-705 PMCID:PMC6364144

[72] Editorial Office. Erratum to miR-499a-5p promotes 5-FU resistance and the cell proliferation and migration through activating PI3K/Akt signaling by targeting PTEN in pancreatic cancer.Ann Transl Med2022;10:651 PMCID:PMC9263791

[73] Zhao L,Wei X.MiRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1.Tumour Biol2016;Online ahead of print:

[74] Chu H,Xu J.CMPK1 regulated by mir-130b attenuates response to 5-FU treatment in gastric cancer.Front Oncol2021;11:637470 PMCID:PMC8013733

[75] Liu JB,Liu HX.A microRNA-4516 inhibitor sensitizes chemo-resistant gastric cancer cells to chemotherapy by upregulating ING4.RSC Adv2018;8:37795-803 PMCID:PMC9089411

[76] Nishibeppu K,Imamura T.Plasma microRNA profiles: identification of miR-1229-3p as a novel chemoresistant and prognostic biomarker in gastric cancer.Sci Rep2020;10:3161 PMCID:PMC7035283

[77] Wang Y,Herbst A.miR-221 mediates chemoresistance of esophageal adenocarcinoma by direct targeting of DKK2 expression.Ann Surg2016;264:804-14

[78] Bian Z,Zhang J.LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.Sci Rep2016;6:23892 PMCID:PMC4820696

[79] Xian Z,Wang T.lncRNA UCA1 contributes to 5-fluorouracil resistance of colorectal cancer cells through miR-23b-3p/ZNF281 axis.Onco Targets Ther2020;13:7571-83 PMCID:PMC7402858

[80] Wang M,Yuan Z.Long non-coding RNA H19 confers 5-Fu resistance in colorectal cancer by promoting SIRT1-mediated autophagy.Cell Death Dis2018;9:1149 PMCID:PMC6242979

[81] Zhang L,Zhang Y,Chu F.Induction of lncRNA NORAD accounts for hypoxia-induced chemoresistance and vasculogenic mimicry in colorectal cancer by sponging the miR-495-3p/ hypoxia-inducible factor-1α (HIF-1α).Bioengineered2022;13:950-62 PMCID:PMC8805945

[82] Wang M,Wang Y.Long non-coding RNA TUG1 mediates 5-fluorouracil resistance by acting as a ceRNA of miR-197-3p in colorectal cancer.J Cancer2019;10:4603-13 PMCID:PMC6746119

[83] Li P,Wang L.lncRNA HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-κB/TS signaling in colorectal cancer.Mol Ther Nucleic Acids2017;8:356-69 PMCID:PMC5537205

[84] Wu H,He H.Long non-coding RNA PCAT6 targets miR-204 to modulate the chemoresistance of colorectal cancer cells to 5-fluorouracil-based treatment through HMGA2 signaling.Cancer Med2019;8:2484-95 PMCID:PMC6536993

[85] Yao F,Xie Z.LINC02418 upregulates EPHA2 by competitively sponging miR-372-3p to promote 5-Fu/DDP chemoresistance in colorectal cancer.Carcinogenesis2022;43:895-907 PMCID:PMC9587682

[86] Zhu Z,Weng J.LncRNA GAS6-AS1 contributes to 5-fluorouracil resistance in colorectal cancer by facilitating the binding of PCBP1 with MCM3.Cancer Lett2024;589:216828

[87] Jiang L,Su P.Long non-coding RNA HNF1A-AS1 induces 5-FU resistance of gastric cancer through miR-30b-5p/EIF5A2 pathway.Transl Oncol2022;18:101351 PMCID:PMC8802127

[88] Ding Y,Zheng J.Blocking lncRNA-SNHG16 sensitizes gastric cancer cells to 5-Fu through targeting the miR-506-3p-PTBP1-mediated glucose metabolism.Cancer Metab2022;10:20 PMCID:PMC9707261

[89] Du P,Qin Y.LncRNA PVT1 mediates antiapoptosis and 5-fluorouracil resistance via increasing Bcl2 expression in gastric cancer.J Oncol2019;2019:9325407 PMCID:PMC6530232

