Abstract
BackgroundHuman 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.MethodsMTP18 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.ResultsMTP18 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.ConclusionsMTP18 plays a pivotal oncogenic role in hepatocellular carcinogenesis; its overexpression may serve as a novel prognostic factor and a therapeutic target in HCC.
Highlights
Liver cancer, primarily hepatocellular carcinoma (HCC), is the second leading cause of cancer death worldwide[1]
Representative MTP18 staining images and intensity scores (Fig. 1e) demonstrated that MTP18 is significantly higher in HCC tissues compared with adjacent non-tumor tissues, which further confirmed the results from quantitative real-time PCR (qRT-PCR) and western blot
Correlation analysis between the expression levels of MTP18 and clinicopathological features such as age, gender, virus infection, serum alpha fetoprotein (AFP), tumor size, TNM stage and tumor differentiation showed that higher expression of MTP18 was significantly associated with higher incidence of portal vein tumor thrombosis (PVTT) and larger tumor size, while no correlation was found between the expression levels of MTP18 and other clinicopathological features (Table 1)
Summary
Primarily hepatocellular carcinoma (HCC), is the second leading cause of cancer death worldwide[1]. Altered mitochondrial function has been considered as a hallmark for many types of cancer[3,4], including HCC5. Identification of novel molecular regulators involved in the disruption of mitochondrial function may provide insights into the biological basis of cancer development. This is important for revealing new diagnostic markers and therapeutic targets for treatment of this disease. 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
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