Dicer1重编程肿瘤间质介导卵巢癌侵袭的机制探讨

The Cancer Genome Atlas (TCGA) project of epithelial ovarian cancer (EOC) has revealed that the ‘mesenchymal’ cluster represents the poorest outcome, indicating a crucial role of stromal cancer-associated fibroblasts (CAFs) in EOC progression. The cancer-promoting ability of CAFs is dependent on their activation; however, this process has not been fully explored. The search of underlying regulators driving CAFs activation means a lot to the interpretation of the ‘mesenchymal’ phenotype and development of targeted intervention. Dicer1 acts as the processing machinery of microRNAs (miRs) in organism, and dysregulation of Dicer1 will leads to the perturbance of cellular miRs and their targeted mRNAs. In ovarian cancer, we found that Dicer1 was specifically overexpressed in tumor stroma through analyzing tumor stromal profiles and patient specimens, which was strikingly variant from previous recognition that Dicer1 was down-regulated in tumor cells. Furthermore, GSEA (Gene Set Enrichment Assay) analysis confirmed that Dicer1 expression was notably positively correlated with gene signatures representative of stromal CAFs activation and disease prognosis. In this study, we will investigate the exertion of Dicer1 on CAFs activation, analyze the regulatory mechanism of Dicer1 on the reprogramming of miRs and effector mRNAs, and explore the feasibility of targeting Dicer1 and its regulatory network to target tumor stroma. This study will try to reveal the effect of Dicer1 regulation on stromal CAFs activation and supporting of tumor evolution, and provide new target for stroma-oriented intervention of ovarian cancer.

人类癌症基因组图谱计划（TCGA）研究表明“间质”型卵巢癌患者预后最差，提示肿瘤相关成纤维细胞（CAFs）在肿瘤进展中作用关键。CAFs对肿瘤的支持依赖于其活化，而具体机制未知，故而寻找调控CAFs活化的机制对认识“间质”表型和靶向干预意义重大。Dicer1作为调控miRs的关键酶，其表达失调会引起大量miRs和靶基因表达异常。在卵巢癌中，不同于以往报道在肿瘤细胞中低表达，我们在间质芯片和临床标本中均发现Dicer1特异在肿瘤间质高表达。GSEA分析间质芯片发现Dicer1与CAFs活化和间质预后相关功能集显著正相关。本项目将着重探讨Dicer1对卵巢癌间质CAFs的活化，分析Dicer1重编程miRs及CAFs活性分子的调控机制，探讨Dicer1调控网络作为靶向肿瘤间质靶点的可行性。本研究可揭示Dicer1在调控CAFs活化及支持肿瘤进展中的作用，可为卵巢癌靶向肿瘤间质治疗提供新的靶点。

卵巢癌是妇科恶性肿瘤患者死亡的主要原因。随着对基因组学认识的提高，卵巢癌被分成了组织学和分子生物学上定义的不同亚型别。卵巢癌分子分析大数据显示，肿瘤间质活化的亚型患者预后最差，这强调了肿瘤微环境，尤其是间质成纤维细胞在卵巢癌进展中的重要性。成纤维细胞向肿瘤相关成纤维细胞的转化及其持续性激活对支持肿瘤生长至关重要。此外，成纤维细胞的激活与基质炎症和促肿瘤炎性细胞的聚集有关，而后者是癌症的一个重要标志事件。在卵巢癌治疗中，针对间质成纤维细胞和炎症介质的研究正得到越来越多的关注。这些成功的尝试表明，同时干扰基质激活和炎症在阻碍卵巢癌转移方面有很大的希望。. 在我们的研究中，发现Dicer在肿瘤间质中反常高表达，并与间质激活相关。Dicer的下调阻碍了成纤维细胞的活化，减少了间质炎症和成纤维细胞在支持异种移植瘤生长中的作用。Dicer在间质成纤维细胞中通过NFκB信号通路调控炎症相关基因簇表达。进一步研究表明miR6780b介导了Dicer对NFκB通路和下游的炎症基因族的调控。我们的数据表明Dicer1在肿瘤间质中显著的促进肿瘤生长的作用,确定了Dicer-miR6780b-NFκB轴在卵巢癌发生和展过程中的重要性,提示该通路可能成为遏制卵巢癌进展的潜在的治疗目标。. Dicer既往在卵巢癌上皮细胞中被鉴定为抑癌基因。在此，我们补充性的描述了Dicer的新作用:维持活性肿瘤间质和间质炎症。我们的研究表明在间质成纤维细胞中, Dicer正向调控NFκB信号通路活化对成纤维细胞的持续性活化和炎症细胞浸润至关重要。进一步我们发现mir-6780 b是介导Dicer调控NFκB信号的关键miR。这些发现进一步加深了我们对Dicer在卵巢癌进展中的作用的理解，并为靶向肿瘤间质提供了替代治疗方案。我们的工作确定了间质细胞中Dicer一种新的作用，这种作用与其在肿瘤细胞中调节EMT和卵巢癌耐药方面的作用不同，但具有很强的互补性。我们的研究表明,Dicer-miR6780b-NFκB信号通路是一个有效的靶向卵巢癌肿瘤间质的治疗靶点。