miR-5047-PTEN/PI3K/AKT/Slug变异环路介导IGF-I促进乳腺癌细胞肿瘤干性的研究

Cancer stem cells(CSCs) play an important role in tumor recurrence, metastasis and resistance. Our previous study found that the expression levels of a new miR-5047 in tumor spheres of breast cancer cells were significantly up-regulated. Preliminary studies have shown that miR-5047 can directly target tumor suppressor gene PTEN, further activate PI3K / AKT pathway and Slug transcription factor which feedback to induce miR-5047 expression to form a positive feedback loop. In addition, miR-5047 is induced by insulin-like growth factor-I(IGF-I) in breast cancer and may be involved in IGF-I signaling promoting breast cancer epithelial-mesenchymal transition(EMT) and the formation of cancer stem cells. Further we will study on the mechanism that miR-5047 in breast cancer cells can regulate the expression of PTEN / PI3K / AKT / Slug signaling axis to induce the expression of itself, which can be regulated by IGF-I, promote breast cancer EMT and tumor stemness. Further demonstrated that miR-5047 mediates IGF-I to promote breast cancer cell proliferation, metastasis and tumor stemness. Our study firstly reveals miR-5047 as a candidate oncogene, which will provide a new therapeutic target for breast cancer.

肿瘤干细胞在肿瘤复发转移耐药中发挥重要作用。我们前期研究发现一个新的miR-5047在乳腺癌肿瘤球中表达明显上调。初步研究显示，miR-5047可直接靶向抑癌基因PTEN，活化PI3K/AKT通路和Slug转录因子，并反馈诱导其表达，形成变异环路。此外，miR-5047在乳腺癌中被IGF-I通过Slug诱导参与了IGF-I促进乳腺癌上皮间质转化(EMT)及肿瘤干性过程。我们拟对其机制进行深入研究，验证miR-5047在乳腺癌细胞中通过调控PTEN/PI3K/AKT/Slug信号通路反馈诱导其表达形成的变异环路能被IGF-I调控，促进乳腺癌EMT和肿瘤干性特征。进一步证实miR-5047介导IGF-I促进乳腺癌细胞增殖、转移和肿瘤干性。我们的研究将首次确立miR-5047作为候选癌基因，为乳腺癌治疗提供新的靶点。

乳腺癌细胞中存在一群未分化、具有自我更新、多向分化潜能的细胞亚群，称为乳腺癌干细胞。这些细胞具有化疗、放疗及缺氧抵抗性，同时具有高致瘤性、高侵袭转移性，在乳腺癌的耐药、复发、转移中起着极其重要作用。本课题前期在寻找与乳腺癌肿瘤干细胞特性密切相关的miRNAs时，发现miR-5047是其中差异相对更为明显的分子之一，关于miR-5047的相关文献非常之少，其与乳腺癌及肿瘤干细胞的关系亦未见有相关报道。. 我们对miR-5047 在乳腺癌细胞中的功能进行了深入的研究，在细胞水平和动物水平证实miR-5047可以促进乳腺癌细胞的增殖，抑制乳腺癌细胞的凋亡，维持乳腺癌细胞的干性特征。我们进一步探讨miR-5047上游调控的具体机制，证实上游的BACH2/STAT3/p-STAT3信号轴促进了miR-5047的转录，miR-5047通过AKT/p-AKT通路发挥其功能。接着，我们利用乳腺癌组织芯片进行原位杂交染色探究miR-5047在乳腺癌组织中的表达及其与临床特征的关系。发现相较于癌旁组织，miR-5047在癌组织中呈现高表达，高表达miR-5047的乳腺癌患者比低表达miR-5047的乳腺癌患者总生存时间更短，预后更差。我们的研究证实miR-5047为癌基因，为乳腺癌治疗提供了新的靶点。.