title: TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer.
abstract: Non-small-cell lung carcinoma (NSCLC) accounts for 85% of malignant lung tumors and is the leading cause of cancer deaths. Our group previously identified Tripartite Motif 14 (TRIM14) as a component of a prognostic multigene expression signature for NSCLC. Little is known about the function of TRIM14 protein in normal or disease states. We investigated the functional and prognostic role of TRIM14 in NSCLC using in vitro and in vivo perturbation model systems. Firstly, a pooled RNAi screen identified TRIM14 to effect cell proliferation/survival in NSCLC cells. Secondly, silencing of TRIM14 expression significantly enhanced tumor growth in NSCLC xenograft mouse models, while exogenous TRIM14 expression attenuated tumorigenesis. In addition, differences in apoptotic activity between TRIM14-deficient and control tumors suggests that TRIM14 tumor suppressor activity may depend on cell death signaling pathways. TRIM14-deficient cell lines showed both resistance to hypoxia-induced cell death and attenuation of interferon response via STAT1 signaling. Consistent with these phenotypes, multivariate analyses on published mRNA expression datasets of over 600 primary NSCLCs demonstrated that low TRIM14 mRNA levels are significantly associated with poorer prognosis in early stage NSCLC patients. Our functional data therefore establish a novel tumor suppressive role for TRIM14 in NSCLC progression.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Hai
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Chang-Qi
authors.initials: CQ
authors.lastname: Zhu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Shawna L
authors.initials: SL
authors.lastname: Organ
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins; D016513:Mice, SCID; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C481145:TRIM14 protein, human; D000070584:Tripartite Motif Proteins; D046988:Proteasome Endopeptidase Complex