超保守非编码RNA uc.243诱导卵巢癌顺铂耐药的分子机制

Ultraconserved regions (UCRs), a novel class of noncoding RNAs that are highly conserved among the orthologous regions in most vertebrates, have been demonstrated to play important roles in numerous biological processes via modulation of ncRNA-ncRNA network. However, the clinical significance and mechanism of dysregulated ucRNAs in development and progression of cancer remain largely unknown. Recently, we identified an ucRNA, uc.243, was significantly upregulated in chemoresistant ovarian cancer, and positively associated with ovarian cancer recurrence. Furthermore, integrating the results obtained from bioinformatic analysis and biological experiments showed that (1) uc.243 directly associated with pri-miR-155 and prevented cleavage of pri-miR-155 form Drosha, resulting in platinum efflux form ovarian cancer; (2) uc.243 decreased expression of miR-129-5p, resulting in increased capability of damaged DNA repair; (3) uc.243 directly interacted with NF-κB p65 and promoted association of NF-κB p65 with promoters of multiple anti-apoptotic genes. These results suggest that uc.243 might be a key factor in chemoresistance of ovarian cancer. Hence, in the current project, by employing in vivo and in vitro systems combined with clinical samples, we are further investigate the mechanisms of uc.243-induced chemoresistance of ovarian cancer, which could provide a new target for tumor diagnosis and treatment.

新近证明超保守非编码RNA(ucRNA)通过ncRNA-ncRNA网络互作调控而发挥着重要的生物学功能。然而在ucRNA在肿瘤发展发展中临床意义、功能及机制仍不清楚。前期我们采用人源性肿瘤组织异种移植(PDX)小鼠模型，发现一个未知功能的超保守非编码RNA uc.243在耐药卵巢癌组织中表达显著增高并与卵巢癌复发密切相关。进一步生物学实验及生物信息学分析显示：①uc.243直接结合并抑制pri-miR-155剪切而促进卵巢癌细胞对顺铂药物的泵出；②uc.243通过负调控miR-129-5p成熟体的表达而增强卵巢癌细胞对顺铂诱导的DNA损伤的修复能力；③.uc.243与NF-κB p65转录因子直接结合而特异性上调多个抗凋亡基因，从而促进卵巢癌对顺铂的耐受。本项目将承前启后，采用体内体外系统并与临床相结合，深层次解析uc.243在卵巢癌顺铂耐药中的调控作用机制，为卵巢癌诊治提供新的靶位点。

以非编码RNA(ncRNA)调控肿瘤微环境为研究切入点，不仅为肿瘤发生发展增添新的理论依据，还为肿瘤治疗药物的研发提供重要的靶位点。①我们发现RNA结合蛋白RBMS3可通过抑制miR-126-5p所激活的WNT/β-catenin信号通路而促进肿瘤对化疗药物顺铂的敏感性(Clin Cancer Res. 2019；通讯作者)。②我们研究报道用WDR5-MLL相互作用的小分子拮抗剂ORIC-9429小分子抑制β-catenin/JDP2/PRMT5复合物而导致在遗传毒性剂治疗的癌细胞中已经升高的ROS水平的致死性增加，揭示了JDP2在癌症中诱导性化疗耐药的作用(Nat Commun. 2019；通讯作者)。③我们证明沉默Sall2诱导ERα和PTEN的下调，激活Akt/mTOR信号，导致ERα阳性乳腺癌中雌激素依赖性生长和他莫昔芬耐药性。这些结果揭示了SALL2对ERα的调节机制，并提供了一种乳腺癌患者进行分类的标志物(EMBO Mol Med, 2019；共同通讯作者）。④. 我们证明DNA损伤可促进TRIM37入核单泛素化NEMO蛋白而DNA损伤激活的NF-B信号通路，并揭示了食管癌化疗耐药的分子机制 (Cancer Res. 2018;通讯作者)。⑤ 我们研究显示TRIM3可泛素化降解Impotin α3及ACTN4上调，进而维持了肿瘤NF-B炎性通路的持续性 (Oncogene；2019;通讯作者)。⑥. 我们发现HOXC10可促进PRMT5/WDR5复合物在VEGFA启动子上结合并上调VEGFA的表达，为肿瘤抗血管生成治疗的潜在靶点 (Theranostics. 2018;通讯作者)。项目完成期间，共发表(共同)通讯作者文章11篇，11篇> 5分，其中3篇 > 10分。获得授权专利4项，培养博士生5名。