Molecular abnormalities of cell cycle regulations in epidermal keratinocytes for the clinical applications

为了阐明表皮角化细胞细胞周期调控的分子异常以用于临床应用，我们研究了细胞周期调控因子p14、p16、p21、p27和SIRT1在皮肤肿瘤中的表达，包括鳞状细胞癌（SCC）、基底细胞癌（BCC）、Bowen病（BD）、光化性角化病（AK）和脂流性角化病（SK）。p14、p16、p21和p27蛋白产物在体外应激刺激下负向调节细胞周期。SIRT1是一种与细胞周期相关的去乙酰化酶，是酵母Sir2的哺乳动物同源物，可以延长寿命。SIRT1通过p53和叉头转录因子的去乙酰化调节细胞存活，据报道SIRT1的过表达对某些癌症的细胞生长和存活至关重要。我们通过免疫组织化学分析检测了20例SCC、BCC、BD、AK和SK的SIRT1蛋白表达。SIRT1过表达在本研究纳入的各种非黑色素瘤皮肤癌中都很常见。尤其在所有BD病例中均有强表达。此外，在AK和SCC中SIRT1的表达无明显差异，提示SIRT1的过表达可能与早期皮肤癌变有关。我们认为SIRTI可能是未来治疗的关键靶点之一，其目的是抑制非黑色素瘤皮肤癌的细胞增殖和促进细胞凋亡。

To elucidate molecular abnormalities of cell cycle regulations in epidermal keratinocytes for the clinical applications, we have investigated expression of cell cycle regulators of p14,p16,p21,p27, and SIRT1 in skin tumors, including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Bowen's disease (BD), actinic keratosis (AK), and seborrheic keratosis (SK). Protein products of p14,p16,p21 and p27 regulate cell cycle negatively in response to stress stimuli in vitro. SIRT1, a mammalian homolog of yeast Sir2 that increases longevity, is a deacetylase associated with cell cycle. SIRT1 regulates cell survival via deacetylation of p53 and forkhead transcription factors, and overexpression of SIRT1 is reported to be essential for cell growth and survival in some kinds of cancer. We have examined SIRT1 protein expression in 20 cases each of SCC, BCC, BD, AK, and SK by immunohistochemical analysis. Overexpression of SIRT1 is frequently observed in all kinds of non-melanoma skin cancers included in this study. In particular, strong expression was observed in all cases of BD. In addition, no obvious difference between AK and SCC was observed in the expression of SIRT1, suggesting that overexpression of SIRT1 may have some relevance to the early stage of skin carcinogenesis. We suppose that SIRTI could be one of the critical targets for future therapy with the aim of inhibiting cell proliferation and promoting apoptosis in non-melanoma skin cancers.