EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3

Mengxian Tu,Jinying Li,Yang You,Nan Yao,Wei Huang,Jian Hong,Leibo Xu,Lu He,Rongcheng Luo,Chen Qu

doi:10.1038/s41419-020-03040-5

Abstract

Elongation factor Tu GTP binding domain containing 2 (EFTUD2), a spliceosomal GTPase, plays a pivotal role in multiple organ development and innate immune. It has been reported that EFTUD2 is a new host factor with activity against HCV infection. However, the role of EFTUD2 in solid tumors, including hepatocellular carcinoma (HCC), remains unexplored. In this study, we investigated the molecular function of EFTUD2 in HCC. Data from The Cancer Genome Atlas (TCGA) indicated an upregulation of EFTUD2 in HCC tissues compared to that in nontumor liver tissues. Immunohistochemical analysis performed on two independent HCC cohorts confirmed the upregulation of EFTUD2 in HCC tissues and further suggested that a high level of EFTUD2 expression predicted shorter overall and recurrence-free survival in HCC patients. Functional studies suggested that siRNA interference with EFTUD2 expression significantly suppressed cell viability, blocked cell cycle progression, facilitated tumor cell apoptosis, and inhibited metastasis, while the enhancement of EFTUD2 expression promoted the proliferation and migration of HCC cells both in vitro and in vivo. Surprisingly, we also found that the stable knockdown of EFTUD2 expression via lentivirus infection was lethal for HCC cells. This finding suggested that EFTUD2 was essential for maintaining the survival of HCC cells. Mechanistically, RNA sequencing and gene set enrichment analysis (GSEA) suggested that the gene sets of epithelial–mesenchymal transition (EMT) and the JAK/STAT3 pathway were enriched in EFTUD2-overexpressing cells. Further verification indicated that EFTUD2-overexpressing cells exhibited an EMT-like phenotype and had enhanced STAT3 activation, while the STAT3 inhibitor S3I-201 partially blocked these pro-malignant effects of EFTUD2 overexpression. In summary, we report EFTUD2 as a novel oncogene that helps to maintain the survival of HCC cells and promotes HCC progression through the activation of STAT3. The high level of expression of EFTUD2 in HCC tissues indicates shorter overall and recurrence-free survival in HCC patients.

Highlights

Hepatocellular carcinoma (HCC) is an aggressive disease and one of the leading causes of cancer-relatedEFTUD2 is a highly conserved spliceosomal GTPase that plays a crucial role in diverse biological functions, includingOfficial journal of the Cell Death Differentiation AssociationTu et al Cell Death and Disease (2020)11:830 developmental defects[5,6], spliceosome activation[7], and immune responses[8,9]
EFTUD2 is upregulated in HCC tissues To determine the role of EFTUD2 in HCC, we first analyzed the mRNA expression of EFTUD2 in 365 primary HCC tissues and 50 nontumor tissues from the HCC dataset of the Cancer Genome Atlas (TCGA)
Our results indicated that a stable EFTUD2 knockdown with a lentivirus vector was lethal for two different HCC cell lines, while a transient knockdown of EFTUD2 with short interfering RNAs (siRNA) inhibited cell viability but was not lethal

Summary

Introduction

Hepatocellular carcinoma (HCC) is an aggressive disease and one of the leading causes of cancer-relatedEFTUD2 is a highly conserved spliceosomal GTPase that plays a crucial role in diverse biological functions, includingOfficial journal of the Cell Death Differentiation AssociationTu et al Cell Death and Disease (2020)11:830 developmental defects[5,6], spliceosome activation[7], and immune responses[8,9]. Hepatocellular carcinoma (HCC) is an aggressive disease and one of the leading causes of cancer-related. EFTUD2 is a highly conserved spliceosomal GTPase that plays a crucial role in diverse biological functions, including. Previous studies have identified a disease-causing role for EFTUD2 in polydysplasia, including mandibulofacial dysostoses[10], dysplastic ears[11], microcephaly, and intellectual disabilities[12,13], and esophageal atresia[14,15]. It has been reported that direct interaction between SNW1 and EFTUD2 is essential for cell survival in breast cancer. Deletion of EFTUD2 inhibits the association of endogenous proteins, leading to increased apoptosis in breast cancer cells[16]. Mutation in the eftud[2] gene has been shown to cause increasing neural precursor cell apoptosis and mitosis[17]. The expression and function of EFTUD2 in HCC is unknown

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