title: SCCA1/SERPINB3 promotes oncogenesis and epithelial-mesenchymal transition via the unfolded protein response and IL6 signaling.
abstract: The serine/cysteine protease inhibitor SCCA1 (SERPINB3) is upregulated in many advanced cancers with poor prognosis, but there is limited information about whether it makes functional contributions to malignancy. Here, we show that SCCA1 expression promoted oncogenic transformation and epithelial-mesenchymal transition (EMT) in mammary epithelial cells, and that SCCA1 silencing in breast cancer cells halted their proliferation. SCCA1 overexpression in neu(+) mammary tumors increased the unfolded protein response (UPR), IL6 expression, and inflammatory phenotypes. Mechanistically, SCCA1 induced a prolonged nonlethal increase in the UPR that was sufficient to activate NF-κB and expression of the protumorigenic cytokine IL6. Overall, our findings established that SCCA1 contributes to tumorigenesis by promoting EMT and a UPR-dependent induction of NF-κB and IL6 autocrine signaling that promotes a protumorigenic inflammation.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York.
authors.forename: Namratha
authors.initials: N
authors.lastname: Sheshadri
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Catanzaro
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Bott
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York.
authors.forename: Erica
authors.initials: E
authors.lastname: Ullman
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York.
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York.
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Pan
authors.affiliation: Department of Applied Math and Statistics, Stony Brook University, Stony Brook, New York.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Department of Pathology, University of Alabama, Birmingham VA Medical Center, Birmingham, Alabama.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York. weixing.zong@stonybrook.edu.
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis; D015843:Serpins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D015843:Serpins; C051072:squamous cell carcinoma-related antigen