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ZEB1 drives epithelial-to-mesenchymal transition in lung cancer
Jill E. Larsen, … , Nicholas K. Hayward, John D. Minna
Jill E. Larsen, … , Nicholas K. Hayward, John D. Minna
Published August 8, 2016
Citation Information: J Clin Invest. 2016;126(9):3219-3235. https://doi.org/10.1172/JCI76725.
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Research Article Oncology

ZEB1 drives epithelial-to-mesenchymal transition in lung cancer

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Abstract

Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-β) or oncogenetic (MYC) factors. Both TGF-β– and MYC-induced EMT required ZEB1, but engaged distinct TGF-β–dependent and vitamin D receptor–dependent (VDR-dependent) pathways, respectively. Functionally, we found that ZEB1 causally promotes malignant progression of HBECs and tumorigenicity, invasion, and metastases in non–small cell lung cancer (NSCLC) lines. Mechanistically, ZEB1 expression in HBECs directly repressed epithelial splicing regulatory protein 1 (ESRP1), leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. In addition, ZEB1 expression in early stage IB primary NSCLC correlated with tumor-node-metastasis stage. These findings indicate that ZEB1-induced EMT and associated molecular changes in ESRP1 and CD44 contribute to early pathogenesis and metastatic potential in established lung cancer. Moreover, TGF-β and VDR signaling and CD44 splicing pathways associated with ZEB1 are potential EMT chemoprevention and therapeutic targets in NSCLC.

Authors

Jill E. Larsen, Vaishnavi Nathan, Jihan K. Osborne, Rebecca K. Farrow, Dhruba Deb, James P. Sullivan, Patrick D. Dospoy, Alexander Augustyn, Suzie K. Hight, Mitsuo Sato, Luc Girard, Carmen Behrens, Ignacio I. Wistuba, Adi F. Gazdar, Nicholas K. Hayward, John D. Minna

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Figure 1

Genetic (MYC) and microenvironmental (TGF-β) oncogenic cues can induce ZEB1-dependent EMT and increase transformation in partially transformed HBEC3p53,KRAS cells, but not in nontransformed HBECs.

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Genetic (MYC) and microenvironmental (TGF-β) oncogenic cues can induce Z...
(A and B) Expression of (A) EMT markers and EMT-TFs and (B) miR-200 family members in HBEC3p53,KRAS, HBEC3p53,KRAS,MYC, and HBEC3p53,KRAS+FBS (whole population and 2 clonal populations, c1 and c11) (mean ± SD). (C) Immunoblot of ZEB1 and E-cadherin across oncogenically manipulated HBECs grown in defined (serum-free) or 10% FBS media with 3 clonal populations of HBEC3p53,KRAS+FBS: c1, c5, and c11. (D) mRNA expression of EMT markers in HBEC3p53,KRAS following 72-hour treatment with 10% FBS with or without 10 μM SB431542 (mean ± SD). (E) mRNA expression of EMT markers in HBEC3p53,KRAS and HBEC3p53,KRAS,shZEB1 following 5 ng/ml TGF-β treatment (left) or MYC overexpression (o/e, right), followed with ZEB1 overexpression rescue (mean ± SD). Data are representative of at least 3 independent experiments.
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