The multistep process in skin carcinogenesis

皮肤癌发生的多步骤过程

• 批准号: 13670888
• 负责人: KUBO Yoshiaki
• 金额: $ 1.86万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670888/
• 关键词: Keratinocyte; Ras; CDK4; Skin carcinogenesis; Squanus cell carcinoma; Cyclin D1; 有棘細胞癌(SCC)

Normal keratinocytes in human epidermis can convert to Squamous cell carcinoma (SCC) through the multistep process that involves activation of proto-oncogenes. However, the process in SCC is currently unknown. To elucidate the process, we tried keratinocytes. Using high efficiebcy retrovial transductions in primary keratinocytes, we expressed RasV12, P53w248, CDK (Cyclin dependent kinase) 4, and Htert either singly or in combination and used these cells to regenerate human skin on SCID mine. Within 3 weeks Ras-CDK4 produced human skin tumors with histologic features of SCC. Ras-CDK4 tumors, similar to human SCC, express increased levels of Cyclin D1, MMP2, and VEGF. Cyclin D1 was necessary but not sufficient for Ras-CDK4 neoplasia as CDK4-D1 failed to induce tumors while an anti-sense D1 retrovector that suppressed D1 tissue protein expression abolished Ras-CDK4 neoplasia. CDK4 synergy with Ras is dependent on intrinsic CDK4 kinase function as the kinase-dead N158 CDK4 point mutant failed to induce neoplasia when co-expressed with Ras. These data identify Ras and CDK4 as capable of converting normal human epidermal tissue into invasive neoplasia and indicate that functional CDK4-D1 is necessary for this process.

人类表皮中的正常角质形成细胞可以通过涉及原始癌基因激活的多步过程转化为鳞状细胞癌（SCC）。但是，SCC中的过程目前尚不清楚。为了阐明该过程，我们尝试了角质形成细胞。使用原代角质形成细胞中的高效率返回转导，我们表达了RASV12，p53W248，CDK，CDK（细胞周期蛋白依赖性激酶）4和HTERT单独或组合，并使用这些细胞并使用这些细胞来再生Scid矿山上的人类皮肤。在3周内，RAS-CDK4产生了具有SCC的组织学特征的人类皮肤肿瘤。与人类SCC相似的Ras-CDK4肿瘤表达细胞周期蛋白D1，MMP2和VEGF的水平升高。 Cyclin D1是必需的，但对于Ras-CDK4肿瘤是必需的，但由于CDK4-D1无法诱导肿瘤，而抑制D1组织蛋白表达消除Ras-CDK4 Neoplasia的抗敏感性D1逆转录器。与RAS的CDK4协同作用取决于固有的CDK4激酶作为激酶DED N158 CDK4点突变体的功能，当与RAS共表达时，无法诱导肿瘤。这些数据将RAS和CDK4识别为能够将正常的人表皮组织转化为侵入性肿瘤，并表明该过程的功能性CDK4-D1是必不可少的。

项目成果

Dajee M..et al.: "NF-kB blockade and oncogenic Ras trigger invasive human epidermal neoplasia"Nature. 421. 639-643 (2003)

Dajee M..等人：“NF-kB 阻断和致癌 Ras 引发侵袭性人类表皮肿瘤”Nature。

Lazaror,M etal.: "CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis"Nature Medicine. 8-10. 1105-1114 (2002)

Lazaror,Metal.：“CDK4 与 Ras 共表达会导致恶性人类表皮肿瘤发生”《自然医学》。

Dajee M. et al.: "NF-κB blockade and Oncogenic Ras trigger invasive human epidermal neoplasia"Nature. 421. 639-643 (2003)

Dajee M. 等人：“NF-κB 阻断和致癌 Ras 引发侵袭性人类表皮肿瘤”，《自然》，421. 639-643 (2003)。

Dajee,M etal.: "NF-KB blpckade and Oncogenic Ras trigger invasive human epidermal neoplasia"Nature. 421. 639-643 (2003)

Dajee,Metal.：“NF-KB blpckade 和致癌 Ras 引发侵袭性人类表皮肿瘤”Nature。

Lazarov M. et al.: "CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis"Nature Medicine. 8(10). 1105-1114 (2002)

Lazarov M. 等人：“CDK4 与 Ras 共表达会导致恶性人类表皮肿瘤发生”《自然医学》。