Silencing the snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells

Tonya C. Walser, Zhe Jing, Linh M. Tran, Ying Q. Lin, Natalie Yakobian, Gerald Wang, Kostyantyn Krysan, Li X. Zhu, Sherven Sharma, Mi Heon Lee, John A. Belperio, Aik T. Ooi, Brigitte N. Gomperts, Jerry W. Shay, Jill E. Larsen, John D. Minna, Long sheng Hong, Michael C. Fishbein, Steven M. Dubinett

Research output: Contribution to journalArticle

4 Scopus citations

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 ALDHþCD44þCD24 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.

Original languageEnglish (US)
Pages (from-to)1986-1999
Number of pages14
JournalCancer Research
Volume78
Issue number8
DOIs
StatePublished - Apr 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Walser, T. C., Jing, Z., Tran, L. M., Lin, Y. Q., Yakobian, N., Wang, G., Krysan, K., Zhu, L. X., Sharma, S., Lee, M. H., Belperio, J. A., Ooi, A. T., Gomperts, B. N., Shay, J. W., Larsen, J. E., Minna, J. D., Hong, L. S., Fishbein, M. C., & Dubinett, S. M. (2018). Silencing the snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells. Cancer Research, 78(8), 1986-1999. https://doi.org/10.1158/0008-5472.CAN-17-0315