Review
Copyright ©The Author(s) 2021.
World J Gastrointest Oncol. Nov 15, 2021; 13(11): 1648-1667
Published online Nov 15, 2021. doi: 10.4251/wjgo.v13.i11.1648
Table 1 Studies of the transforming growth factor-β signaling pathway in drug resistance in gastrointestinal cancer
Cancer type
In vivo/In vitro
Upstream regulator
Alteration of TGF-β signaling
Effect
Downstream antitumor drug
Ref.
CRCSK-CO-1 cellsMED12 knockdownThe activation of TGF-β signaling or TGF-β treatmentResistanceDDP, OXA, and 5-FUBrunen et al[66], 2013
CRCHCT116/HCT116p53KO chemoresistant cell lines-TGF-β1 treatment/TβRI inhibitionResistance/sensitivity5-FURomano et al[82], 2016
CRCHCT116 cells-Smad4 knockdownSensitivityDoxLi et al[103], 2015
CRCin vivo, CRC animal model, stable OXA-resistant cell line HCT116/OXACurcuminInhibition of p-Smad2 and p-Smad3SensitivityOXAYin et al[90], 2019
CRCThe resistant cell model HCT-8/5-FU cell lineHedyotis diffusa WilldInhibition of TGF-β signalingAntimetastasis in 5-FU-resistant cells5-FULai et al[116], 2017
CRCHCT116 and DLD1 CRC cell lines-siRNA-mediated knockdown of SMAD2/3, TGF-β inhibitor SB431542SensitivityOXAKim et al[89], 2019
CRCRKO cells-Silencing of TβRII expression, TβRI inhibitor LY2157299SensitivityBETiShi et al[112], 2016
CRCHCT116 cells-TGF-β inhibitor LY2157299Sensitivity5-FUQuan et al[81], 2019
CRCCT26 cellsChemokine C-C motif ligand-1 secreted by Snail-expression fibroblastsPhosphorylated Smad2Resistance5-FU or paclitaxelLi et al[143], 2018
CRC5-FU resistant cell line(HCT-8/5-FU)Pien Tze Huang (PZH)Suppression of TGF-β and Smad4Overcome MDR and inhibit EMT-Shen et al[117], 2014
CRCPatients-P-Smad3 overexpressionResistance5-FU and leucovorin, capecitabineHuang et al[78], 2015
CRCHCT116 Smad4+/+ and Smad4-/- cell lines-Smad4 defectResistance5-FUPapageorgis et al[76], 2011
CRCin vivo, colorectal tumor biopsies-Normal SMAD4 diploidySensitivity5-FU and mitomycinBoulay et al[73], 2002
CRCDukes CRC patients-Low SMAD4 mRNA and protein levelsResistance5-FU-based adjuvant chemotherapyAlhopuro et al[75], 2005
CRCColorectal tumor biopsies-The amplification of STRAP, an inhibitor of TGF-β signalingResistance5-FU /mitomycin C adjuvant chemotherapyBuess et al[74], 2004
CRCColo205 and RKO cells-TGF-β1 treatmentResistance5-FU, etoposideMoon et al[80], 2019
CRCMouse models-Blockade of TGF-β signalingSensitivityAnti-PD-1-PD-L1 checkpoint therapyTauriello et al[115], 2018
CRCMice models of MC38-derived tumors-1D11 antibody anti-TGF-β mAbSensitivityAnti-PD1 plus anti-CD137 mAbRodríguez-Ruiz et al[114], 2019
CRCSNU-C5/5-FU -resistant cells.(1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1) from Lobophytum spThe increase of Smad-3 phosphorylation and the nuclear localization of p-Smad3 and Smad4Sensitivity5-FUKim et al[118], 2015
CRCThe early stages of colorectal carcinogenesis in rats5-FU/thymoquinone (TQ) combination therapyUpregulation of the TGF-β1, TβRII, Smad4Sensitivity5-FUKensara et al[122], 2016
CRCAzoxymethane (AOM) rat modelVitamin D3/5-FU co-therapyUpregulation of the TGF-β1, TβRII, smad4Sensitivity5-FURefaat et al[77], 2015
