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LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells

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 therapeu...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791215/
https://www.ncbi.nlm.nih.gov/pubmed/26364604
http://dx.doi.org/10.1038/onc.2015.328
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author 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
author_facet 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
author_sort Wei, Q
collection PubMed
description 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.
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spelling pubmed-47912152016-05-21 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 Oncogene Original Article 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. Nature Publishing Group 2016-05-19 2015-09-14 /pmc/articles/PMC4791215/ /pubmed/26364604 http://dx.doi.org/10.1038/onc.2015.328 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Original Article
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
title LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells
title_full LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells
title_fullStr LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells
title_full_unstemmed LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells
title_short LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells
title_sort lztfl1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791215/
https://www.ncbi.nlm.nih.gov/pubmed/26364604
http://dx.doi.org/10.1038/onc.2015.328
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