超保守非编码RNA uc.243诱导卵巢癌顺铂耐药的分子机制

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。

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.