title: PIAS3 expression in squamous cell lung cancer is low and predicts overall survival.
abstract: Unlike lung adenocarcinoma, little progress has been made in the treatment of squamous cell lung carcinoma (SCC). The Cancer Genome Atlas (TCGA) has recently reported that receptor tyrosine kinase signaling pathways are altered in 26% of SCC tumors, validating the importance of downstream Signal Transducers and Activators of Transcription 3 (STAT3) activity as a prime therapeutic target in this cancer. In the present report we examine the status of an endogenous inhibitor of STAT3, called Protein Inhibitor of Activated STAT3 (PIAS3), in SCC and its potential role in this disease. We examine PIAS3 expression in SCC tumors and cell lines by immunohistochemistry of a tissue microarray and western blotting. PIAS3 mRNA expression and survival data are analyzed in the TCGA data set. SCC cell lines are treated with curcumin to regulate PIAS3 expression and cell growth. PIAS3 protein expression is decreased in a majority of lung SCC tumors and cell lines. Analysis of PIAS3 mRNA transcript levels demonstrated that low PIAS3 levels predicted poor survival; Cox regression analysis revealed a hazard ratio of 0.57 (95% CI: 0.37-0.87), indicating a decrease in the risk of death by 43% for every unit elevation in PIAS3 gene expression. Curcumin treatment increased endogenous PIAS3 expression and decreased cell growth and viability in Calu-1 cells, a model of SCC. Our results implicate PIAS3 loss in the pathology of lung SCC and raise the therapeutic possibility of upregulating PIAS3 expression as a single target that can suppress signaling from the multiple receptor tyrosine kinase receptors found to be amplified in SCC.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University Hospitals Medical Center, Case Western Reserve University, Cleveland, Ohio, 44106.
authors.forename: Rime
authors.initials: R
authors.lastname: Abbas
authors.forename: Karen S
authors.initials: KS
authors.lastname: McColl
authors.forename: Adam
authors.initials: A
authors.lastname: Kresak
authors.forename: Michael
authors.initials: M
authors.lastname: Yang
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Gary
authors.initials: G
authors.lastname: Wildey
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D012333:RNA, Messenger; D003474:Curcumin
keywords: PIAS3; STAT3; squamous cell lung cancer; survival