[90] Bai L,Tong D,Wei S.lncRNA HIT000218960 enhances resistance to 5-fluorouracil by promoting HMGA2 and activating the AKT/mTOR/P70S6K pathway in gastric cancer cells.Exp Ther Med2022;24:527 PMCID:PMC9257784

[91] Tan JN,Zhang W.Long noncoding RNA OVAAL enhances nucleotide synthesis through pyruvate carboxylase to promote 5-fluorouracil resistance in gastric cancer.Cancer Sci2022;113:3055-70 PMCID:PMC9459305

[92] Guo Y,Ma Y,Yue P.Upregulation of lncRNA SUMO1P3 promotes proliferation, invasion and drug resistance in gastric cancer through interacting with the CNBP protein.RSC Adv2020;10:6006-16 PMCID:PMC9049591

[93] Chen Z,Li Z,Wang Z.lncRNA LINC02323 predicts adverse neoadjuvant chemotherapy outcomes of gastric cancer patients and regulates cell sensitivity to 5-fluorouracil by negatively modulating miR-139-3p.Ann Med2024;56:2424513 PMCID:PMC11544739

[94] Zhang SR,Chen JX.SMC4 enhances the chemoresistance of hepatoma cells by promoting autophagy.Ann Transl Med2022;10:1308 PMCID:PMC9843382

[95] Xiong H,He J.LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells.Oncogene2017;36:3528-40

[96] Shu G,Wang Z.LINC00680 enhances hepatocellular carcinoma stemness behavior and chemoresistance by sponging miR-568 to upregulate AKT3.J Exp Clin Cancer Res2021;40:45 PMCID:PMC7836199

[97] Zhang L,Li F,Sun D.Lnc-PKD2-2-3/miR-328/GPAM ceRNA network induces cholangiocarcinoma proliferation, invasion and 5-FU chemoresistance.Front Oncol2022;12:871281 PMCID:PMC9372454

[98] Du H,Zhang L,Yu T.LncRNA FALEC increases the proliferation, migration and drug resistance of cholangiocarcinoma through competitive regulation of miR-20a-5p/SHOC2 axis.Aging2023;15:3759-70 PMCID:PMC10449288

[99] Tasaki Y,Katsushima K.Cancer-specific targeting of taurine-upregulated gene 1 enhances the effects of chemotherapy in pancreatic cancer.Cancer Res2021;81:1654-66

[100] Pardini B,Naccarati A.5-fluorouracil-based chemotherapy for colorectal cancer and MTHFR/MTRR genotypes.Br J Clin Pharmacol2011;72:162-3 PMCID:PMC3141199

[101] Zhang S,Zhang L.LncRNA HOTAIR-mediated MTHFR methylation inhibits 5-fluorouracil sensitivity in esophageal cancer cells.J Exp Clin Cancer Res2020;39:131 PMCID:PMC7353690

[102] Zhao K,Ye Z.Exosome-mediated transfer of circ_0000338 enhances 5-fluorouracil resistance in colorectal cancer through regulating microRNA 217 (miR-217) and miR-485-3p.Mol Cell Biol2021;41:e00517-20 PMCID:PMC8088270

[103] Li S.Down-regulation of circ_0032833 sensitizes colorectal cancer to 5-fluorouracil and oxaliplatin partly depending on the regulation of miR-125-5p and MSI1.Cancer Manag Res2020;12:11257-69 PMCID:PMC7649231

[104] Xu G,Wu J,Tao Y.Circular RNA circNRIP1 sponges microRNA-138-5p to maintain hypoxia-induced resistance to 5-fluorouracil through HIF-1α-dependent glucose metabolism in gastric carcinoma.Cancer Manag Res2020;12:2789-802 PMCID:PMC7186590

[105] Fang L,Xuan Z.Circular CPM promotes chemoresistance of gastric cancer via activating PRKAA2-mediated autophagy.Clin Transl Med2022;12:e708 PMCID:PMC8787023

