脂代谢相关基因SREBP1调控乳腺癌进展转移及其机制的研究

Breast cancer has become one of the most common malignant tumors, progression and metastasis were the main causes for the death of breast cancer patients. Abnormal metabolism is one of the hallmarks for tumor cells. Sterol regulatory element-binding protein 1 (SREBP1), an important transcription factor in lipogenesis pathway, connect oncogenic signal with lipogenesis signal for tumor cells. However, little is known about the role of SREBP1 in breast cancer progression and metastasis. Previously, we have found that the expression of SREBP1 in breast cancer tissue samples was significantly correlated with the progression and prognosis of breast cancer, suggesting that SREBP1 was the potential oncogenic factor. To further investigate the role of SREBP1 in breast cancer progression and metastasis, we used the stable breast cancer cell lines which has been knockdown of SREBP1 to clarify the effect of SREBP1 on breast cancer proliferation, apoptosis, invasion, metastasis and lipogenesis both in vitro and in vivo. We will further apply gene microarray to identify the detailed molecular mechanism. In order to evaluate the clinical significance of SREBP1, SREBP1 expression in the normal and malignant breast tissues will also be detected and analyzed. Our work will help elucidate the role of SREBP1 in the progression and metastasis of breast cancer, and also help identify novel targets for the diagnosis and treatment for breast cancer.

乳腺癌已成为最常见的恶性肿瘤之一，进展转移仍是乳腺癌患者死亡的主要原因。代谢异常是肿瘤细胞区别于正常细胞的重要标志，固醇调节元件结合蛋白-1（SREBP1）作为脂质代谢途径中的重要转录因子，可将致癌信号转化为肿瘤脂质代谢信号，但是目前我们对SREBP1在肿瘤进展转移中所起的作用却知之甚少。前期通过乳腺癌临床样本，我们发现SREBP1的表达与乳腺癌进展转移显著相关，提示SREBP1是乳腺癌的潜在致癌因子。为了更深入研究SREBP1在乳腺癌进展转移中的重要作用，本项目拟利用稳定干扰SREBP1的乳腺癌细胞系进行体内外实验，分析SREBP1对乳腺癌细胞增殖凋亡、浸润转移及脂质代谢的影响，并利用基因芯片技术探讨其具体分子机制，并通过检测SREBP1在良恶性乳腺组织中的表达以评价其临床应用价值。此项课题的完成，将有助于阐明SREBP1在乳腺癌进展转移中所起的作用，也将为乳腺癌的诊治提供新的靶点。

乳腺癌是全球女性最常见的恶性肿瘤之一，复发转移是导致乳腺癌患者死亡的主要原因，尤以肺转移发生率最高。近年来，microRNA的出现为肿瘤的研究带来了新的思路，在本项目中我们主要探讨了microRNA对肿瘤进展转移的贡献以及导致其表达改变的调节机制。为找到调控乳腺癌肺转移的microRNA，我们首先构建了乳腺癌肺高转移能细胞亚系，运用microRNA芯片筛选出与肺转移密切相关的miR-17-92簇并进行验证，最终确立了其中下调最为明显的miR-18a-5p作为研究对象。过表达和敲除实验证明了miR-18a-5p具有抑制乳腺癌细胞迁移和侵袭的能力。通过生物信息学综合分析，发现控制脂代谢的主要转录因子固醇调节元件结合转录蛋白1（SREBP1）是miR-18a-5p的候选靶标，这种调节作用通过荧光素酶报告实验得以证实。通过对收集的临床样本进行分析，发现SREBP1高表达与乳腺癌预后不良密切相关。体内和体外实验发现SREBP1促进乳腺癌的生长和转移。为了揭示SREBP1介导的转移的潜在机制，我们将SREBP干扰和对照组的mRNA送芯片并进行基因富集分析（GSEA），发现SREBP1与上皮-间质转化（EMT）显著相关。此外，我们发现SREBP1介导的E-cadherin抑制依赖于去乙酰化，并且通过募集Snail/HDAC1/2阻遏复合物而增强。基于以上数据，我们认为miR-18a-5p的表达降低会导致SREBP1表达升高，进而SREBP1通过促进EMT促进乳腺癌的进展转移。综上所述，我们发现miR-18a-5p和SREBP1在EMT和转移中具有关键作用，希望能够为晚期乳腺癌的针对性治疗提供有希望的药物靶标。