LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells

Q. Wei, Z. H. Chen, L. Wang, T. Zhang, L. Duan, C. Behrens, I. I. Wistuba, J. D. Minna, B. Gao, J. H. Luo, Z. P. Liu

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Lung cancer is the leading cause of cancer-related death in the United States, and metastatic behavior is largely responsible for this mortality. Mutations in multiple ‘driver’ oncogenes and tumor suppressors are known to contribute to the lung tumorigenesis and in some cases represent therapeutic targets. Leucine Zipper Transcription Factor-like 1 (LZTFL1) is located in the chromosome region 3p21.3 where allelic loss and genetic alterations occur early and frequently in lung cancers. Previously, we found that LZTFL1 is downregulated in epithelial tumors, including lung cancer, and functions as a tumor suppressor in gastric cancers. However, the functional role of LZTFL1 in lung oncogenesis is undefined. We show here that downregulation of LZTFL1 expression in non-small cell lung cancer is associated with recurrence and poor survival, whereas re-expression of LZTFL1 in lung tumor cells inhibited extravasation/colonization of circulating tumor cells to the lung and inhibited tumor growth in vivo. Mechanistically, we found that LZTFL1 is expressed in ciliated human bronchial epithelial cells (HBECs) and its expression correlates with HBEC differentiation. LZTFL1 inhibits transforming growth factor β-activated mitogen-activated protein kinase and hedgehog signaling. Alteration of intracellular levels of LZTFL1 resulted in changes of expression of genes associated with epithelial-to-mesenchymal transition (EMT). We conclude that LZTFL1 inhibits lung tumorigenesis, possibly by maintaining epithelial cell differentiation and/or inhibition of signalings that lead to EMT and suggest that reactivation of LZTFL1 expression in tumor cells may be a novel lung cancer therapeutic approach.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.328.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Sep 14 2015

Fingerprint

Leucine Zippers
Carcinogenesis
Transcription Factors
Epithelial Cells
Lung
Lung Neoplasms
Neoplasms
Epithelial-Mesenchymal Transition
Oncogenes
Cell Differentiation
Down-Regulation
Circulating Neoplastic Cells
Loss of Heterozygosity
Transforming Growth Factors
Mitogen-Activated Protein Kinases
Non-Small Cell Lung Carcinoma
Stomach Neoplasms
Publications
Chromosomes
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells. / Wei, Q.; Chen, Z. H.; Wang, L.; Zhang, T.; Duan, L.; Behrens, C.; Wistuba, I. I.; Minna, J. D.; Gao, B.; Luo, J. H.; Liu, Z. P.

In: Oncogene, 14.09.2015.

Research output: Contribution to journalArticle

Wei, Q. ; Chen, Z. H. ; Wang, L. ; Zhang, T. ; Duan, L. ; Behrens, C. ; Wistuba, I. I. ; Minna, J. D. ; Gao, B. ; Luo, J. H. ; Liu, Z. P. / LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells. In: Oncogene. 2015.
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