TYRO3-mediated regulation of MITF: a novel target in melanoma?
TYRO3-mediated regulation of MITF: a novel target in melanoma?
复制标题
TYRO3 介导的 MITF 调节：黑色素瘤的新靶点？
DOI：
10.1111/j.1755-148x.2009.00649.x
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发表时间：
2010
影响因子：
4.3
通讯作者：
Samuels,Yardena
中科院分区：
文献类型：
--
作者：
Rudloff,Udo;Samuels,Yardena
虽然黑色素瘤的早期阶段可以通过适当的手术治愈，但转移性黑色素瘤的患者预后很差。目前使用的任何细胞毒性或生物疗法都没有令人信服地证明可以提高总存活率，欧洲癌症研究和治疗组织(欧洲癌症研究和治疗组织)18991大型随机第三阶段试验的最新结果再次证实了这一经验(埃格蒙特等人，2008年)。越来越多的无效但往往剧毒的治疗方法，以及分子靶向药物的不断成功和添加，使人们对恶性黑色素瘤的基因和通路导向靶向治疗的类似进展寄予厚望。小黑色素瘤相关转录因子(MITF)被认为是激活恶性黑色素瘤致癌生存和增殖信号的主要“枢纽”。MITF激活对正常色素细胞生理、黑素细胞存活、细胞周期调节和生长至关重要的多个下游调节因子，包括促进黑素细胞存活的原癌基因Bcl-2、衰老抑制因子TBX2、c-Met和CDK2，所有这些都参与了与生长相关的信号转导。MITF在黑色素瘤的发生和发展中也发挥着核心作用，无论是通过重新激活早期发育途径，还是通过致癌信号激活导致继发性调节失调。MITF的过度表达与BRAFV600突变一起导致黑素细胞的恶性转化，而MITF活性的降低使黑色素瘤细胞对化疗药物敏感(Garraway等人，2005年)。染色体3p上的MITF基因座在10-20%的黑色素瘤中被扩增，这种基因改变在良性痣中未见。转移性肿瘤中扩增的发生率是原发灶的两倍，并且与较差的预后有关。此外，20%的转移性黑色素瘤和14%的原发肿瘤在黑色素瘤形成过程中MITF途径存在体细胞突变，改变MITF功能(Cronin等人，2009年)。
While the early stages of melanoma are eminently curable with adequate surgery, patients with metastatic melanoma have a dismal prognosis. None of the currently administered cytotoxic or biological therapies have convincingly been shown to improve overall survival, an experience again re-affirmed by the latest results of the large, randomized phase III trial 18991 of the European Organization for Research and Treatment of Cancer (EORTC)(Eggermont et al., 2008). This growing number of ineffective, but often highly toxic, treatment modalities and the emerging success and addition of molecular targeted agents to the treatment armentarium of other cancers has raised great expectations for similar progress in genotype-and pathway-directed targeted therapy in malignant melanoma.Microphtalmia-associated transcription factor (MITF) is known to be a major ‘hub’for the activation of oncogenic survival and proliferation signaling in malignant melanoma. MITF activates multiple downstream mediators critical for normal pigment cell physiology, melanocyte survival, cell cycle regulation, and growth including proto-oncogene Bcl-2, which enhances melanocyte survival, TBX2, a suppressor of senescence, c-met and CDK2, all involved in growth-related signal transduction. MITF also plays a central role in the development and progression of melanoma, either through re-activation of early developmental pathways or dysregulation secondary due to oncogenic signal activation. Overexpression of MITF in conjunction with BRAFV600 mutations leads to malignant transformation of melanocytes, and reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents (Garraway et al., 2005). The MITF locus on chromosome 3p is amplified in 10–20% of melanoma, a genetic alteration not seen in benign nevi. Amplifications occured twice as common in metastatic tumor compared to primary lesions, and are associated with a poorer prognosis. Furthermore, 20% of metastatic melanoma and 14% of primary tumors harbor somatic mutations in the MITF pathway altering MITF function during melanomagenesis (Cronin et al., 2009).