Disruptive cell cycle regulation involving epigenetic downregulation of Cdkn2a (p16^Ink4a) in early-stage liver tumor-promotion facilitating liver cell regeneration in rats

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• 作者：Takuma Tsuchiya ; Liyun Wang ; Atsunori Yafune ; Masayuki Kimura ; Takumi Ohishi ; Kazuhiko Suzuki ; Kunitoshi Mitsumori ; Makoto Shibutani
• 关键词：BNF ; ¦Â-naphthoflavone ; Cdc2 ; cell division cycle 2 ; Cdc25c ; cell division cycle 25 homolog C (S. pombe) ; Cdk ; cyclin-dependent kinase ; Chk1 ; checkpoint kinase 1 ; CKI ; cyclin-dependent kinase inhibitor ; DEN ; N-diethylnitrosamine ; FB ; fenbendazole ; ¦ÃH2AX
• 刊名：Toxicology
• 出版年：2012
• 出版时间：28 September, 2012
• 年：2012
• 卷：299
• 期：2-3
• 页码：146-154
• 全文大小：1934 K

文摘

Cell cycle aberration was immunohistochemically examined in relation to preneoplastic liver cell foci expressing glutathione S-transferase placental form (GST-P) at early stages of tumor-promotion in rats with thioacetamide (TAA), a hepatocarcinogen facilitating liver cell regeneration. Immunoexpression of p16^Ink4a following exposure to other hepatocarcinogens/promoters and its DNA methylation status were also analyzed during early and late tumor-promotion stages. GST-P⁺ liver cell foci increased cell proliferation and decreased apoptosis when compared with surrounding liver cells. In concordance with GST-P⁺ foci, checkpoint proteins at G₁/S (p21^Cip1, p27^Kip1 and p16^Ink4a) and G₂/M (phospho-checkpoint kinase 1, Cdc25c and phospho-Wee1) were either up- or downregulated. Cellular distribution within GST-P⁺ foci was either increased or decreased with proteins related to G₂-M phase or DNA damage (topoisomerase II¦Á, phospho-histone H2AX, phospho-histone H3 and Cdc2). In particular, p16^Ink4a typically downregulated in GST-P⁺ foci and regenerative nodules at early tumor-promotion stage with hepatocarcinogens facilitating liver cell regeneration and in neoplastic lesions at late tumor-promotion stage with hepatocarcinogens/promoters irrespective of regenerating potential. Hypermethylation at exon 2 of Cdkn2a was detected at both early- and late-stages. Thus, diverse disruptive expression of G₁/S and G₂/M proteins, which allows for clonal selection of GST-P⁺ foci, results in the acquisition of multiple aberrant phenotypes to disrupt checkpoint function. Moreover, increased DNA-damage responses within GST-P⁺ foci may be the signature of genetic alterations. Intraexonic hypermethylation may be responsible for p16^Ink4a-downregulation, which facilitates cell cycle progression in early preneoplastic lesions produced by repeated cell regeneration and late-stage neoplastic lesions irrespective of the carcinogenic mechanism.