KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma

• Published in: Protein & cell Vol. 12; no. 10; pp. 788 - 809
• Main Authors: Wei, Shi, Dai, Miaomiao, Zhang, Chi, Teng, Kai, Wang, Fengwei, Li, Hongbo, Sun, Weipeng, Feng, Zihao, Kang, Tiebang, Guan, Xinyuan, Xu, Ruihua, Cai, Muyan, Xie, Dan
• Format: Journal Article
• Language: English
• Published: Beijing Higher Education Press 01.10.2021; Springer Nature B.V
• Subjects: Adult; Aged; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biochemistry; Biomedical and Life Sciences; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Developmental Biology; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; HCC; Hepatocellular carcinoma; Human Genetics; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; KIF2C; Kinesin; Kinesins - antagonists & inhibitors; Kinesins - genetics; Kinesins - metabolism; Life Sciences; Liver cancer; Liver Neoplasms - diagnosis; Liver Neoplasms - genetics; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Male; Malignancy; Metastases; Mice; Mice, Inbred BALB C; Middle Aged; Molecular modelling; mTORC1 signaling; Neoplasm Staging; Prognosis; Protein Binding; Protein Science; Rapamycin; Research Article; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal transduction; Stem Cells; Survival Analysis; TBC1D7; TOR protein; Tumor Burden; Tumors; Wnt protein; Wnt Signaling Pathway; Wnt/β-catenin signaling; Xenograft Model Antitumor Assays; β-Catenin; Wnt/β-catenin signaling; HCC; mTORC1 signaling; KIF2C; TBC1D7
• ISSN: 1674-800X; 1674-8018
• DOI: 10.1007/s13238-020-00766-y

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.