IQGAP1 promotes anoikis resistance and metastasis through Rac1-dependent ROS accumulation and activation of Src/FAK signalling in hepatocellular carcinoma

• Published in: British journal of cancer Vol. 123; no. 7; pp. 1154 - 1163
• Main Authors: Mo, Chun-fen, Li, Jun, Yang, Shu-xia, Guo, Hui-jie, Liu, Yang, Luo, Xing-yan, Wang, Yan-tang, Li, Min-hui, Li, Jing-yi, Zou, Qiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.09.2020; Nature Publishing Group
• Subjects: 631/67/322; 631/80/86; Animals; Anoikis; Antioxidants; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Drug Resistance; Epidemiology; Female; Focal adhesion kinase; Focal Adhesion Kinase 1 - physiology; Hepatitis B; Hepatitis B - complications; Hepatocellular carcinoma; Humans; Immunohistochemistry; Immunoprecipitation; IQGAP1 protein; Liver cancer; Liver Neoplasms - pathology; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Molecular Medicine; Neoplasm Metastasis; Oncology; Phosphorylation; rac1 GTP-Binding Protein - physiology; Rac1 protein; ras GTPase-Activating Proteins - physiology; Reactive Oxygen Species - metabolism; Signal transduction; Signal Transduction - physiology; src-Family Kinases - physiology; Therapeutic targets; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0970-z

Background Hepatitis 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. Methods IQGAP1 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. Results IQGAP1 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. Conclusions Our 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.