KIAA1199 promotes sorafenib tolerance and the metastasis of hepatocellular carcinoma by activating the EGF/EGFR-dependent epithelial-mesenchymal transition program

• Published in: Cancer letters 2019-07, Vol.454, p.78-89
• Main Authors: Xu, Yanmin, Xu, Huailong, Li, Mingyuan, Wu, Hua, Guo, Yanhe, Chen, Jun, Shan, Juanjuan, Chen, Xuejiao, Shen, Junjie, Ma, Qinghua, Liu, Jingxia, Wang, Meiling, Zhao, Wenxu, Hong, Juan, Qi, Yanan, Yao, Chao, Zhang, Qianzhen, Yang, Zhi, Qian, Cheng, Li, Jianming
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell adhesion & migration; Cell culture; Cell growth; Cell Line, Tumor; Cloning; Cytotoxicity; Drug Resistance, Neoplasm; Efficiency; EMT; Epidermal Growth Factor - metabolism; Epidermal growth factor receptors; Epithelial-Mesenchymal Transition; ErbB Receptors - metabolism; Female; Gene expression; Hep G2 Cells; Hepatocellular carcinoma; Heterografts; Humans; Hyaluronoglucosaminidase - biosynthesis; Hyaluronoglucosaminidase - genetics; Hyaluronoglucosaminidase - metabolism; Immunological tolerance; Inhibitor drugs; KIAA1199; Kinases; Laboratory animals; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Medical prognosis; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Phosphorylation; Software; Sorafenib - pharmacology; Sorafenib tolerance; Targeted cancer therapy; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.03.049

Patients with advanced hepatocellular carcinoma (HCC) will almost always develop acquired tolerance after sorafenib therapy, and the molecular mechanism of sorafenib tolerance remains poorly characterized. Here, using our established sorafenib-resistant HCC cell and xenograft models, we identified a novel gene, KIAA1199, which was markedly elevated among the differentially expressed genes involved in sorafenib tolerance. Moreover, elevated expression of KIAA1199 was positively correlated with a high risk of recurrence and metastasis and advanced TNM stage in HCC patients. Functionally, loss- and gain-of-function studies showed that KIAA1199 promoted the migration, invasion, and metastasis of sorafenib-resistant HCC cells. Mechanistically, KIAA1199 is required for EGF-induced epithelial-mesenchymal transition (EMT) in sorafenib-resistant HCC cells by aiding in EGFR phosphorylation. In summary, our data uncover KIAA1199 as a novel sorafenib-tolerant promoting gene that plays an indispensable role in maintaining sorafenib-resistant HCC cell metastasis. •Sorafenib-resistant HCC xenografts models were established to illustrate sorafenib resistance in HCC.•KIAA1199 was positively correlated to high risk of recurrence and metastasis in HCC patients.•KIAA1199 enhanced the metastasis of sorafenib-resistant HCC cells by activation of EGF/EGFR-dependent EMT programs.