LINC00857 Interacting with YBX1 to Regulate Apoptosis and Autophagy via MET and Phosphor-AMPKa Signaling

Wenmei Su,Lihui Wang,Huijie Zhao,Shengmin Hu,Yi Zhou,Chunfang Guo,Bin Wu,Lixia Li,Zhixiong Yang,David G Beer,Guoan Chen

doi:10.1016/j.omtn.2020.10.025

Abstract

Long noncoding RNA (lncRNA) LINC00857 has been reported to be upregulated in lung cancer and related to poor patient survival. It can regulate cell proliferation and tumor growth in lung cancer as well as several other cancers. However, the underlying molecular mechanisms that are regulated by LINC00857 are unclear. In this study, we found that LINC00857 silencing can impair cell proliferation in 14 different genomic alterations of lung cancer cell lines. These alterations are EGFR, KRAS, TP53, MET, and LKB1 mutations. The cell apoptosis and autophagy were induced upon LINC00857 silencing in lung cancer cells. Mechanistically, LINC00857 can bind to the Y-box binding protein 1 (YBX1) protein, prevent it from proteasomal degradation, and increase its nuclear translocation. LINC00857 regulated MET expression via YBX1 at a transcriptional level. Induced cell autophagy by LINC00857 knockdown was mainly through increased phosphor-AMP-activated protein kinase (p-AMPK)a. Collectively, LINC00857-YBX1-MET/p-AMPKa signaling is critical to regulate cell proliferation, apoptosis, and autophagy, which may provide a potential clinically therapeutic target in lung cancer.

Highlights

Based on the Global Cancer Observatory (GLOBOCAN) statistics, lung cancer is the most frequent cancer (2.094 million in 2018) and the leading cause of cancer-related death worldwide (1.761 million deaths in 2018).[1,2,3] Pathologically, lung cancer is classified into two major subtypes: small cell lung carcinoma (SCLC) and non-small cell lung cancer (NSCLC)
New approaches have emerged during past decades in the treatment of lung cancer patients, including reagents that target epidermal growth factor receptor (EGFR) mutation, alkaline phosphatase (ALK) fusion, and programmed death ligand 1 (PD-L1) immunotherapy,[6,7,8,9] the 5year survival rate of NSCLC remains less than 18%
We found that the cell survival rate was from 32% to 85% on these 14 tested NSCLC cell lines upon LINC00857 knockdown with small interfering RNA (siRNA), indicating that

Summary

Introduction

Based on the Global Cancer Observatory (GLOBOCAN) statistics, lung cancer is the most frequent cancer (2.094 million in 2018) and the leading cause of cancer-related death worldwide (1.761 million deaths in 2018).[1,2,3] Pathologically, lung cancer is classified into two major subtypes: small cell lung carcinoma (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs comprise 85% of all lung cancer cases and are subclassified into adenocarcinoma (AD), squamous cell carcinoma (SCC), and large cell carcinoma.[4,5] new approaches have emerged during past decades in the treatment of lung cancer patients, including reagents that target epidermal growth factor receptor (EGFR) mutation, alkaline phosphatase (ALK) fusion, and programmed death ligand 1 (PD-L1) immunotherapy,[6,7,8,9] the 5year survival rate of NSCLC remains less than 18%.2,3. The poor prognosis and high recurrence rate of lung cancer may be partially due to the histological and molecular heterogeneity of this disease.[5,10] it is crucial to establish the underlying molecular mechanisms underlying lung cancer and to develop new, effective diagnostic biomarkers and treatment strategies to improve patient survival.[11] NSCLCs comprise 85% of all lung cancer cases and are subclassified into adenocarcinoma (AD), squamous cell carcinoma (SCC), and large cell carcinoma.[4,5] new approaches have emerged during past decades in the treatment of lung cancer patients, including reagents that target epidermal growth factor receptor (EGFR) mutation, alkaline phosphatase (ALK) fusion, and programmed death ligand 1 (PD-L1) immunotherapy,[6,7,8,9] the 5year survival rate of NSCLC remains less than 18%.2,3 The poor prognosis and high recurrence rate of lung cancer may be partially due to the histological and molecular heterogeneity of this disease.[5,10] it is crucial to establish the underlying molecular mechanisms underlying lung cancer and to develop new, effective diagnostic biomarkers and treatment strategies to improve patient survival.[11]

Methods

Results

Conclusion