Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression  

作　　者：Hao Peng Meng Yang Kun Feng Qingpeng Lv Yewei Zhang 

机构地区：[1]Medical School,Southeast University,Nanjing 210009,China [2]Department of Ultrasound,State Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Chinese Academy of Medical,Sciences,Peking Union Medical College,Beijing 100730,China [3]Hepatopancreatobiliary Center,The Second Affiliated Hospital of Nanjing Medical University,Nanjing 210009,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第8期3429-3448,共20页信号转导与靶向治疗（英文）

基　　金：This study was supported by the National Natural Science Foundation of China(Nos.62331016,62227803,U22A2023,62325112);the Leading-edge Technology Programme of Jiangsu Natural Science Foundation:BE2022812,BK20212021。

摘　　要：More than 90% of hepatocellular carcinoma(HCC)cases develop in the presence of fibrosis or cirrhosis,making the tumor microenvironment(TME)of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts(CAFs)and cancer stem cells(CSCs),which collectively regulate HCC progression.However,the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive.Our study unveils a significant upregulation of Sema3C in fibrotic liver,HCC tissues,peripheral blood of HCC patients,as well as sorafenib-resistant tissues and cells,with its overexpression correlating with the acquisition of stemness properties in HCC.We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C,activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation.Additionally,HCCcells-derived Sema3Cfacilitated extracellular matrix(ECM)contraction and collagen deposition in vivo,while also promoting the proliferation and activation of hepatic stellate cells(HSCs).Mechanistically,Sema3C interacted with NRP1 and ITGB1 in HSCs,activating downstream NF-kB signaling,thereby stimulating the release of IL-6 and upregulating HMGCR expression,consequently enhancing cholesterol synthesis in HSCs.Furthermore,CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells,establishing a positive feedback loop that accelerates HCC progression.Notably,blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo.In sum,our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CsCs and stroma during hepatocarcinogenesis,thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.

关 键 词：SEMA HEPATOCELLULAR thereby 

分 类 号：R735.7[医药卫生—肿瘤]