Cancer Research
Cancer Research
5 years ago

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

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

Publisher URL: http://doi.org/10.1158/0008-5472.CAN-17-0315

DOI: 10.1158/0008-5472.CAN-17-0315

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