MTP18 overexpression contributes to tumor growth and metastasis and associates with poor survival in hepatocellular carcinoma

BACKGROUND: Human MTP18 (mitochondrial protein 18 kDa) is a novel nuclear-encoded mitochondrial membrane protein that is involved in controlling mitochondrial fission. Our bioinformatic analysis of TCGA data revealed an aberrant overexpression of MTP18 in hepatocellular carcinoma (HCC). We analyzed its biological effects and prognostic significance in this malignancy. METHODS: MTP18 expression was evaluated by qRT-PCR and western blot analysis in 20 paired tumor and peritumor tissues. Clinical impact of MTP18 overexpression was assessed in 156 patients with HCC. The effects of MTP18 knockdown or overexpression on cell growth and metastasis were determined by cell proliferation, colony formation, cell cycle, apoptosis, migration, and invasion assays. Furthermore, the underlying molecular mechanisms by which MTP18 overexpression promoted HCC cell growth and metastasis were explored. RESULTS: MTP18 was commonly overexpressed in HCC tissues mainly due to the downregulation of miR-125b, which significantly contributed to poor prognosis of HCC patients. Functional experiments revealed that MTP18 promoted both the growth and metastasis of HCC cells by inducing the progression of cell cycle, epithelial to mesenchymal transition (EMT) and production of MMP–9, and suppressing cell apoptosis. Mechanistically, increased mitochondrial fission and subsequent ROS production was found to be involved in the promotion of growth and metastasis by MTP18 in HCC cells. CONCLUSIONS: MTP18 plays a pivotal oncogenic role in hepatocellular carcinogenesis; its overexpression may serve as a novel prognostic factor and a therapeutic target in HCC.