Open AccessNOTCH3 Overexpression and Posttranscriptional Regulation by miR-150 Were Associated With EGFR‐TKI Resistance in Lung Adenocarcinoma
Author(s) -
Youwei Zhang,
Chen Bi,
Yongsheng Wang,
Qi Zhao,
Weijun Wu,
Peiying Zhang,
Liyun Miao,
Shuai Sun
Publication year - 2019
Publication title -
oncology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 57
eISSN - 1555-3906
pISSN - 0965-0407
DOI - 10.3727/096504018x15372657298381
Subject(s) - gefitinib , gene knockdown , adenocarcinoma , cancer research , downregulation and upregulation , biology , epidermal growth factor receptor , erlotinib , tyrosine kinase inhibitor , transfection , tyrosine kinase , cell culture , microrna , medicine , signal transduction , microbiology and biotechnology , receptor , cancer , gene , genetics
Acquired resistance remains a key challenge in epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) therapy in lung adenocarcinoma (LUAD). Recent studies have shown that Notch signaling is associated with drug resistance. However, its role and possible mechanisms in EGFR-TKI resistance are not yet clear. In our study, we found that among four members of NOTCH1‐4, only NOTCH3 was upregulated in LUAD tissues and TKI-resistant cell line (HCC827GR6). Knockdown of NOTCH3 by siRNA significantly inhibited proliferative ability, and decreased colony and sphere formation in HCC827GR6 cells. Then miR-150 was identified as a posttranscriptional regulator of NOTCH3. Its expression was downregulated in LUAD tissues and negatively correlated with NOTCH3 mRNA. The cell proliferation and IC 50 of gefitinib were decreased in HCC827GR6 cells transfected with miR-150 mimic, but was reversed when cotransfected with NOTCH3 overexpressed vector. Moreover, we also enrolled 20 patients with advanced LUAD who have taken TKIs as first-line therapy in this study. We found that collagen 1A1 (COL1A1) expression was increased significantly in LUAD tissues both at mRNA and protein levels, and positively correlated with NOTCH3 expression verified in our data and TCGA data. Univariate survival analysis showed that patients with high protein expression of NOTCH3 or COL1A1 were associated with shorter overall survival (OS). Taken together, these results suggest that miR-150/NOTCH3/COL1A1 axis contributed to EGFR‐TKI resistance in LUAD, which provide a potential therapeutic target for LUAD treatment.