HBV HBx-Downregulated lncRNA LINC01010 Attenuates Cell Proliferation by Interacting with Vimentin.

Lipeng Gan,Dandan Qi,Yan Zhao,Fang Zhang,Xiaomei Tong,Xin Ye,Qilin Shangguan

doi:10.3390/ijms222212497

Abstract

Hepatitis B virus (HBV) infection is closely related to hepatocellular carcinoma (HCC) development. To investigate the mechanism of HBV causing HCC, we previously analyzed the transcription of the HBV-transgenic cell line HepG2-4D14 and parental HepG2 cells and identified a subset of long noncoding RNAs (lncRNAs) differentially expressed between them. In this study, we focus on lncRNA LINC01010, as it is significantly downregulated in HepG2-4D14 cells and in liver tissues of HCC patients, and positively correlated with survival. We found that HBV-encoded HBx can reduce the transcription of LINC01010. Functional analysis showed that the overexpression of LINC01010 inhibits proliferation, migration and invasion of HepG2 cells while the knockdown of LINC01010 promotes these processes. By taking the approach of RNA immunoprecipitation (RIP) and mass spectrometry, we identified that LINC01010 can interact with vimentin. Further studies demonstrated that LINC01010 negatively affects the vimentin network extension and causes more rapid subunit exchange and lower stability of vimentin filaments. In addition, LINC01010 can reduce the amount of insoluble vimentin within cells, which suggests that LINC01010 interfers with vimentin polymerization. These data indicate that LINC01010 can inhibit the assembly of vimentin filament. Thus, we revealed that HBV HBx-downregulated LINC01010, which suppresses cell proliferation and migration by negatively regulating the formation of vimentin filament. Taken together, LINC01010 is a potential tumor suppressor that may restrain HBV-related HCC development.

Highlights

Liver cancer is the fourth most lethal cancer with a low five-year survival rate
In order to identify the genes affected by hepatitis B virus (HBV), we previously compared the transcriptional profiles of the HBV-transgenic cell line HepG2-4D14 and its parental cell line HepG2 and identified 64 downregulated long noncoding RNAs (lncRNAs) [25]
Among the top five downregulated genes, lncRNA LINC01010 is the one correlated with Hepatocellular carcinoma (HCC) based on the data of the overall survival and disease-free survival in patients in the TCGA liver hepatocellular carcinoma (TCGA-LIHC) cohort (Figure 1A)

Summary

Introduction

Liver cancer is the fourth most lethal cancer with a low five-year survival rate. there are about 841,000 new cases and 782,000 deaths annually worldwide [1]. More than 50% of HCC cases are related to hepatitis B virus (HBV) infection [4,5,6]. HBV contributes to HCC directly via altering the genomic stability [7]. HBV contributes to HCC development indirectly through HBV virus proteins. HBV-encoded HBx is a key regulatory protein that acts as a transcriptional coactivator and hijacks the host factor, playing a leading role in the development of HCC [11,12]. HBx binds to CBP/P300 and enhances CREB transcriptional activity, which in turn promotes cell transformation [14]. HBx is reported to upregulate the stability and transcriptional activity of the hypoxia-inducible factor 1-alpha (HIF1α) which leads to angiogenesis [15]

Methods

Results

Conclusion