Regulation of RUNX3 tumor suppressor gene expression in cutaneous melanoma.
Regulation of RUNX3 tumor suppressor gene expression in cutaneous melanoma.
复制标题
皮肤黑色素瘤中 RUNX3 抑癌基因表达的调节。
DOI：
10.1158/1078-0432.ccr-08-3172
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发表时间：
2009-05-01
期刊：
影响因子：
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通讯作者：
Hoon DS
中科院分区：
文献类型：
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作者：
Kitago M;Martinez SR;Nakamura T;Sim MS;Hoon DS
RUNX 3是已知的几种癌中的肿瘤抑制基因。RUNX 3表达的异常尚未在皮肤黑色素瘤中描述。因此，我们评估了RUNX 3在皮肤黑色素瘤中的表达及其与肿瘤进展相关的调节机制。在黑色素瘤细胞系以及原发性和转移性黑色素瘤肿瘤中评估了RUNX 3 mRNA和miR-532- 5 p（microRNA）的表达。与正常黑素细胞相比，11/11（100%）转移性黑色素瘤细胞系中RUNX 3 mRNA表达下调（P < 0.001）。在123例原发性和转移性黑色素瘤肿瘤和12例正常皮肤样本中，与正常皮肤（n = 12）相比，RUNX 3表达在原发性黑色素瘤（n = 82; P = 0.02）和黑色素瘤转移（n = 41; P < 0.0001）中显著下调。这表明RUNX 3下调可能在黑色素瘤的发生和进展中起作用。使用甲基化特异性PCR评估RUNX 3启动子区域超甲基化作为RUNX 3表达的可能调节因子。RUNX 3启动子区域甲基化的评估显示，17个黑色素瘤株中只有5个（29%）、52个原发性黑色素瘤中只有2个（4%）和30个转移性黑色素瘤中只有5个（17%）具有启动子区域的超甲基化。一种微小RNA（miR-532- 5 p）被鉴定为RUNX 3 mRNA序列的靶标。miR-532- 5 p的表达在黑色素瘤细胞系和转移性黑色素瘤中分别相对于正常黑色素细胞和原发性黑色素瘤显著上调。为了研究RUNX 3和miR-532- 5 p之间的关系，将anti-miR-532- 5 p转染到黑素瘤细胞系中。抑制miR-532- 5 p可上调RUNX 3 mRNA和蛋白表达。RUNX 3在黑色素瘤进展过程中下调，miR-532- 5 p是RUNX 3表达的调节因子。
RUNX3 is a known tumor suppressor gene in several carcinomas. Aberration in RUNX3 expression has not been described for cutaneous melanoma. Therefore, we assessed the expression of RUNX3 in cutaneous melanoma andits regulatory mechanisms relative to tumor progression. The expression of RUNX3 mRNA and miR-532-5p (microRNA) was assessed in melanoma lines and in primary and metastatic melanoma tumors. RUNX3 mRNA expression was down-regulated in 11 of 11 (100%) metastatic melanoma lines relative to normal melanocytes (P < 0.001). Among 123 primary and metastatic melanoma tumors and 12 normal skin samples, RUNX3 expression was significantly down-regulated in primary melanomas (n = 82; P = 0.02) and in melanoma metastasis (n = 41; P < 0.0001) versus normal skin (n = 12). This suggested that RUNX3 down-regulation may play a role in the development and progression of melanoma. RUNX3 promoter region hypermethylation was assessed as a possible regulator of RUNX3 expression using methylation-specific PCR. Assessment of RUNX3 promoter region methylation showed that only 5 of 17 (29%) melanoma lines, 2 of 52 (4%) primary melanomas, and 5 of 30 (17%) metastatic melanomas had hypermethylation of the promoter region. A microRNA (miR-532-5p) was identified as a target of RUNX3 mRNA sequences. miR-532-5p expression was shown to be significantly up-regulated in melanoma lines and metastatic melanoma tumors relative to normal melanocytes and primary melanomas, respectively. To investigate the relation between RUNX3 and miR-532-5p, anti − miR-532-5p was transfected into melanoma lines. Inhibition of miR-532-5p up-regulated both RUNX3 mRNA and protein expression. RUNX3 is down-regulated during melanoma progression and miR-532-5p is a regulatory factor of RUNX3 expression.