miR1/Lnc MALAT1/Circ YLPM1构成ceRNA网络调控14-3-3ζ介导的乳腺癌侵袭转移的机制研究

Recurrence and metastasis are the major cause of breast cancer poor prognosis. It is reported that 14-3-3ζ overexpression will decrease overall survival of breast cancer patients. Our previous studies confirmed that 14-3-3ζ contributed breast cancer cell metastasis. Through bioinformatics prediction and microarray analysis, we got potential ceRNA, lnc-MALAT1 and circ-YLPM1, as well as their competitive miR-1-3p. Overexpression of 14-3-3ζ up-regulated SMAD2 and transcription factors FOXA1, FOXP2, c-myc. Through JASPAR prediction, FOXA1 can combine with the promoter region of lnc-MALAT1 and act as a transcription regulatory factor. We speculate that lnc-MALAT1 and circ-YLPM1 can act as ceRNA regulatory network, combining with miR-1-3p competitively. Then, they activate SMAD2/TGF-β pathway and its downstream transcription factor FOXA1 by adjusting 14-3-3ζ mRNA expression. Also, FOXA1 will contribute lnc-MALAT1 transcription by combining with the promoter region of lnc-MALAT1. This process can affect breast cancer cell proliferation and invasion ultimately. Our research will from a new view of 14-3-3ζ regulatory mechanism and provide theoretical basis.

复发转移是乳腺癌预后不良的主要原因。文献报道，14-3-3ζ过表达的乳腺癌患者生存期显著降低。我们前期研究证实，14-3-3ζ 增强乳腺癌细胞侵袭能力，并筛选出其潜在ceRNA，lnc-MALAT1、circ-YLPM1以及其竞争性结合的miR-1-3p；过表达14-3-3ζ上调SMAD2及TGF-β下游转录因子FOXA1、FOXP2、c-myc；生物信息学分析提示FOXA1可与lnc-MALAT1启动子区域结合。我们推测lnc-MALAT1与circ-YLPM1构成ceRNA调控网络，竞争性结合miR-1-3p，通过调节14-3-3ζ mRNA表达激活Smad2/TGF-β通路及其下游转录因子FOXA1，并且FOXA1可与lnc-MALAT1启动子区域结合，促进MALAT1转录，从而影响乳腺癌细胞侵袭转移。研究结果将为从新视角认识14-3-3ζ表达的调控机制提供理论依据。

乳腺癌一直是威胁全球公共卫生的重要问题，深入探索乳腺癌发生发展的分子机制，寻找复发转移的治疗靶点，是提高生存率的根本途径。本项目阐明MALAT1作为ceRNA通过竞争性结合miR-1-3p调控14-3-3ζ影响乳腺癌发生发展的分子机制。首次发现 lncRNA CTD-2108O9.1 在乳腺癌组织中显著低表达，且其表达水平与淋巴结转移显著相关，深入探索lncRNA CTD-2108O9.1抑制乳腺癌转移的机制，证明了lncRNA CTD-2108O9.1可通过LIFR和EMT相关RNA抑制乳腺癌转移的发生，为揭示乳腺癌发展及侵袭转移的相关机制提供新的思路。本团队筛选出与线粒体生物合成和线粒体代谢功能密切相关的基因线粒体核糖体蛋白MRPL52，证实肿瘤缺氧可诱导MRPL52表达升高，且MRPL52在乳腺癌中具有抗凋亡和促转移的生物学功能。MRPL52通过双向调节细胞内线粒体氧自由基的产生水平，帮助乳腺癌细胞抵抗过度氧化应激造成的细胞凋亡，同时介导氧自由基-Notch1-Snail信号通路的活化，促进乳腺癌的侵袭转移。构建 MRPL52 的小分子拮抗剂可干预上述调控，逆转转移表型，为抗乳腺癌转移提供了新靶点，具有良好的临床转化前景。