P53-Induced LINC00893 Regulates RBFOX2 Stability to Suppress Gastric Cancer Progression.

Xinde Ou,Shirong Cai,Deliang Fang,Haohan Liu,Jianbo Xu,Jin Li,Jinning Ye,Yulong He,Xingyu Zhou,Qinbo Cai

doi:10.3389/fcell.2021.796451

Abstract

Long noncoding RNAs (lncRNAs) have been reported to regulate diverse tumorigenic processes. However, little is known about long intergenic non-protein coding RNA 00893 (LINC00893) and its role in gastric cancer (GC). Herein we investigated its biological functions and molecular mechanism in GC. LINC00893 was decreased in GC tissues but significantly elevated in AGS cells after treatment with Nutlin-3. In GC patients, it was found that low expression of LINC00893 was correlated with tumor growth, metastasis and poor survival. Functionally, overexpression of LINC00893 suppressed the proliferation, migration and invasion of GC cells. Mechanistically, LINC00893 regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins by binding to RNA binding fox-1 homolog 2 (RBFOX2) and promoting its ubiquitin-mediated degradation, thus suppressing the EMT and related functions of GC. In addition, the transcription factor p53 can regulate the expression of LINC00893 in an indirect way. Taken together, these results suggested that LINC00893 regulated by p53 repressed GC proliferation, migration and invasion by functioning as a binding site for RBFOX2 to regulate its stability and the expression of EMT-related proteins. LINC00893 acts as a tumor-inhibiting lncRNA that is induced by p53 in GC and regulates EMT by binding to RBFOX2, thus providing a novel experimental basis for the clinical treatment of GC.

Highlights

Gastric cancer (GC) is one of the leading causes of cancer-related human mortalities, and remains the fourth leading cause of cancer-related deaths in 2020 (Sung et al, 2021)
Nutlin-3 is an inhibitor of human homolog of murine double minute 2 (MDM2), which is a negative regulator of p53 (Endo et al, 2011)
We cross-analyzed the Long noncoding RNAs (lncRNAs) differentially expressed in gastric tissues and AGS cells elevated after the accumulation of p53, and we found there were 40 lncRNAs differentially expressed in both sequencing data (Figure 1E)

Summary

Introduction

Gastric cancer (GC) is one of the leading causes of cancer-related human mortalities, and remains the fourth leading cause of cancer-related deaths in 2020 (Sung et al, 2021). GC cases in China account for about 42% of all cases worldwide, mainly owing to the high prevalence of Helicobacter pylori infection (Cai et al, 2021). Massive efforts have been made by researchers to develop noninvasive biomarkers and therapeutic targets to reduce GC mortality, little success has been achieved in increasing the overall survival rate. Novel biomarkers for improving the early diagnosis, tumor grading and prognostic evaluation of GC are urgently needed. Owing to the rapid development in high-throughput sequencing, it has been determined that nonprotein coding RNA accounts for the vast majority of RNA transcribed from human

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Conclusion