Hwang Hun-Way, Baxter Laura L, Loftus Stacie K, Cronin Julia C, Trivedi Niraj S, Borate Bhavesh, Pavan William J
Genetic Disease Research Branch, Department of Health and Human Services, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Pigment Cell Melanoma Res. 2014 Sep;27(5):777-87. doi: 10.1111/pcmr.12255. Epub 2014 May 27.
The complex genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, including transcripts regulated by either transforming growth factor, beta 1 (TGFβ1) pathways, or microphthalmia-associated transcription factor (MITF)/SRY-box containing gene 10 (SOX10) pathways. We extended this knowledge by discovering that melanoma cell lines with these two expression programs exhibit distinctive microRNA (miRNA) expression patterns. We also demonstrated that hypoxia-inducible factor 1 alpha (HIF1A) is increased in TGFβ1 pathway-expressing melanoma cells and that HIF1A upregulates miR-210, miR-218, miR-224, and miR-452. Reduced expression of these four miRNAs in TGFβ1 pathway-expressing melanoma cells arrests the cell cycle, while their overexpression in mouse melanoma cells increases the expression of the hypoxic response gene Bnip3. Taken together, these data suggest that HIF1A may regulate some of the gene expression and biological behavior of TGFβ1 pathway-expressing melanoma cells, in part via alterations in these four miRNAs.
为开发新的有效治疗方法，需要解读转移性黑色素瘤潜在的复杂基因变化。此前，对人类黑色素瘤进行的全基因组微阵列分析确定了两个相互的基因表达程序，包括由转化生长因子β1（TGFβ1）途径或小眼相关转录因子（MITF）/含SRY盒基因10（SOX10）途径调控的转录本。我们通过发现具有这两种表达程序的黑色素瘤细胞系表现出独特的微小RNA（miRNA）表达模式，扩展了这方面的知识。我们还证明，缺氧诱导因子1α（HIF1A）在表达TGFβ1途径的黑色素瘤细胞中增加，并且HIF1A上调miR-210、miR-218、miR-224和miR-452。在表达TGFβ1途径的黑色素瘤细胞中，这四种miRNA的表达降低会使细胞周期停滞，而在小鼠黑色素瘤细胞中过表达这些miRNA会增加缺氧反应基因Bnip3的表达。综上所述，这些数据表明，HIF1A可能部分通过这四种miRNA的改变来调节表达TGFβ1途径的黑色素瘤细胞的一些基因表达和生物学行为。
