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

表皮角质形成细胞细胞周期调控的分子异常及其临床应用

• 批准号: 17591173
• 负责人: KUBO Yoshiaki
• 金额: $ 2.18万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591173/
• 关键词: squamous cell carcinoma; basal cell carcinoma; Bowen's disease; actinic keratosis; seborrheic keratosis; cell cycle; SIRT1; immunohistochemical analysis; p27

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.

为了阐明表皮角质形成细胞细胞周期调控的分子异常以供临床应用，我们研究了皮肤肿瘤中p14、p16、p21、p27和SIRT1的细胞周期调节因子的表达，包括鳞状细胞癌（SCC）、基底细胞癌（BCC）、鲍文氏病（BD）、光化性角化病 （AK）和脂溢性角化病（SK）。 p14、p16、p21 和 p27 的蛋白质产物响应体外应激刺激而负调节细胞周期。 SIRT1 是酵母 Sir2 的哺乳动物同源物，可延长寿命，是一种与细胞周期相关的脱乙酰酶。 SIRT1 通过 p53 和叉头转录因子的脱乙酰化来调节细胞存活，据报道 SIRT1 的过度表达对于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 中 SIRT1 蛋白的表达。 SIRT1 过度表达常见于本研究中的所有非黑色素瘤皮肤癌中。特别是，在所有 BD 病例中均观察到强表达。此外，AK和SCC之间SIRT1的表达没有观察到明显的差异，提示SIRT1的过度表达可能与皮肤癌变的早期阶段有一定的相关性。我们认为 SIRTI 可能是未来治疗的关键靶点之一，旨在抑制非黑色素瘤皮肤癌的细胞增殖并促进细胞凋亡。