Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib  

作　　者：JungWoo Eun Jung Hwan Yoon Hye Ri Ahn Seokhwi Kim Young Bae Kim Su Bin Lim Won Park TaeWook Kang Geum Ok Baek Moon Gyeong Yoon Ju A Son Ji HyangWeon Soon Sun Kim Hyo Jung Cho Jae Youn Cheong 

机构地区：[1]Department of Gastroenterology,Ajou University School of Medicine,Suwon,South Korea [2]Department of Pathology,College of Medicine,The Catholic University of Korea,Seoul,South Korea [3]Department of Biomedical Sciences,AjouUniversity Graduate School of Medicine,Suwon,South Korea [4]Department of Pathology,Ajou University School of Medicine,Suwon,South Korea [5]Department of Biochemistry&Molecular Biology,Ajou University School of Medicine,Suwon,South Korea [6]The Moagen,Inc,Daejeon,South Korea

出　　处：《Cancer Communications》2023年第4期455-479,共25页癌症通讯（英文）

摘　　要：Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.

关 键 词：drug resistance epithelial-to-mesenchymal transition hepatocellular carcinoma secreted phosphoprotein 1 

分 类 号：R735.7[医药卫生—肿瘤]