LncRNA CRNDE Promotes ATG4B-Mediated Autophagy and Alleviates the Sensitivity of Sorafenib in Hepatocellular Carcinoma Cells.

Lingxi Chen,Hanxi Xiao,Jiqin Lian,Xiaodong Shen,Yongzhan Nie,Tao Li,Xuequan Huang,Yan Zhang,Dehong Tan,Fengtian He,Yueting Zhang,Wei Xiang,Liangbo Sun,Xiaojing Yan,Shiming Yang,Xufang Dai,Gang Huang

doi:10.3389/fcell.2021.687524

Abstract

Autophagy is closely related to the growth and drug resistance of cancer cells, and autophagy related 4B (ATG4B) performs a crucial role in the process of autophagy. The long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) promotes the progression of hepatocellular carcinoma (HCC), but it is unclear whether the tumor-promoting effect of CRNDE is associated with the regulation of ATG4B and autophagy. Herein, we for the first time demonstrated that CRNDE triggered autophagy via upregulating ATG4B in HCC cells. Mechanistically, CRNDE enhanced the stability of ATG4B mRNA by sequestrating miR-543, leading to the elevation of ATG4B and autophagy in HCC cells. Moreover, sorafenib induced CRNDE and ATG4B as well as autophagy in HCC cells. Knockdown of CRNDE sensitized HCC cells to sorafenib in vitro and in vivo. Collectively, these results reveal that CRNDE drives ATG4B-mediated autophagy, which attenuates the sensitivity of sorafenib in HCC cells, suggesting that the pathway CRNDE/ATG4B/autophagy may be a novel target to develop sensitizing measures of sorafenib in HCC treatment.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in human digestive system with high incidence and low survival rate (Siegel et al, 2020; Sung et al, 2021)
The in vivo experiments in nude mice showed that knockdown of colorectal neoplasia differentially expressed (CRNDE) strengthened the anti-hepatocellular carcinoma (HCC) effect of sorafenib. These findings demonstrate that CRNDE promotes autophagy related 4B (ATG4B)-mediated autophagy, which alleviates the sensitivity of sorafenib in HCC cells, suggesting that the pathway CRNDE/ATG4B/autophagy may be a promising target to improve the sensitivity of sorafenib against HCC
The results showed that both CRNDE and ATG4B mRNA levels in HCC tissues were significantly higher than those in non-cancerous liver tissues (Figures 1A,B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in human digestive system with high incidence and low survival rate (Siegel et al, 2020; Sung et al, 2021). Therapeutic reagents are increasingly used to treat HCC, but the efficacy tends to be limited due to acquired drug resistance (Llovet et al, 2018; Yang et al, 2019). Mounting studies have verified that autophagy attenuates the sensitivity of therapeutic drugs such as sorafenib, 5-fluorouracil (5-FU) and oxaliplatin, protecting cancer cells from death (Guo et al, 2014; Xiong et al, 2017; Li W. et al, 2019).

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