title: The mechanism of CIRP in inhibition of keratinocytes growth arrest and apoptosis following low dose UVB radiation.
abstract: UV induces CIRP expression and subsequent Stat3 activation, but the biological function and mechanism of CIRP and Stat3 in mediating UVB-induced skin carcinogenesis have not been fully elucidated. In this study, we demonstrate that CIRP is elevated in all tested melanoma and non-melanoma skin cancer cell lines; and the expression of CIRP is upregulated in keratinocytes after being irradiated with relatively low dose (<5 mJ/cm2), but not high dose (50 mJ/cm2), UVB acutely and chronically. The increased expression of CIRP, either induced by UVB or through overexpression, leads to resistance of keratinocytes to UVB-induced growth arrest and death; and reduced expression of CIRP by RNA knockdown sensitizes keratinocyte cells to the low dose UVB radiation. We also demonstrated that CIRP expression is required for the low dose UVB-induced Tyr705-phosphorylation, but not total amount, of Stat3. The p-Stat3 level is correlated with the expression levels of cyclin D1 and VEGF, two known downstream cell growth regulators of Stat3, as well as Bag-1/S, an apoptosis regulator. Inhibition of Stat3 DNA-binding activity by S3I-201 leads to a reduction of the p-Stat3 and Bag-1/S along with growth and survival of keratinocytes post-UVB; and the effect of S3I-201 on the UVB-irradiated cells can be partially inhibited by overexpression of CIRP or Bag-1/S. Furthermore, the overexpression of Bag-1/S can totally inhibit UVB-induced PARP cleavage and caspase 3 activation. The results presented above led us to propose that CIRP-p(705)Stat3 cascade promotes cell proliferation and survival post-UVB via upregulating the expression of cyclin D1 and Bag-1/S, respectively. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.|Department of Chemistry and Biochemistry, 101 Konneker Laboratories, Edison Biotechnology Institute, Athens, Ohio.|Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.|Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Feng
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Liling
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Chemistry and Biochemistry, 101 Konneker Laboratories, Edison Biotechnology Institute, Athens, Ohio.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: C091732:BCL2-associated athanogene 1 protein; C491390:CIRBP protein, human; D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors
keywords: Bag-1/S; CIRP; Stat3; UVB irradiation; cell survival