COL5A2 drives regorafenib resistance-induced metastatic phenotype via reducing LIFR expression in hepatocellular carcinoma  

作　　者：Shaoqin Zhang Xuezhen Xue Fengdan Chen Yahan Yang Nan Zhang Yan Chen Wenda Wu Jichuang Wang Ning Zheng 

机构地区：[1]Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases,The School of Basic Medical Sciences,Fujian Medical University,Fuzhou 350122,China [2]Department of Pharmacology,The School of Pharmacy,Fujian Provincial Key Laboratory of Natural Medicine Pharmacology,Fujian Medical University,Fuzhou 350122,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第7期997-1010,共14页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Natural Science Foundation of Fujian Province(Nos.2020J01597 and 2021J01695);the Joint Funds for the Innovation of Science and Technology,Fujian Province(No.2020Y9001);the Startup Fund for Scientific Research of High-Level Talent of Fujian Medical University(No.XRCZX2019034).

摘　　要：Systemic therapies,the ultimate strategies for patients with advanced hepatocellular carcinoma(HCC),are suffering from serious clinical challenges,such as the occurrence and development of drug resistance.Treatment resistance aggravates tumor progression partly by inducing tumor metastasis.Regorafenib-resistant HCC cells exhibit a highly striking metastatic phenotype,but the detailed mechanisms underlying these aggressive behaviors remain elusive.Here,we conduct transcriptome sequencing analysis to identify COL5A2 as a crucial driver of the metastatic characteristics of regorafenib-resistant HCC cells.COL5A2 is aberrantly highly expressed in resistant cells,and its genetic depletion significantly suppresses proliferation,migration,invasion,vasculogenic mimicry(VM)formation and lung metastasis in vitro and in vivo,concomitant with the downregulation of VE-cadherin,EphA2,Twist1,p-p38 and p-STAT3 expressions.LIFR is confirmed to be an essential downstream molecule of COL5A2,and its expression is observably elevated by COL5A2 depletion.Ectopic overexpression of LIFR drastically attenuates the proliferation,migration,invasion and VM of regorafenib-resistant cells and represses the expressions of VM-related molecules and the activation of p38/STAT3 signaling pathway.Interestingly,rescue experiments show that the inhibition of the above aggressive features of resistant cells by COL5A2 loss is clearly alleviated by silencing of LIFR.Collectively,our results reveal that COL5A2 promotes the ability of regorafenib-resistant HCC cells to acquire a metastatic phenotype by attenuating LIFR expression and suggest that therapeutic regimens targeting the COL5A2/LIFR axis may be beneficial for HCC patients with therapeutic resistance.

关 键 词：regorafenib resistance hepatocellular carcinoma COL5A2/LIFR axis migration and invasion vasculogenic mimicry 

分 类 号：R735.7[医药卫生—肿瘤]