[106] Xue L,Chen H,Fu X.Circ_0003998 upregulates ARK5 expression to elevate 5-fluorouracil resistance in hepatocellular carcinoma through binding to miR-513a-5p.Anticancer Drugs2022;33:1103-13

[107] Kim SA,Yoon SK,Kuh HJ.Indirect modulation of sensitivity to 5-fluorouracil by microRNA-96 in human colorectal cancer cells.Arch Pharm Res2015;38:239-48

[108] Borralho PM,Castro RE,Steer CJ.MicroRNA-143 reduces viability and increases sensitivity to 5-fluorouracil in HCT116 human colorectal cancer cells.FEBS J2009;276:6689-700

[109] Meng X.miR-206 regulates 5-FU resistance by targeting Bcl-2 in colon cancer cells.Onco Targets Ther2018;11:1757-65 PMCID:PMC5881530

[110] Karaayvaz M,Ju J.miR-129 promotes apoptosis and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.Cell Death Dis2013;4:e659 PMCID:PMC3702282

[111] Li PL,Wang LL.MicroRNA-218 is a prognostic indicator in colorectal cancer and enhances 5-fluorouracil-induced apoptosis by targeting BIRC5.Carcinogenesis2015;36:1484-93

[112] Zhang H,Li C.MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells.Cancer Lett2015;356:781-90

[113] Xu F,Zhang YP.MicroRNA-375-3p enhances chemosensitivity to 5-fluorouracil by targeting thymidylate synthase in colorectal cancer.Cancer Sci2020;111:1528-41 PMCID:PMC7226198

[114] Li T,Zhang XP.miR-203 enhances chemosensitivity to 5-fluorouracil by targeting thymidylate synthase in colorectal cancer.Oncol Rep2015;33:607-14

[115] Chai J,Xie C.MicroRNA-494 sensitizes colon cancer cells to fluorouracil through regulation of DPYD.IUBMB Life2015;67:191-201

[116] He J,Tong J.Overexpression of microRNA-122 re-sensitizes 5-FU-resistant colon cancer cells to 5-FU through the inhibition of PKM2 in vitro and in vivo.Cell Biochem Biophys2014;70:1343-50

[117] To KKW.Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance.Cancer Drug Resist2022;5:577-94 PMCID:PMC9511811

[118] Liu RL,Deng YZ,Li WD.Tumor suppressor miR-145 reverses drug resistance by directly targeting DNA damage-related gene RAD18 in colorectal cancer.Tumour Biol2015;36:5011-9

[119] Cao S,Xia X.MicroRNA-761 promotes the sensitivity of colorectal cancer cells to 5-fluorouracil through targeting FOXM1.Oncotarget2018;9:321-31 PMCID:PMC5787468

[120] Cai D,Chang S,Huang C.MicroRNA-302b enhances the sensitivity of hepatocellular carcinoma cell lines to 5-FU via targeting Mcl-1 and DPYD.Int J Mol Sci2015;16:23668-82 PMCID:PMC4632720

[121] Jiang JX,Pan YZ,Sun CY.Overexpression of microRNA-125b sensitizes human hepatocellular carcinoma cells to 5-fluorouracil through inhibition of glycolysis by targeting hexokinase II.Mol Med Rep2014;10:995-1002

[122] Chen Z,Huang C.MiR-27a modulates the MDR1/P-glycoprotein expression by inhibiting FZD7/β-catenin pathway in hepatocellular carcinoma cells.Cell Signal2013;25:2693-701

[123] Yang X,Pan X.miR-503 inhibits proliferation making human hepatocellular carcinoma cells susceptible to 5fluorouracil by targeting EIF4E.Oncol Rep2017;37:563-70

[124] Li LQ,Chen Q.Sensitization of gastric cancer cells to 5-FU by microRNA-204 through targeting the TGFBR2-mediated epithelial to mesenchymal transition.Cell Physiol Biochem2018;47:1533-45

