LncRNA SNHG15 regulates EGFR-TKI acquired resistance in lung adenocarcinoma through sponging miR-451 to upregulate MDR-1

Jiayuan Huang,Banzhou Pan,Chenchen Li,Guohao Xia,Jingni Zhu,Jifeng Feng

doi:10.1038/s41419-020-2683-x

Jiayuan Huang, Banzhou Pan + Show 4 more

Open Access

https://doi.org/10.1038/s41419-020-2683-x

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Abstract

Lung adenocarcinoma (LUAD) is the main component of non-small-cell lung cancer (NSCLC) and causes a great health concern globally. The top priority of LUAD treatment is to deal with gefitinib resistance. Long non-coding RNAs are certified to modify gefitinib resistance in the course of tumor aggravation. The study focuses on addressing the function of small nucleolar RNA host gene 15 (SNHG15) on modifying gefitinib resistance in LUAD. Previously, NOTCH pathway is implicated in LUAD chemo-resistance. SNHG15 level was boosted following the depletion of NOTCH-1 in A549/GR and H1975/GR cells. Functional studies indicated that SNHG15 and multidrug resistance protein 1 (MDR-1) were overexpressed and possess tumor-promoting functions in gefitinib-resistant LUAD cells while miR-451 was downregulated and possess tumor-suppressive behaviors in gefitinib-resistant LUAD cells. Mechanically, the SNHG15 was cytoplasmically distributed in GR LUAD cells. In addition, SNHG15 released MDR-1 from the suppression of miR-451, leading to MDR-1 promotion. In addition, the elevation of SNHG15 could be attributed to ZEB1. Rescue assays highlighted that downstream molecules MDR-1 and miR-451 could reverse the effects of SNHG15 downregulation on gefitinib-resistant LUAD cells. SNHG15 could alter chemo-resistance of LUAD cells to Gefitinib via regulating miR-451/MDR-1, which could be inspiring findings for the advancement of chemo-therapies for LUAD.

Highlights

Lung cancer is identified as one of the most malignant tumors, and causes countless deaths annually around the world[1]
Given that geftinib is an EGFR-TKI, we detected the influence of NOTCH-1 on EGFR expression
We observed that small nucleolar RNA host gene 15 (SNHG15) level decreased upon NOTCH-1 silence in A549/gefitinib resistance (GR) and H1975/GR cells (Fig. 1d), indicating that SNHG15 might participate in NOTCH-1 effect on GR in Lung adenocarcinoma (LUAD) cells

Summary

Introduction

Lung cancer is identified as one of the most malignant tumors, and causes countless deaths annually around the world[1]. In the last few decades, depressing survival rate LUAD patients has been to some extent improved by drug therapies, such as the clinical applications of paclitaxel, docetaxel, gemcitabine, and vinorelbine, the poor prognosis remains a problem due to tumor metastasis or spread[2]. It is a serious challenge for us to explore the mechanisms of drug resistance in LUAD, clarify the interactions among key regulatory targets, develop effective therapy methods, In previous studies, we have confirmed that NOTCH-1, a major receptor in the NOTCH signaling pathway, affects the development of lung cancers[3,4]. The researching significance of NOTCH pathway has been demonstrated in other cancers, such as breast cancer[6], gastric cancer[7], and esophageal carcinoma[8]

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