KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3

• Published in: International journal of molecular sciences 2021-12, Vol.23 (1), p.104
• Main Authors: Wang, Yanhong, Li, Na, Zheng, Yanping, Wang, Anqing, Yu, Chunlei, Song, Zhenbo, Wang, Shuyue, Sun, Ying, Zheng, Lihua, Wang, Guannan, Liu, Lei, Yi, Jingwen, Huang, Yanxin, Zhang, Muqing, Bao, Yongli, Sun, Luguo
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell adhesion & migration; Cell growth; Cell Line; Cell Line, Tumor; Cell Movement - genetics; Cytoplasm; epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic - genetics; Genes; HEK293 Cells; Hep G2 Cells; Hepatocellular carcinoma; Humans; Janus kinase; KIAA1217; Liver cancer; Liver cirrhosis; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lungs; Macromolecules; Medical prognosis; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular modelling; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Prognosis; Proteins; STAT3; Stat3 protein; STAT3 Transcription Factor - genetics; Survival; Therapeutic targets; Transcriptional Activation - genetics; Up-Regulation - genetics; Wnt protein; Wnt Signaling Pathway - genetics; Wound healing; β-Catenin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23010104

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/β-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.