title: LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells.
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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Surgical Oncology and Institute of Clinical Medicine, Sir Run Run Shaw Hospital College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Urology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Duan
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.|Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.|Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: I I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Urology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: J-H
authors.initials: JH
authors.lastname: Luo
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Z P
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D004847:Epithelial Cells / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; C431701:LZTFL1 protein, human; C509239:SHH protein, human; D014157:Transcription Factors; D053506:Matrix Metalloproteinase 10