IQGAP1 promotes anoikis resistance and metastasis through Rac1-dependent ROS accumulation and activation of Src/FAK signalling in hepatocellular carcinoma.
IQGAP1 promotes anoikis resistance and metastasis through Rac1-dependent ROS accumulation and activation of Src/FAK signalling in hepatocellular carcinoma.
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IQGAP1 通过 Rac1 依赖性 ROS 积累和肝细胞癌中 Src/FAK 信号传导的激活促进失巢凋亡抵抗和转移
DOI：
10.1038/s41416-020-0970-z
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发表时间：
2020-09
影响因子：
8.8
通讯作者：
Zou Q
中科院分区：
文献类型：
--
作者：
Mo CF;Li J;Yang SX;Guo HJ;Liu Y;Luo XY;Wang YT;Li MH;Li JY;Zou Q
背景B型肝炎病毒（HBV）在肝细胞癌（HCC）的发生发展中起重要作用。肿瘤细胞必须发展抗失巢凋亡，以便在转移前存活。本研究旨在探讨IQGAP 1在HBV介导的肝癌细胞失巢凋亡逃避和转移中的作用机制。采用慢病毒介导的稳定上调或敲低IGAQP 1、免疫共沉淀等方法，对IQGAP 1在HBV阳性肝癌细胞和组织中的表达进行了研究。IQGAP 1与HBV相关HCC患者的不良预后呈正相关。IQGAP 1过表达显著增强了非锚定依赖性生长和转移，而IQGAP 1缺陷的HCC细胞对失巢凋亡更敏感。从机制上讲，我们发现HBV诱导的ROS增强了IQGAP 1和Rac 1的结合，从而激活Rac 1，导致Src/FAK通路的磷酸化。抗氧化剂有效地抑制IQGAP 1介导的失巢凋亡抵抗和metastasis.ConclusionsOur研究表明，一个重要的机制，通过上调IQGAP 1 HBV促进失巢凋亡抵抗，迁移和肝癌细胞的侵袭通过Rac 1依赖的ROS积累和激活Src/FAK信号，这表明IQGAP 1作为一个预后指标和一个新的治疗靶点，在肝癌患者HBV感染。
BackgroundHepatitis B virus (HBV) has a crucial role in the progression of hepatocellular carcinoma (HCC). Tumour cells must develop anoikis resistance in order to survive before metastasis. This study aimed to investigate the mechanism of IQGAP1 in HBV-mediated anoikis evasion and metastasis in HCC cells.MethodsIQGAP1 expression was detected by immunohistochemistry, real-time PCR and immunoblot analysis. Lentiviral-mediated stable upregulation or knockdown of IGAQP1, immunoprecipitation, etc. were used in function and mechanism study.ResultsIQGAP1 was markedly upregulated in HBV-positive compared with HBV-negative HCC cells and tissues. IQGAP1 was positively correlated to poor prognosis of HBV-associated HCC patients. IQGAP1 overexpression significantly enhanced the anchorage-independent growth and metastasis, whereas IQGAP1-deficient HCC cells are more sensitive to anoikis. Mechanistically, we found that HBV-induced ROS enhanced the association of IQGAP1 and Rac1 that activated Rac1, leading to phosphorylation of Src/FAK pathway. Antioxidants efficiently inhibited IQGAP1-mediated anoikis resistance and metastasis.ConclusionsOur study indicated an important mechanism by which upregulated IQGAP1 by HBV promoted anoikis resistance, migration and invasion of HCC cells through Rac1-dependent ROS accumulation and activation of Src/FAK signalling, suggesting IQGAP1 as a prognostic indicator and a novel therapeutic target in HCC patients with HBV infection.
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