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Cancer Res. 2018 Apr 15;78(8):1986-1999. doi: 10.1158/0008-5472.CAN-17-0315. Epub 2018 Feb 5.

Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells.

Walser TC1,2,3, Jing Z1,2,3, Tran LM1,2,3, Lin YQ1,2,3, Yakobian N1,2,3, Wang G1,2,3, Krysan K1,2,3, Zhu LX1,2,3,4, Sharma S1,2,3,4, Lee MH5, Belperio JA1,2,3, Ooi AT3,6,7, Gomperts BN3,6,7, Shay JW8, Larsen JE9, Minna JD10, Hong LS11, Fishbein MC11, Dubinett SM12,2,3,4,11,13.

Author information

1
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
2
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
3
Lung Cancer Research Program, Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California.
4
VA Greater Los Angeles Health Care System, Los Angeles, California.
5
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
6
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California.
7
Mattel Children's Hospital at UCLA, Los Angeles, California.
8
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas.
9
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
10
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas.
11
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
12
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. sdubinett@mednet.ucla.edu.
13
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.

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+CD44+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. Cancer Res; 78(8); 1986-99. ©2018 AACR.

PMID:
29431637
PMCID:
PMC5899686
[Available on 2019-04-15]
DOI:
10.1158/0008-5472.CAN-17-0315

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