Miller Arlo J, Du Jinyan, Rowan Sheldon, Hershey Christine L, Widlund Hans R, Fisher David E
Dana-Farber Cancer Institute and Children's Hospital, Department of Pediatric Hematology/Oncology, Boston, Massachusetts, USA.
Cancer Res. 2004 Jan 15;64(2):509-16. doi: 10.1158/0008-5472.can-03-2440.
Determining the metastatic potential of intermediate thickness lesions remains a major challenge in the management of melanoma. Clinical studies have demonstrated that expression of melastatin/TRPM1 strongly predicts nonmetastatic propensity and correlates with improved outcome, leading to a national cooperative prospective study, which is ongoing currently. Similarly, the melanocytic markers MLANA/MART1 and MITF also have been shown to lose relative expression during melanoma progression. Recent studies have revealed that MITF, an essential transcription factor for melanocyte development, directly regulates expression of MLANA. This prompted examination of whether MITF also might transcriptionally regulate TRPM1 expression. The TRPM1 promoter contains multiple MITF consensus binding elements that were seen by chromatin immunoprecipitation to be occupied by endogenous MITF within melanoma cells. Endogenous TRPM1 expression responded strongly to MITF up- or down-regulation, as did TRPM1 promoter-driven reporters. In addition, MITF and TRPM1 mRNA levels were correlated tightly across a series of human melanoma cell lines. Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation. These studies identify MITF as a major transcriptional regulator of TRPM1 and suggest that its prognostic value may be linked to MITF-mediated regulation of cellular differentiation.
确定中等厚度病变的转移潜能仍然是黑色素瘤治疗中的一项重大挑战。临床研究表明，褪黑素/瞬时受体电位阳离子通道亚家族M成员1（TRPM1）的表达强烈预示着非转移倾向，并与改善的预后相关，从而引发了一项正在进行的全国性合作前瞻性研究。同样，黑素细胞标志物黑素瘤抗原（MLANA）/黑色素瘤相关抗原（MART1）和小眼畸形相关转录因子（MITF）在黑色素瘤进展过程中也显示出相对表达的丧失。最近的研究表明，MITF是黑素细胞发育所必需的转录因子，可直接调节MLANA的表达。这促使人们研究MITF是否也可能转录调节TRPM1的表达。TRPM1启动子包含多个MITF共有结合元件，通过染色质免疫沉淀发现这些元件在黑色素瘤细胞内被内源性MITF占据。内源性TRPM1的表达对MITF的上调或下调有强烈反应，TRPM1启动子驱动的报告基因也是如此。此外，在一系列人类黑色素瘤细胞系中，MITF和TRPM1的mRNA水平紧密相关。MITF纯合突变的小鼠显示TRPM1表达显著降低。最后，与其他MITF靶基因相比，MITF诱导TRPM1的斜率特别陡峭，这表明它是MITF表达以及相应黑素细胞分化的敏感指标。这些研究确定MITF是TRPM1的主要转录调节因子，并表明其预后价值可能与MITF介导的细胞分化调节有关。
