MARCH5 overexpression contributes to tumor growth and metastasis and associates with poor survival in breast cancer

BACKGROUND: Human MARCH5 is a mitochondrial localized E3 ubiquitin-protein ligase that is critical for the regulation of mitochondrial dynamics. A body of evidence has indicated the close links between unbalanced mitochondrial dynamics and cancers. However, the expression, biological functions, and prognostic significance of MARCH5 in breast cancer (BC) have not been determined. MATERIALS AND METHODS: The mRNA and protein expressions of MARCH5 were evaluated by quantitative real-time PCR and Western blot analysis in BC cell lines and tumor tissues. Clinical prognostic significance of MARCH5 was assessed in 65 patients with BC. The biological functions of MARCH5 were determined by in vitro cell proliferation, apoptosis, cell cycle, migration and invasion assays, and in vivo tumor growth and metastasis assays through knockdown or overexpression of MARCH5 in BC cells. In addition, the underlying mechanisms by which MARCH5 regulated BC cell growth and metastasis were explored. RESULTS: MARCH5 was substantially upregulated in BC cells mainly due to the downregulation of miR-30a, which contributed to the poor survival of BC patients. MARCH5 promoted the growth and metastasis of BC cells both in vitro and in vivo by inducing G1–S cell cycle arrest and epithelial–mesenchymal transition. Mechanistic investigations revealed that the oncogenic effect of MARCH5 was mainly mediated by increased mitochondrial fission and subsequent ROS production in BC cells. CONCLUSION: Our findings demonstrate that MARCH5 plays a critical oncogenic role in BC cells, which provides experimental evidence supporting MARCH5 as a potential therapeutic target in BC therapy.