The mechanism of CIRP in inhibition of keratinocytes growth arrest and apoptosis following low dose UVB radiation

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.

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