DPPA靶向microRNA-1调控网络抑制乳腺癌增殖作用机制研究

Breast cancer is the most common malignant tumors, which is harmful to women's health. Phospholipid metabolism and microRNA play an important role in tumor development. Dipalmitoyl phosphatidic acid (DPPA), a part of common phospholipids, produced by phospholipase D 1 through the hydrolysis of phosphatidylcholine. DPPA can regulates the cell growth and proliferation via the activation of PKC signal transduction pathway. We first indicated that DPPA was decreased in genetically engineered mouse models for breast cancer (MMTV-PyMT). However, the function of DPPA in the development of breast cancer is still unknown. Our results showed that overexpression of DPPA was significantly reduce tumor volume and growth in breast cancer xenograft model and MMTV-PyMT mice. Meanwhile, we also found that overexpression of DPPA can up-regulated the expression of miR-1 in the tumor tissue of MMTV-PyMT mice, and bioinformatics analysis predicts that some proliferation-related genes are the potential directly targets of miR-1. However, DPPA whether inhibits the proliferation of breast cancer through reglated miR-1 network? We will clarify the molecular mechanism of DPPA in the inhibition of breast cancer growth through tumor cells and transgenic mice. This study will combined metabolomics and RNomics analysis for provide the basis for investigate the new target for the treatment of breast cancer.

乳腺癌是威胁女性健康的恶性肿瘤之一。磷脂代谢与microRNA均可以调控肿瘤的发生、发展。二棕榈酰磷脂酸 (DPPA) 是磷脂类物质，由相应的磷脂酰胆碱经磷脂酶D1催化水解产生，介导PKC信号转导通路，参与细胞生长、增殖等过程的调控。我们首次发现自发乳腺癌小鼠（MMTV-PyMT）DPPA含量减少，其在乳腺癌发生、发展中的作用尚无报道；研究发现对乳腺癌移植瘤及MMTV-PyMT小鼠补充DPPA，肿瘤体积和细胞增殖显著抑制；进一步发现DPPA能够诱导MMTV-PyMT小鼠肿瘤组织中miR-1表达上调；并且生物信息学分析表明，与增殖相关的一些基因可能是miR-1直接作用的靶基因。那么，DPPA是否通过调节miR-1调控网络抑制乳腺癌肿瘤增殖？我们将在细胞及转基因动物模型中明确DPPA抑制乳腺癌肿瘤增殖的作用机制。本研究将代谢组学与RNA组学研究方法结合，为乳腺癌治疗新靶点提供科学依据。

乳腺癌是最常见的恶性肿瘤之一，近年来我国女性乳腺癌的发病率呈上升趋势，发病年龄有年轻化趋势。乳腺癌目前已成为一种严重威胁女性身心健康甚至危及生命的常见的恶性肿瘤。磷脂代谢物可以调控肿瘤的发生、发展。二棕榈酰磷脂酸 (DPPA) 是磷脂类物质，由相应的磷脂酰胆碱经磷脂酶D1（PLD1）催化水解产生，介导PKC信号转导通路，参与细胞生长、增殖等过程的调控。然而DPPA代谢途径对乳腺癌发生发展作用机制尚不清楚。通过本项目研究发现调控水解反应产生DPPA的PLD1表达受转录因子C/EBP β调控，随病理进程加重逐渐降低；并且其代谢产物DPPA对HER2-,ER+,PR+和三阴性乳腺癌自发肿瘤及移植瘤模型小鼠肿瘤体积和重量有显著抑制作用；进一步发现DPPA能够诱导HER2-,ER+,PR+的MCF-7细胞miR-133a表达上调；并且生物信息学分析表明，LASP1基因是其直接作用的靶基因，对三阴性乳腺癌细胞MDA-MB-231研究发现，DPPA可以通过下调CCNB1的表达将细胞周期阻滞在G2/M期。本研究通过深入探讨DPPA抑制乳腺癌增殖的分子作用机制，为乳腺癌治疗新靶点和抗乳腺癌药物开发提供理论依据。