MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

Shuhua Zhao,Hong Yang,Bing Wu,Xiaohong Zhang,Yuan Shi,Tingting Song,Jia Li,Lu Cheng

doi:10.1186/s13046-020-01802-9

Abstract

BackgroundIncreasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC).MethodsThe expression and clinical significance of MIEF2 were determined by qRT-PCR, western blot and immunohistochemistry analyses in tissues and cell lines of OC. The biological functions of MIEF2 in OC were determined by in vitro and in vivo cell growth and metastasis assays. Furthermore, the effect of MIEF2 on metabolic reprogramming of OC was determined by metabolomics and glucose metabolism analyses.ResultsMIEF2 expression was significantly increased in OC mainly due to the down-regulation of miR-424-5p, which predicts poor survival for patients with OC. Knockdown of MIEF2 significantly suppressed OC cell growth and metastasis both in vitro and in vivo by inhibiting G1-S cell transition, epithelial-to-mesenchymal transition (EMT) and inducing cell apoptosis, while forced expression of MIEF2 had the opposite effects. Mechanistically, mitochondrial fragmentation-suppressed cristae formation and thus glucose metabolism switch from oxidative phosphorylation to glycolysis was found to be involved in the promotion of growth and metastasis by MIEF2 in OC cells.ConclusionsMIEF2 plays a critical role in the progression of OC and may serve as a valuable prognostic biomarker and therapeutic target in the treatment of this malignancy.

Highlights

Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer
Our results showed a significantly up-regulation of Mitochondrial elongation factor 2 (MIEF2) in ovarian cancer (OC) tissues when compared with peritumor tissues (Fig. 1a)
Our results showed that knockdown of MIEF2 in OVCAR3 cells significantly increased the rate of oxygen consumption (Fig. 7a), activities of respiratory chain complexes I-V (Fig. 7b) and Adenosine triphosphate (ATP) production (Fig. 7c), while forced MIEF2 expression exhibited the opposite effects in SKOV3 cells (Fig. 7a-c)

Summary

Introduction

Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. The molecular mechanisms involved in ovarian carcinogenesis are still poorly defined, which limited the effective methods for clinical treatment [2, 3]. Identification of novel molecular alterations contribute to the metastatic growth of OC is critical for development of novel diagnostic and therapeutic strategies to obtain more effective treatment in this malignancy. Emerging studies has revealed mitochondrial dysfunction as one of the most common reasons for increased aerobic glycolysis in cancer cells [8,9,10,11], suggesting that identification of novel regulators contributing mitochondrial dysfunction may uncover molecular mechanisms underlying the increased aerobic glycolysis in cancer cells

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Results

Discussion

Conclusion