Aberrant microRNA expression in radiation-induced rat mammary cancer: the potential role of miR-194 overexpression in cancer cell proliferation.

Aberrant expression of microRNAs (miRNAs) is frequently associated with a variety of cancers, including breast cancer. We and others have demonstrated that radiation-induced rat mammary cancer exhibits a characteristic gene expression profile and a random increase in aberrant DNA copy number; however, the role of aberrant miRNA expression is unclear. We performed a microarray analysis of frozen samples of eight mammary cancers induced by gamma-irradiation (2 Gy), eight spontaneous mammary cancers, and seven normal mammary samples. We found that a small set of miRNAs was characteristically overexpressed in radiation-induced cancer. Quantitative RT-PCR analysis confirmed that miR-135b, miR-192, miR-194, and miR-211 were significantly upregulated in radiation-induced mammary cancer compared with spontaneous cancer and normal mammary tissue. The expression of miR-192 and miR-194 also was upregulated in human breast cancer cell lines compared with non-cancer cells. Manipulation of the miR-194 expression level using a synthetic inhibiting RNA produced a small but significant suppression of cell proliferation and upregulation in the expression of several genes that are suggested to act as tumor suppressors in MCF-7 and T47D breast cancer cells. Thus, the induction of rat mammary cancer by radiation involves aberrant expression of miRNAs, which may favor cell proliferation.微小核糖核酸（microRNAs, miRNAs）的异常表达常与包括乳腺癌在内的多种癌症密切相关。本课题组与其他研究团队已证实，辐射诱导的大鼠乳腺癌具有特征性的基因表达谱，且伴随DNA拷贝数异常的随机增多，但异常miRNA表达所发挥的具体作用仍不明确。我们对8例经2 Gy γ射线照射诱导的大鼠乳腺癌冷冻样本、8例自发性大鼠乳腺癌冷冻样本以及7例正常乳腺组织样本开展了微阵列分析。结果显示，一小部分miRNA在辐射诱导的乳腺癌中呈现特征性高表达模式。实时定量逆转录聚合酶链反应（quantitative RT-PCR）验证结果表明，相较于自发性乳腺癌与正常乳腺组织，miR-135b、miR-192、miR-194及miR-211在辐射诱导的大鼠乳腺癌中显著上调。进一步研究发现，与非癌细胞相比，人乳腺癌细胞系中miR-192与miR-194的表达同样存在上调。通过合成抑制RNA调控miR-194的表达水平，可轻微但显著地抑制MCF-7与T47D乳腺癌细胞的增殖，并上调若干被认为可在乳腺癌中发挥肿瘤抑制因子作用的基因的表达。综上，辐射诱导大鼠乳腺癌的过程涉及miRNA的异常表达，这类异常表达可能会促进肿瘤细胞的增殖。