Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers

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.
CRC	SK-CO-1 cells	MED12 knockdown	The activation of TGF-β signaling or TGF-β treatment	Resistance	DDP, OXA, and 5-FU	Brunen et al[66], 2013
CRC	HCT116/HCT116p53KO chemoresistant cell lines	-	TGF-β1 treatment/TβRI inhibition	Resistance/sensitivity	5-FU	Romano et al[82], 2016
CRC	HCT116 cells	-	Smad4 knockdown	Sensitivity	Dox	Li et al[103], 2015
CRC	in vivo, CRC animal model, stable OXA-resistant cell line HCT116/OXA	Curcumin	Inhibition of p-Smad2 and p-Smad3	Sensitivity	OXA	Yin et al[90], 2019
CRC	The resistant cell model HCT-8/5-FU cell line	Hedyotis diffusa Willd	Inhibition of TGF-β signaling	Antimetastasis in 5-FU-resistant cells	5-FU	Lai et al[116], 2017
CRC	HCT116 and DLD1 CRC cell lines	-	siRNA-mediated knockdown of SMAD2/3, TGF-β inhibitor SB431542	Sensitivity	OXA	Kim et al[89], 2019
CRC	RKO cells	-	Silencing of TβRII expression, TβRI inhibitor LY2157299	Sensitivity	BETi	Shi et al[112], 2016
CRC	HCT116 cells	-	TGF-β inhibitor LY2157299	Sensitivity	5-FU	Quan et al[81], 2019
CRC	CT26 cells	Chemokine C-C motif ligand-1 secreted by Snail-expression fibroblasts	Phosphorylated Smad2	Resistance	5-FU or paclitaxel	Li et al[143], 2018
CRC	5-FU resistant cell line(HCT-8/5-FU)	Pien Tze Huang (PZH)	Suppression of TGF-β and Smad4	Overcome MDR and inhibit EMT	-	Shen et al[117], 2014
CRC	Patients	-	P-Smad3 overexpression	Resistance	5-FU and leucovorin, capecitabine	Huang et al[78], 2015
CRC	HCT116 Smad4+/+ and Smad4-/- cell lines	-	Smad4 defect	Resistance	5-FU	Papageorgis et al[76], 2011
CRC	in vivo, colorectal tumor biopsies	-	Normal SMAD4 diploidy	Sensitivity	5-FU and mitomycin	Boulay et al[73], 2002
CRC	Dukes CRC patients	-	Low SMAD4 mRNA and protein levels	Resistance	5-FU-based adjuvant chemotherapy	Alhopuro et al[75], 2005
CRC	Colorectal tumor biopsies	-	The amplification of STRAP, an inhibitor of TGF-β signaling	Resistance	5-FU /mitomycin C adjuvant chemotherapy	Buess et al[74], 2004
CRC	Colo205 and RKO cells	-	TGF-β1 treatment	Resistance	5-FU, etoposide	Moon et al[80], 2019
CRC	Mouse models	-	Blockade of TGF-β signaling	Sensitivity	Anti-PD-1-PD-L1 checkpoint therapy	Tauriello et al[115], 2018
CRC	Mice models of MC38-derived tumors	-	1D11 antibody anti-TGF-β mAb	Sensitivity	Anti-PD1 plus anti-CD137 mAb	Rodríguez-Ruiz et al[114], 2019
CRC	SNU-C5/5-FU -resistant cells.	(1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1) from Lobophytum sp	The increase of Smad-3 phosphorylation and the nuclear localization of p-Smad3 and Smad4	Sensitivity	5-FU	Kim et al[118], 2015
CRC	The early stages of colorectal carcinogenesis in rats	5-FU/thymoquinone (TQ) combination therapy	Upregulation of the TGF-β1, TβRII, Smad4	Sensitivity	5-FU	Kensara et al[122], 2016
CRC	Azoxymethane (AOM) rat model	Vitamin D3/5-FU co-therapy	Upregulation of the TGF-β1, TβRII, smad4	Sensitivity	5-FU	Refaat et al[77], 2015
CRC	RKO cells	Oxymatrine	Inhibition of the Smad2 phosphorylation and the formation of Smad2/3/4	Sensitivity	-	Wang et al[119], 2017
EC	Paclitaxel-resistant EC109 cells	-	BMP-4 and p-Smad1/5 overexpression	Resistance	Paclitaxel	Zhou et al[100], 2017
ESCC	KYSE-150 and KYSE-180 cells, xenograft tumors in nude mice	-	TβRI inhibitor LY2157299	Sensitivity	DDP and taxol	Zhang et al[142], 2017
ESCC	Xenotransplanted tumor mice model	-	Dual PD-1/PD-L1 and TGF-β blockades	Sensitivity	PD-1/PD-L1 blockade	Chen et al[139], 2018
EC and GC	EC cells T.T, GC cells MKN28 and MKN45	-	Pretreatment with TGF-β	Sensitivity	Adriamycin	Izutani et al[104], 2002
EAC	EAC cells, EAC patient-derived xenograft tumors	-	TβR inhibitor and trastuzumab, pertuzumab	Sensitivity	Trastuzumab and Pertuzumab	Ebbing et al[106], 2017
EC	KYSE150 andKYSE450 cells	Garcinol	Inhibition of the p300/CBP and p-Smad2/3 expression	Sensitivity	-	Wang et al[120], 2020
ESCC	Patients	-	High serum levels of VEGF-A and TGF-β1	Resistance	Taxane-based/5-FU -based chemotherapy	Cheng et al[79], 2014
ESCC	TE1	-	Anti-TGF-β2 neutralizing mAb and SB-431542	Sensitivity	Trastuzumab	Mimura et al[110], 2005
ESCC	TE1/TE5	-	Anti-TGF-β2 neutralizing mAb/exogenous addition of TGF-β2	Sensitivity/resistance	Cetuximab	Kawaguchi et al[109], 2007
ESCC	ECA109 and TE1 cells	Overexpression of LEF1	Upregulation of p-Smad2, p-Smad3, and TGF-β	Resistance	DDP	Zhao et al[130], 2019
GC	AGS cells	Glycoprotein from the Capsosiphon fulvescens	Inhibition of TGF-β1-activated FAK/PI3K/AKT pathways	Sensitivity	-	Kim et al[121], 2013
GC	SGC7901 and BGC823 cells	HMMR	Upregulation of p-Smad2 level and the nuclearaccumulation of Smad2	Resistance	5-FU	Zhang et al[84], 2019
GC	A peritoneal-metastatic cell line, 60As6	-	TGF-β treatment	Sensitivity	Docetaxel	Fujita et al[99], 2015
GC	MKN-45 cells	Eribulin	Inhibition of the TGF-β/Smad pathway	Sensitivity	-	Kurata et al[126], 2018
GC	Peritoneal mesothelial cells (HPMCs)	Paclitaxel	Inhibition of phosphorylation of Smad2	Reduce stromal fibrosis	-	Tsukada et al[98], 2013
GC	NCI-N87 cells	-	TGF-β treatment	Resistance	Trastuzumab	Zhou et al[107], 2018
	AGS and MKN45 cells	MSCs	Activated TGF-β signaling	Resistance	5-FU and OXA	He et al[146], 2019
CRC	Patients	-	TGF-β2 expression	Sensitivity	Fluoropyrimidine	Kim et al[68], 2009

