Shen Jie, Ambrosone Christine B, Zhao Hua
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Int J Cancer. 2009 Mar 1;124(5):1178-82. doi: 10.1002/ijc.24008.
MicroRNA (miRNA) plays an important role in tumorigenesis, but whether miRNA is a cancer predisposition factor or not is still unknown. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis, we screened genetic variants in 17 selected miRNA genes, which are predicted to regulate key breast cancer genes, in 42 patients with familial breast cancer. Seven novel genetic variants were observed in 7 primary or precursor miRNA genes. Among them, 1 rare variant in the precursor of miR-30c-1 and 1 rare variant in the primary precursor of miR-17 were only observed in noncarriers of BRCA1/2 mutations. In functional assays, these 2 variants resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-30c-1 and miR-17. In the target in vitro assay, we observed that miR-17 could bind to the 3'UTR of BRCA1 mRNAs, which is predicted to be a target for miR-17. Our findings suggest that functional genetic variants in miRNA genes can potentially alter the regulation of key breast cancer genes. Whether they confer genetic susceptibility to breast cancer remains to be determined.
微小RNA（miRNA）在肿瘤发生过程中发挥着重要作用，但miRNA是否为癌症易感因素仍不清楚。鉴于miRNA可调控多个肿瘤抑制基因（TSG）和癌基因，miRNA基因的遗传变异可能会影响TSG或癌基因的表达水平，进而影响癌症风险。为验证这一假设，我们在42例家族性乳腺癌患者中筛选了17个选定的miRNA基因中的遗传变异，这些基因被预测可调控关键的乳腺癌基因。在7个初级或前体miRNA基因中观察到7个新的遗传变异。其中，仅在BRCA1/2突变非携带者中观察到1个位于miR-30c-1前体的罕见变异和1个位于miR-17初级前体的罕见变异。在功能试验中，这2个变异导致预测二级结构发生构象变化，从而改变了成熟miR-30c-1和miR-17的表达。在体外靶标试验中，我们观察到miR-17可与BRCA1 mRNA的3'UTR结合，该区域被预测为miR-17的靶标。我们的研究结果表明，miRNA基因中的功能性遗传变异可能会潜在地改变关键乳腺癌基因的调控。它们是否赋予乳腺癌遗传易感性仍有待确定。
