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Genes Dev.:恶性黑色素瘤发病机制

来源:生物谷 2007-11-20 09:37

    每个人身上都有大小不等的黑痣,大多数长年不变,但有些也会发展成恶性黑色素瘤(一种皮肤癌)。法国研究人员的一项最新研究揭示了恶性黑色素瘤的发病机制,这项成果发表在最新一期美国《基因与发育》(Gene  and  Development)杂志上。

    黑痣中的黑色素细胞往往在经过初期的分裂增殖后进入衰老期,停止继续分裂。然而经过数年的“休眠”后,某些黑痣中已经衰老的黑色素细胞会重新开始分裂增殖,从而形成癌细胞。

    法国国家科研中心的研究人员对黑色素细胞的分裂机制进行了长期研究。他们发现,导致黑色素细胞“不死”的始作俑者是一种被称为“β-catenin”的蛋白质,它抑制了一种负责控制细胞衰亡的“p16Ink4a”基因的正常表达,从而导致已经衰老的黑色素细胞又重新开始分裂增殖。

    研究人员说,医学界早已发现“β-catenin”蛋白质在皮肤癌细胞分裂中发挥了某种作用,但此前一直没能揭开其导致细胞“不死”的秘密。

    法国国家科研中心11月18日发表公报说,这项研究大大推动了科学界对恶性黑色素瘤发病机制的认识,研究人员正在此基础上加紧研发新型治疗药物和对该病的新疗法。(新华网)

原始出处:

GENES & DEVELOPMENT 21:2923-2935, 2007

β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development

Véronique Delmas1, Friedrich Beermann2,3, Silvia Martinozzi1, Suzanne Carreira4, Julien Ackermann2, Mayuko Kumasaka1, Laurence Denat1, Jane Goodall4, Flavie Luciani1, Amaya Viros5, Nese Demirkan1,6, Boris C. Bastian5, Colin R. Goding4, and Lionel Larue1,7

1 Developmental Genetics of Melanocytes, UMR 146, Centre National de la Recherche Scientifique (CNRS)-Institut Curie, 91405 Orsay Cedex, France; 2 The Swiss Institute for Experimental Cancer Research (ISREC), Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, 1066 Epalinges, Switzerland; 3 Ecole Polytechnique Fédérale de Lausanne (EPFL) School of Sciences, CH-1066 Epalinges, Switzerland; 4 Signalling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, United Kingdom; 5 Department of Dermatology and Department of Pathology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA; 6 Pamukkale Üniversitesi, Tp Fakültesi, Patoloji Anabilim Dal, Knkl-Denizli 20003, Turkey

Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16Ink4a gene. Melanomas also frequently exhibit constitutive activation of the Wnt/-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized -catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized -catenin bypasses the requirement for p16Ink4a mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.

[Keywords: Mitf; Wnt; senescence; development; tumor suppressor; oncogene]]

Received July 23, 2007; revised version accepted September 27, 2007.

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