Open Access
ARTICLE
NOTCH3 Overexpression and Posttranscriptional Regulation by miR-150 Were Associated With EGFR–TKI Resistance in Lung Adenocarcinoma
Youwei Zhang*, Bi Chen†, Yongsheng Wang‡, Qi Zhao‡, Weijun Wu§, Peiying Zhang*,
Liyun Miao‡, Sanyuan Sun*
* Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, Xuzhou, P.R. China
† Department of Respiratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, P.R. China
‡ Department of Respiratory Medicine, Drum Tower Hospital Affiliated to Medical School of Nanjing University,
Nanjing, P.R. China
§ Department of Clinical Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University,
Nanjing, P.R. China
Oncology Research 2019, 27(7), 751-761. https://doi.org/10.3727/096504018X15372657298381
Abstract
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.
Keywords
Cite This Article
Zhang, Y., Chen, B., Wang, Y., Zhao, Q., Wu, W. et al. (2019). NOTCH3 Overexpression and Posttranscriptional Regulation by miR-150 Were Associated With EGFR–TKI Resistance in Lung Adenocarcinoma.
Oncology Research, 27(7), 751–761.