Genetic analysis and preliminary function study of miR-423 in breast cancer
Genetic analysis and preliminary function study of miR-423 in breast cancer
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miR-423在乳腺癌中的遗传分析及初步功能研究
DOI：
10.1007/s13277-015-3126-7
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发表时间：
2015-06-01
期刊：
影响因子：
--
通讯作者：
Zhu, Zhengmao
中科院分区：
文献类型：
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作者：
Zhao, Huanhuan;Gao, Ang;Zhu, Zhengmao
microRNA（miRNA）基因中常见的遗传变异（单核苷酸多态性SNPs）可能会改变其成熟或表达，并在人类癌症的形成中发挥作用。最近，在不同的人群和一系列癌症中，经常评估pre-miR-423中SNP rs6505162与癌症风险之间的关联。在本研究中，我们在5个匹配的细胞系中测定了SNP rs6505162的基因型（乳腺癌细胞系及其相应的外周血细胞系）和114例匹配的临床标本（临床乳腺癌标本及其相应的正常组织），比较了pri-miRNA与pre-miR-423- 12 C之间成熟形式的加工效率（野生型）和pre-miR-423- 12 A（突变型）表达载体，并评估miR-423对细胞增殖的功能。我们的数据显示，五分之二的乳腺癌细胞系和8.77%（10/114）的肿瘤发生了rs6505162 SNP的体细胞突变，体细胞突变状态与临床病理变量、增殖细胞核抗原（PCNA）和突变型p53的表达显著相关。pre-miR-423- 12 C SNP阻断了pri-miR-423向其两个成熟miRNA的内源加工。有趣的是，所选的pre-miR-423- 12 C稳定细胞群具有比pre-miR-423- 12 A稳定细胞群更低的增殖能力。此外，miR-423通过其miR-423- 3 p链而不是miR-423- 5 p促进乳腺癌细胞系中的细胞增殖。综上所述，这些结果表明，前体miR-423中的SNP rs6505162影响成熟miR的表达，并且miR-423在乳腺肿瘤发生中发挥潜在的致癌作用。
Common genetic variants (single nucleotide polymorphisms SNPs) in microRNA (miRNA) genes may alter their maturation or expression and play a role in the formation of human cancer. Recently, the association between the SNP rs6505162 in pre-miR-423 and cancer risk has been frequently evaluated in diverse populations and in a range of cancers. In this study, we determined the genotypes of SNP rs6505162 in 5 matched cell lines (breast cancer cell lines and their corresponding peripheral blood cell lines) and 114 matched clinical specimens (clinical breast carcinoma specimens and their corresponding normal tissues), compared the processing efficiency of pri-miRNA to mature forms between pre-miR-423-12C (wild-type) and pre-miR-423-12A (mutant-type) expression vectors, and evaluated the function of miR-423 on cell proliferation. Our data showed that two out of five breast cancer cell lines and 8.77 % (10/114) of tumors underwent somatic mutations of the rs6505162 SNP, and somatic mutation state was significantly correlated with the expression of clinicopathologic variables, proliferating cell nuclear antigen (PCNA) and mutant p53. The pre-miR-423-12C SNP blocked the endogenous processing of pri-miR-423 to its two mature miRNAs. Interestingly, selected pre-miR-423-12C stable cell population had lower proliferation ability than pre-miR-423-12A stable cell population. Moreover, miR-423 promoted cell proliferation in breast cancer cell lines through its miR-423-3p strand, not miR-423-5p. Taken together, these results suggest that the SNP rs6505162 in pre-miR-423 affects the mature miR expression, and miR-423 plays a potentially oncogenic role in breast tumorigenesis.