乳腺癌相关miRNA及其靶位点多态性研究

Breast cancer is a prevalent carcinoma worldwide. It has been shown that miRNA gene mutation or deregulation of miRNA expression leads to the miRNA-dependent network imbalance, giving the cells malignant phenotypes such as unlimited proliferation, resistance to apoptosis, invasion and metastasis, angiogenesis.Most recently, an increasing body of evidence has demonstrated single nucleotide polymorphism of miRNA genes and its binding sites are closely related to the cancer development. For further deciphering the mechanism of miRNAs in breast cancer from multidimensional perspective, we plan to investigate miRNA founctions and the association between these variants and breast cancer risk, calcification and prognosis systemically based on our previous work. First, we will integrate the in-lab data, the data reported in the literature and the dbSNP database information to establish a polymorphism database of breast cancer-related miRNAs and its binding sites. Then, we will conduct experimental and clinical studies to figure out the functional SNPs which are in the key node of breast cancer molecular regulatory network. Our work is expected to provide new clues to early diagnosis and prognosis of sporadic breast cancer.

乳腺癌是危害妇女身体健康的最普遍的恶性肿瘤之一。业巳表明,miRNA基因突变或者表达失调均可导致以其为核心辐射式的调控网络结构失衡，从而赋予细胞无限增殖、抵抗凋亡、侵袭转移、促血管生成等恶性表型。新近的证据还表明， miRNA基因及其绑定位点上的单核苷酸多态性也与癌症的发生发展密切相关。本研究拟在本室已有工作基础上，系统探讨乳腺癌相关miRNA的功能及其作用靶点多态性与乳腺癌发生、发展和预后的关系, 从多维视角解析这些小分子RNA在乳腺癌中的作用机制。首先我们将整合本实验室研究结果、文献报道的结果和dbSNP数据库信息建立乳腺癌相关miRNA及其靶基因绑定位点多态性数据库；其次根据数据库信息我们将对乳腺癌分子调控网络关键节点基因进行实验研究和临床研究。我们的工作有望为散发性乳腺癌早期诊断和预后判断提供新的线索。

本课题的整体目标是系统探讨乳腺癌相关miRNA的功能及其作用靶点多态性与乳腺癌发生、发展和预后的关系, 从多维视角解析这些小分子RNA在乳腺癌中的作用机制。首先我们已初步完成整合本实验室研究结果、文献报道的结果和dbSNP数据库信息建立乳腺癌相关miRNA及其靶基因绑定位点多态性数据库；其次根据数据库信息我们将对乳腺癌分子调控网络关键节点基因进行实验研究和临床研究，发现了两个miRNA的三个SNP位点的改变与乳腺癌相关（基于目前对100乳腺癌组织250个正常人进行筛选）。并进一步验证了miR-200a新的作用靶标是Nras，miR-487b新的作用靶标是Rab6a。有趣的是我们首次发现Rab6a在乳腺癌细胞系和癌组织中均显著升高。这些研究结果已总结成三篇研究论文待发表。本课题遗憾的是时间仅一年，课题经费有限，无法对备选SNP的基因型分析进行大规模临床样品测序和其它工作。概而言之，在课题组全体同仁的共同努力下，基本完成了课题任务合同规定的任务。