miRNA在TSP50诱导的乳腺癌发生中的作用及机制研究

Breast cancer is one of the most frequently diagnosed cancers with high morbidity and mortality, and the mechanisms underlying carcinogenesis of breast cancer remain unclear.TSP50 is oncogene which is highly correlated with initiation of breast cancer. Previous studies have suggested that TSP50 was normally expressed only in human testes. However, it was abnormally activated in 90% breast cancer biopsies. Our recent results indicated that TSP50 could promote tumorigenesis and metastasis by activating NF-κB signaling, indicating that TSP50 played a key role in initiation and development of tumors, so it was very significant to study the regulation mechanisms of TSP50 expression. miRNA is a small non-coding RNA molecule, which can bind to complementary sequences in the 3’ UTR of multiple target mRNAs, usually resulting in gene silencing via translational repression or target degradation. However, whether miRNA is also involved in regulation of TSP50 expression remain unclear. In the present project, we will investigate the effects and mechanisms of the miRNAs in TSP50-induced breast cancer and provide a solid theoretical foundation for diagnosis and treatment of TSP50 associated breast cancer.

乳腺癌是一种发病率和死亡率都非常高的恶性肿瘤，其发生机制目前尚未完全阐明。睾丸特异性蛋白50是一个与乳腺癌发生密切相关的癌基因，其在正常情况下只表达于人的睾丸组织中，但在90%以上的乳腺癌组织中也呈现异常高表达。我们最近的研究表明，TSP50可以通过激活NF-κB信号通路促进肿瘤发生和转移，这些结果表明TSP50在肿瘤的发生和发展中发挥着至关重要的作用，因此深入研究TSP50的表达调控机制具有重要意义。miRNA是一类非编码RNA，通过和靶标mRNA的3’UTR互补结合抑制翻译或使mRNA降解导致基因沉默，其在癌基因的表达调节和肿瘤发生中发挥着重要作用，但是miRNA是否也参与了TSP50的表达调控尚不清楚。本研究拟对调控TSP50表达的miRNA及其在TSP50诱导的乳腺癌发生中的作用和分子机制进行探讨，从而为以TSP50为靶点的乳腺癌诊断和治疗奠定坚实的理论基础。

乳腺癌严重威胁着全世界妇女的身心健康，且其发病呈现出年轻化趋势。乳腺癌是一种多因素诱导的疾病，其中原癌基因的激活以及其异常高表达在乳腺癌的发生中发挥重要作用。已有研究显示，原癌基因TSP50在多种乳腺癌组织中异常高表达，且已被研究证实具有促细胞增殖、迁移及侵袭的作用，但目前对TSP50的表达调控的报道较少。.我们通过生物信息学软件miRBase和Targetscan预测并分析了可能与TSP50 mRNA 3’UTR相结合的6种miRNA。qRT-PCR和Western blot结果显示，miR-490-3p、miR-937-5P和miR-4709-3p均有效抑制了TSP50的表达。我们还在体外检测miR-4709-3p对乳腺癌细胞及乳腺上皮细胞增殖及迁移能力的影响，结果显示，过表达miR-4709-3p模拟物使乳腺癌细胞的增殖和侵袭能力受到抑制，而过表达miR-4709-3p抑制剂则能够促进乳腺上皮细胞增殖和侵袭。另外，体内的研究结果也表明，miR-4709-3p能够使裸鼠肿瘤的体积和重量显著减小，说明miR-4709-3p可以通过靶向TSP50从而抑制乳腺癌细胞的成瘤能力。.最后，我们分析了miR-4709-3p抑制TSP50相关的乳腺癌发生的分子机制。我们发现，在miR-4709-3p诱导的乳腺癌抑制过程中，NF-κB信号通路的抑制和激活素信号通路的激活发挥着关键作用。