CRCRKO cellsOxymatrineInhibition of the Smad2 phosphorylation and the formation of Smad2/3/4Sensitivity-Wang et al[119], 2017
ECPaclitaxel-resistant EC109 cells-BMP-4 and p-Smad1/5 overexpressionResistancePaclitaxelZhou et al[100], 2017
ESCCKYSE-150 and KYSE-180 cells, xenograft tumors in nude mice-TβRI inhibitor LY2157299SensitivityDDP and taxolZhang et al[142], 2017
ESCCXenotransplanted tumor mice model-Dual PD-1/PD-L1 and TGF-β blockadesSensitivityPD-1/PD-L1 blockadeChen et al[139], 2018
EC and GCEC cells T.T, GC cells MKN28 and MKN45-Pretreatment with TGF-βSensitivityAdriamycinIzutani et al[104], 2002
EACEAC cells, EAC patient-derived xenograft tumors-TβR inhibitor and trastuzumab, pertuzumabSensitivityTrastuzumab and PertuzumabEbbing et al[106], 2017
ECKYSE150 andKYSE450 cellsGarcinolInhibition of the p300/CBP and p-Smad2/3 expressionSensitivity-Wang et al[120], 2020
ESCCPatients-High serum levels of VEGF-A and TGF-β1ResistanceTaxane-based/5-FU -based chemotherapyCheng et al[79], 2014
ESCCTE1-Anti-TGF-β2 neutralizing mAb and SB-431542SensitivityTrastuzumabMimura et al[110], 2005
ESCCTE1/TE5-Anti-TGF-β2 neutralizing mAb/exogenous addition of TGF-β2Sensitivity/resistanceCetuximabKawaguchi et al[109], 2007
ESCCECA109 and TE1 cellsOverexpression of LEF1Upregulation of p-Smad2, p-Smad3, and TGF-βResistanceDDPZhao et al[130], 2019
GCAGS cellsGlycoprotein from the Capsosiphon fulvescensInhibition of TGF-β1-activated FAK/PI3K/AKT pathwaysSensitivity-Kim et al[121], 2013
GCSGC7901 and BGC823 cellsHMMRUpregulation of p-Smad2 level and the nuclearaccumulation of Smad2Resistance5-FUZhang et al[84], 2019
GCA peritoneal-metastatic cell line, 60As6-TGF-β treatmentSensitivityDocetaxelFujita et al[99], 2015
GCMKN-45 cellsEribulinInhibition of the TGF-β/Smad pathwaySensitivity-Kurata et al[126], 2018
GCPeritoneal mesothelial cells (HPMCs)PaclitaxelInhibition of phosphorylation of Smad2Reduce stromal fibrosis-Tsukada et al[98], 2013
GCNCI-N87 cells-TGF-β treatmentResistanceTrastuzumabZhou et al[107], 2018
AGS and MKN45 cellsMSCsActivated TGF-β signalingResistance5-FU and OXAHe et al[146], 2019
CRCPatients-TGF-β2 expressionSensitivityFluoropyrimidineKim et al[68], 2009
Table 2 Studies evaluating the relationship between miRNAs and drug resistance related to the transforming growth factor-β signaling pathway in gastrointestinal cancer
miRNA
Tumor type
Target
Effect on drug resistance
Ref.
miR-21CRC cell line HCT-116Downregulation of TβRIIInduction of stemnessYu et al[148], 2012
miR-552CRC tissues of patients, CRC cell lines SW-480 and SW-620The 3′-UTR of Smad2Reduction 5-FU resistanceZhao et al[150], 2019
miR-34aCRC cell line HT29Downregulation of the TGF-β/Smad4 signaling pathwayAcquired chemoresistance to oxaliplatinSun et al[149], 2017
miR-455-3pESCC cell lines Eca109 and Kyse30Enhanced expression level of p-Smad2Resistance to DDP and docetaxelLiu et al[151], 2017
miR-27ESCC cell line TE10TGF-β secreted from CAF-like fibroblastsResistance to DDPTanaka et al[91], 2015
miR-187DDP-resistant GC cells SGC7901/DDPDownregulated TGF-β1 and p-Smad4Alleviates DDP-resistanceZhu et al[153], 2019
miR-204GC cell lines AGS and SGC-7901Target TβRIISensitizes GC cells to 5-FULi et al[154], 2018