5-FU: 5-fluorouracil; BETi: Bromodomain and extraterminal domain protein inhibitors; BMP-4: Bone morphogenetic protein 4; CRC: Colorectal cancer; DDP: Cisplatin; Dox: Doxorubicin; EC: Esophageal cancer; ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer; MDR: Multidrug resistance; MSCs: Mesenchymal stem cells; TGF-β: Transforming growth factor-β; TβRI: Type 1 TGF-β receptor; TβRII: Type 2 TGF-β receptor.

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-21	CRC cell line HCT-116	Downregulation of TβRII	Induction of stemness	Yu et al[148], 2012
miR-552	CRC tissues of patients, CRC cell lines SW-480 and SW-620	The 3′-UTR of Smad2	Reduction 5-FU resistance	Zhao et al[150], 2019
miR-34a	CRC cell line HT29	Downregulation of the TGF-β/Smad4 signaling pathway	Acquired chemoresistance to oxaliplatin	Sun et al[149], 2017
miR-455-3p	ESCC cell lines Eca109 and Kyse30	Enhanced expression level of p-Smad2	Resistance to DDP and docetaxel	Liu et al[151], 2017
miR-27	ESCC cell line TE10	TGF-β secreted from CAF-like fibroblasts	Resistance to DDP	Tanaka et al[91], 2015
miR-187	DDP-resistant GC cells SGC7901/DDP	Downregulated TGF-β1 and p-Smad4	Alleviates DDP-resistance	Zhu et al[153], 2019
miR-204	GC cell lines AGS and SGC-7901	Target TβRII	Sensitizes GC cells to 5-FU	Li et al[154], 2018

5-FU: 5-fluorouracil; CAF: Cancer-associated fibroblast; CRC: Colorectal cancer; DDP: Cisplatin; ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer; miRNA: Microribonucleic acid; TGF-β: Transforming growth factor-β.