Elevated TEFM expression promotes growth and metastasis through activation of ROS/ERK signaling in hepatocellular carcinoma

Lixin Wan,Shuang Hui,Menglan Niu,Meng Ni,Yang Wang,Dengke Bao,Zijie Zhang,Bo Wan,Yuanyuan Wu,Yongxia Dang,Jiaxin Wang,Yating Yang

doi:10.1038/s41419-021-03618-7

Abstract

TEFM (transcription elongation factor of mitochondria) has been identified as a novel nuclear-encoded transcription elongation factor in the transcription of mitochondrial genome. Our bioinformatics analysis of TCGA data revealed an aberrant over-expression of TEFM in hepatocellular carcinoma (HCC). We analyzed its biological effects and clinical significance in this malignancy. TEFM expression was analyzed by quantitative real-time PCR, western blot, and immunohistochemistry analysis in HCC tissues and cell lines. The effects of TEFM on HCC cell growth and metastasis were determined by cell proliferation, colony formation, flow cytometric cell cycle and apoptosis, migration, and invasion assays. TEFM expression was significantly increased in HCC tissues mainly caused by down-regulation of miR-194-5p. Its increased expression is correlated with poor prognosis of HCC patients. TEFM promoted HCC growth and metastasis both in vitro and in vivo by promoting G1–S cell transition, epithelial-to-mesenchymal transition (EMT), and suppressing cell apoptosis. Mechanistically, TEFM exerts its tumor growth and metastasis promoting effects at least partly through increasing ROS production and subsequently by activation of ERK signaling. Our study suggests that TEFM functions as a vital oncogene in promoting growth and metastasis in HCC and may contribute to the targeted therapy of HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common human cancer type worldwide[1]
Survival analysis showed that patients with high TEFM levels experienced shorter overall survival (OS) and recurrence-free survival (RFS) compared with those have low TEFM levels (Fig. 1G, H), which was further supported by the bioinformatics prognostic significance analysis from the online web portal UALCAN (Fig. 1I) and Kaplan–Meier Plotter[7,8] (Fig. S1A–1D)
These data suggest that TEFM is up-regulated in HCC cells, and its up-regulation predicts a poor prognosis for patients with HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common human cancer type worldwide[1]. Despite progress in surgical resection and adjuvant therapy, the prognosis continues to be poor for HCC patients[2] Human TEFM (transcription elongation factor of mitochondria) has been identified as a novel nuclearencoded transcription elongation factor in the transcription of mitochondrial genome, which encodes 13 subunits of the oxidative phosphorylation machinery[3]. It has long been accepted that cancer cells exhibit reprogrammed metabolism, characterized by increased aerobic glycolysis and decreased mitochondrial oxidative phosphorylation, to meet their metabolic demands for development and progression[4].

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Conclusion