[125] Chen Z,Li L,Chen X.HOXA13, negatively regulated by miR-139-5p, decreases the sensitivity of gastric cancer to 5-fluorouracil possibly by targeting ABCC4.Front Oncol2021;11:645979 PMCID:PMC8175971

[126] Yu C,Chen M,Jiang J.Upregulation of microRNA1385p inhibits pancreatic cancer cell migration and increases chemotherapy sensitivity.Mol Med Rep2015;12:5135-40

[127] Xiao J,Yu C.microRNA-137 modulates pancreatic cancer cells tumor growth, invasion and sensitivity to chemotherapy.Int J Clin Exp Pathol2014;7:7442-50. PMCID:PMC4270551

[128] Jiao D,Shui S.miR-106b regulates the 5-fluorouracil resistance by targeting Zbtb7a in cholangiocarcinoma.Oncotarget2017;8:52913-22 PMCID:PMC5581081

[129] Han L,Li B.MicroRNA-338-5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells by targeting Id-1.Cancer Sci2019;110:3677-88 PMCID:PMC6890449

[130] Jiang Z,Hou Z.LncRNA HAND2-AS1 inhibits 5-fluorouracil resistance by modulating miR-20a/PDCD4 axis in colorectal cancer.Cell Signal2020;66:109483

[131] Li J,Cen C,Lin C.The long non-coding RNA ENST00000547547 reduces 5-fluorouracil resistance of colorectal cancer cells via competitive binding to microRNA-31.Oncol Rep2018;39:217-26

[132] Wu L,Wei X.lncRNA KRAL reverses 5-fluorouracil resistance in hepatocellular carcinoma cells by acting as a ceRNA against miR-141.Cell Commun Signal2018;16:47 PMCID:PMC6098660

[133] Xu F,Wu Y,Ao J.Overexpressing lncRNA SNHG16 inhibited HCC proliferation and chemoresistance by functionally sponging hsa-miR-93.Onco Targets Ther2018;11:8855-63 PMCID:PMC6290873

[134] Gao ZQ,Chen DH.Long non-coding RNA GAS5 antagonizes the chemoresistance of pancreatic cancer cells through down-regulation of miR-181c-5p.Biomed Pharmacother2018;97:809-17

[135] Lin K,Zhuang SS.Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.FASEB J2019;33:1972-88

[136] Kjersem JB,Lingjaerde OC,Tveit KM.Plasma microRNAs predicting clinical outcome in metastatic colorectal cancer patients receiving first-line oxaliplatin-based treatment.Mol Oncol2014;8:59-67 PMCID:PMC5528512

[137] Bie LY,Deng WY,Guo P.Serum miR-191 and miR-425 as diagnostic and prognostic markers of advanced gastric cancer can predict the sensitivity of FOLFOX chemotherapy regimen.Onco Targets Ther2020;13:1705-15 PMCID:PMC7049268

[138] Perez-Carbonell L,Alberts SR.MiR-320e is a novel prognostic biomarker in colorectal cancer.Br J Cancer2015;113:83-90 PMCID:PMC4647533

[139] Xiao Y,Yosypovych SV.Long noncoding RNA XIST is a prognostic factor in colorectal cancer and inhibits 5-fluorouracil-induced cell cytotoxicity through promoting thymidylate synthase expression.Oncotarget2017;8:83171-82 PMCID:PMC5669958

[140] Yu C,Liu HX,Lu JW.Rosmarinic acid reduces the resistance of gastric carcinoma cells to 5-fluorouracil by downregulating FOXO4-targeting miR-6785-5p.Biomed Pharmacother2019;109:2327-34

[141] Wang D,Zheng L.Enhancing the management of metastatic tumors by robust Co-delivery of 5-fluorouracil/microRNA-10b inhibitor using EGFR-targeted nanovehicles.Adv Healthc Mater2023;12:e2202989

[142] Guo S,Huang W.Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma.Mol Ther Nucleic Acids2020;19:228-39 PMCID:PMC6921186