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 language | English (US) |
|---|---|
| Pages (from-to) | 1986-1999 |
| Number of pages | 14 |
| Journal | Cancer Research |
| Volume | 78 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 15 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Silencing the snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells. / Walser, Tonya C.; Jing, Zhe; Tran, Linh M.; Lin, Ying Q.; Yakobian, Natalie; Wang, Gerald; Krysan, Kostyantyn; Zhu, Li X.; Sharma, Sherven; Lee, Mi Heon; Belperio, John A.; Ooi, Aik T.; Gomperts, Brigitte N.; Shay, Jerry W.; Larsen, Jill E.; Minna, John D.; Hong, Long sheng; Fishbein, Michael C.; Dubinett, Steven M.
In: Cancer Research, Vol. 78, No. 8, 15.04.2018, p. 1986-1999.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Silencing the snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells
AU - Walser, Tonya C.
AU - Jing, Zhe
AU - Tran, Linh M.
AU - Lin, Ying Q.
AU - Yakobian, Natalie
AU - Wang, Gerald
AU - Krysan, Kostyantyn
AU - Zhu, Li X.
AU - Sharma, Sherven
AU - Lee, Mi Heon
AU - Belperio, John A.
AU - Ooi, Aik T.
AU - Gomperts, Brigitte N.
AU - Shay, Jerry W.
AU - Larsen, Jill E.
AU - Minna, John D.
AU - Hong, Long sheng
AU - Fishbein, Michael C.
AU - Dubinett, Steven M.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047857375&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047857375&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-0315
DO - 10.1158/0008-5472.CAN-17-0315
M3 - Article
C2 - 29431637
AN - SCOPUS:85047857375
VL - 78
SP - 1986
EP - 1999
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 8
ER -