@article{ffeb9b9a4c1249d796287cdff418272d,
title = "Silencing the snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells",
abstract = "Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non–small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo. Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDH{\th}CD44{\th}CD24 pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC. Significance: This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities.",
author = "Walser, {Tonya C.} and Zhe Jing and Tran, {Linh M.} and Lin, {Ying Q.} and Natalie Yakobian and Gerald Wang and Kostyantyn Krysan and Zhu, {Li X.} and Sherven Sharma and Lee, {Mi Heon} and Belperio, {John A.} and Ooi, {Aik T.} and Gomperts, {Brigitte N.} and Shay, {Jerry W.} and Larsen, {Jill E.} and Minna, {John D.} and Hong, {Long sheng} and Fishbein, {Michael C.} and Dubinett, {Steven M.}",
note = "Funding Information: This research was supported in part by funding from the National Cancer Institute (NCI; #T32-HL072752 and #U01-CA152751 to S.M. Dubinett; #U01-CA176284 and #P50-CA70907 to J.D. Minna), Department of Defense (DOD; #W81XWH-10-1-1006 and #W81XWH-13-1-0460, both to S.M. Dubinett), Department of Veteran Affairs (VA; #5I01BX000359 and #2I01BX000359, both to S.M. Dubinett), University of California Tobacco-Related Disease Research Program (TRDRP; #18FT-0060 and #20KT-0055, both to T.C. Walser), and Cancer Prevention and Research Institute of Texas (CPRIT; #RP110708 to J. D. Minna). The authors acknowledge the following core facilities and core funding sources: The UCLA Translational Pathology Core Laboratory; The UCLA GenoSeq and Clinical Microarray Cores; The UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core, supported by the National Institutes of Health (NIH; #CA-16042 and #AI-28697). Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",
year = "2018",
month = apr,
day = "15",
doi = "10.1158/0008-5472.CAN-17-0315",
language = "English (US)",
volume = "78",
pages = "1986--1999",
journal = "Cancer Research",
issn = "0008-5472",
number = "8",
}