@Article{096504018X15372657298381,
AUTHOR = {Youwei Zhang, Bi Chen, Yongsheng Wang, Qi Zhao, Weijun Wu, Peiying Zhang, 
Liyun Miao, Sanyuan Sun},
TITLE = {NOTCH3 Overexpression and Posttranscriptional Regulation by miR-150  Were Associated With EGFR–TKI Resistance in Lung Adenocarcinoma},
JOURNAL = {Oncology Research},
VOLUME = {27},
YEAR = {2019},
NUMBER = {7},
PAGES = {751--761},
URL = {http://www.techscience.com/or/v27n7/48604},
ISSN = {1555-3906},
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<sub>50</sub> 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.},
DOI = {10.3727/096504018X15372657298381}
}