线粒体分子伴侣mortalin表达调控机制探讨

Our previous studies showed mitochondrial chaperone mortalin, as a potential therapeutic target, involved in tumorigenesis, invasion and drug resistance in ovarian cancer. However, the regulation of mortalin expression is not very clear. Transcription factors and microRNAs are two largest families of trans-acting factors, which can co-regulate the same target genes expression. Transcription factors, microRNAs and target genes contribute to the complex regulatory netmork, including feed-forward loop, involve in various biological processes of carcinoma. Through bioinformatics analysis and previous studies, we found the possible transcriotion factors (NF-κB、HIF-1α) and microRNAs (miR200b/c、miR-217), which may target and regulate mortalin expression. The aim of this study is to confirm the relationship between the transcription factors and the microRNAs with mortalin, and elucidate the co-regulatory mechanism of mortalin by transcription factors and microRNAs in ovarian cancer. And we hope all the results can provide a theoretical basis for finding and designing the drugs or compounds which can inhibit mortalin.

申请人先前的研究表明线粒体分子伴侣mortalin与卵巢癌发生、发展及侵袭、耐药有关，可作为卵巢癌治疗和逆转耐药的潜在靶点。然而mortalin表达调控机制尚不清楚。转录因子和microRNA是两大类反式作用因子家族，可以共调控同一靶基因。转录因子、microRNA 和靶基因组成的包括前馈环在内的多种作用模式构成了复杂的基因调控网络，影响肿瘤的各种生物学行为。申请人通过一系列生物信息学分析及前期实验探讨，结合相关文献，筛选出可能直接调控mortalin的转录因子（NF-κB、HIF-1α）和microRNA （miR200b/c、miR-217）。本课题拟证实在卵巢癌耐药过程中上述转录因子和microRNA与mortalin的直接调控关系，并阐明它们共调控mortalin的作用模式，从而为寻找和合成下调mortalin表达的药物或小分子化合物提供理论依据和研究基础。

线粒体分子伴侣mortalin与多种肿瘤的发生、发展及侵袭、耐药相关，可以作为肿瘤治疗的潜在靶点。然而国内外的研究鲜见有关mortalin基因表达调控的报道。本课题通过体内、外系列实验阐明了在转录水平，转录因子NF-κB p65能通过直接结合并调控mortalin表达影响卵巢癌细胞的增殖和迁移；在转录后水平，miR-200b/c通过与mortalin的3’UTR区域直接结合，抑制mortalin的表达，进而调控卵巢癌细胞的增殖和迁移；miR200c能通过抑制mortalin增加卵巢癌细胞对顺铂的敏感性；且在卵巢癌细胞中NF-κB p65、 miR-200b/c和mortalin存在前馈环的网络基序，即NF-κB p65和miR-200b/c共调控mortalin的同时，NF-κB p65又靶向调控miR-200b/c的编码基因。在不同的肿瘤中，mortalin可能存在不同的调控方式，本课题还发现在翻译后水平，TRAF2可以通过TRAF-N结构域泛素化mortalin，进而影响外周T细胞淋巴瘤的增殖与耐药。除了影响肿瘤细胞本身，mortalin也可以通过影响肿瘤微环境参与肿瘤的转移，研究发现高血糖可在巨核细胞中通过转录因子MYC显著上调mortalin的表达，进而通过影响血小板的产生促进肿瘤转移。至此，本课题首次阐明了转录水平、转录后水平和翻译后水平mortalin的表达调控机制，为寻找和合成靶向mortalin表达的药物或小分子化合物提供了理论依据和研究基础。