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+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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 12, 2018
- Source ID
- 10.1158/0008-5472.can-17-0315
Entities
People
- Aik T. Ooi
- Brigitte N. Gomperts
- Gerald Wang
- Jerry W. Shay
- Jill E. Larsen
- John A. Belperio
- John D. Minna
- Kostyantyn Krysan
- Li X. Zhu
- Linh M. Tran
- Long-sheng Hong
- Mi-heon Lee
- Michael C. Fishbein
- Natalie Yakobian
- Sherven Sharma
- Steven M. Dubinett
- Tonya C. Walser
- Ying Q. Lin
- Zhe Jing
Organizations
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- National Institutes of Health
- Tobacco-Related Disease Research Program
- UCLA David Geffen School of Medicine
- United States Department of Defense
- United States Department of Veterans Affairs
- University of California, Los Angeles
- University of Texas Southwestern Medical Center