JNCI：科学家鉴别出可增强卵巢癌化疗耐药性反应的生物标志物

  近日，来自德克萨斯大学MD癌症研究中心的研究人员通过研究发现一种可以控制基因表达的特殊分子在控制卵巢癌患者机体化疗耐药性上扮演着重要的角色，相关研究发表于国际杂志Journal of the National Cancer Institute上。
  研究者在文章中鉴别出了一种名为miR-506的非编码“micro”RNA分子，其是上皮卵巢癌化疗的主要临床标志物，同时该分子由于可以使得癌细胞对化疗敏感而成为开发潜在抗癌疗法的靶点；上皮卵巢癌在所有卵巢癌中占到了90%的比例，而卵巢癌在美国是引发女性因妇科癌症死亡的主要原因。
  博士Wei Zhang说道，miR-506和个体对疗法的较好反应、癌症长期无进展及总体生存率直接相关；文章中我们对小鼠模型进行了研究，当将miR-506加入到顺铂和奥拉帕尼化疗药物中我们观察了小鼠机体中系统性的显著提高反应表现，标准的疗法包括外科手术和基于铂的化疗方法，而且患恶性卵巢癌患者的五年平均生存率仅为30%至40%。
  化疗耐药性是目前癌症疗法的主要挑战，本文研究为克服耐药性提供了新的思路，研究者表示，miR-506或许是肿瘤发生过程中上皮细胞间充质转化（EMT）的主要潜在抑制子，而EMT过程和化疗耐药性直接相关；本文研究也为后期阐明miR-506分子通过直接影响癌细胞的DNA修复来放大化疗效应的角色提供新的思路。
  目前研究者发现miR-506分子可以抑制癌细胞的EMT过程，同时该分子也可以调节RAD51蛋白，该蛋白主要参与DNA的修复过程，当RAD51过量表达时，其往往会参与促进化疗耐药性的DNA修复过程中。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

Augmentation of Response to Chemotherapy by microRNA-506 Through Regulation of RAD51 in Serous Ovarian Cancers
JNCI     doi: 10.1093/jnci/djv108
Guoyan Liu, Da Yang*, Rajesha Rupaimoole, Chad V. Pecot*, Yan Sun, Lingegowda S. Mangala, Xia Li, Ping Ji, David Cogdell, Limei Hu, Yingmei Wang, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Ilya Shmulevich, Loris De Cecco, Kexin Chen, Delia Mezzanzanica, Fengxia Xue, Anil K. Sood and Wei Zhang
Background: Chemoresistance is a major challenge in cancer treatment. miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT), which is also associated with chemoresistance. We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers.

Methods: We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents. We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity. All statistical tests were two-sided.

Results: MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P < .0001; TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04). MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51. Systemic delivery of miR-506 in 8–12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36±0.05g vs 0.07±0.02g, P < .001; control miRNA plus olaparib vs miR-506 plus olaparib: 0.32±0.13g vs 0.05±0.02g, P = .045, respectively), thus recapitulating the clinical observation.

Conclusions: MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy.