Liu Guoyan, Yang Da, Rupaimoole Rajesha, Pecot Chad V, Sun Yan, Mangala Lingegowda S, Li Xia, Ji Ping, Cogdell David, Hu Limei, Wang Yingmei, Rodriguez-Aguayo Cristian, Lopez-Berestein Gabriel, Shmulevich Ilya, De Cecco Loris, Chen Kexin, Mezzanzanica Delia, Xue Fengxia, Sood Anil K, Zhang Wei
: Departments of Pathology (GL, DY, YS, XL, PJ, DC, LH, WZ), Experimental Therapeutics (CRA, GLB), and Gynecologic Oncology and Reproductive Medicine (RR, LSM, AKS), Division of Cancer Medicine (CVP), Center for RNAi and Non-Coding RNA (RR, CVP, LSM, CRA, GLB, AKS, WZ), the University of Texas MD Anderson Cancer Center, Houston, TX; Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China (GL, YW, FX); Department of Pathology (YS) and Epidemiology (KC), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, the Fourth Military Medical University, Xi'an, China (XL); Institute for Systems Biology, Seattle, WA (IS); Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (LDC, DM).
J Natl Cancer Inst. 2015 May 20;107(7). doi: 10.1093/jnci/djv108. Print 2015 Jul.
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.
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.
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.
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.
化疗耐药是癌症治疗中的一项重大挑战。miR-506是上皮-间质转化（EMT）的有效抑制剂，而EMT也与化疗耐药相关。我们对miR-506在高级别浆液性卵巢癌化疗反应中的作用进行了特征分析。
我们使用Kaplan-Meier法和对数秩检验分析了癌症基因组图谱（TCGA）（n = 468）和巴尼奥利（Bagnoli）（n = 130）数据集中miR-506与无进展生存期和总生存期之间的关系，通过体外实验研究miR-506是否与同源重组以及对化疗药物的反应相关。我们使用原位卵巢癌小鼠模型（每组n = 10）来测试miR-506对顺铂和PARP抑制剂敏感性的影响。所有统计检验均为双侧检验。
在两个独立的上皮性卵巢癌患者队列中，miR-506与更好的治疗反应以及更长的无进展生存期和总生存期相关（无进展生存期：miR-506高表达与低表达；巴尼奥利：风险比[HR] = 3.06，95%置信区间[CI] = 1.90至4.70，P <.0001；TCGA：HR = 1.49，95% CI = 1.00至2.25，P = 0.04）。miR-506通过直接靶向双链DNA损伤修复基因RAD51使细胞对DNA损伤敏感。在8至12周龄雌性无胸腺裸鼠中全身递送miR-506在统计学上显著增强了顺铂和奥拉帕尼的反应（平均肿瘤重量±标准差；对照miRNA加顺铂与miR-506加顺铂：0.36±0.05g对0.07±0.02g，P <.001；对照miRNA加奥拉帕尼与miR-506加奥拉帕尼：0.32±0.13g对0.05±0.02g，P = 0.045），从而重现了临床观察结果。
miR-506是浆液性卵巢癌化疗反应和生存的有力临床标志物，在使癌细胞对化疗敏感方面具有重要的治疗价值。
