The online version of this article (doi:10.1186/s13048-017-0321-8) contains supplementary material, which is available to authorized users.
Resistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment. The human let-7 family contains 13 members located on nine different chromosomes, and most members have been implicated in the modulation of drug sensitivity in cancers. Our previous study showed that deregulation of let-7e in epithelial ovarian cancer (EOC) promoted the development of resistance to cisplatin. In the present study, we aimed to investigate the underlying mechanism and further evaluate the clinical value of let-7e in predicting chemo-response and prognosis in EOC.
In situ hybridization assays revealed a significantly decreased expression of let-7e in chemo-resistant EOC tissues compared with chemo-sensitive cases. Transfection with let-7e agomir sensitized EOC cells to cisplatin, down-regulated BRCA1 and Rad51 expression, and repressed the repair of cisplatin-induced DNA double strand break, while let-7e inhibitor exerted the opposite effects. In human EOC tissues, BRCA1 and Rad51 levels were increased in the chemo-resistant group compared with the sensitive group and were negatively correlated with let-7e. Low let-7e and high Rad51 were significantly associated with poor progression-free survival and overall survival and multivariate regression analyses showed that let-7e was an independent predictor for overall survival and chemotherapy response in EOC. Receiver operating characteristic analysis indicated that let-7e level was highly predictive of resistance to platinum-taxane chemotherapy with an area under the curve of 0.826.
In EOC, low let-7e leads to activation of BRCA1 and Rad51 expression and subsequent enhancement of DSB repair, which in turn results in cisplatin-resistance. Let-7e is a potential predictor for survival and chemo-response in EOC and re-expression of let-7e might be an effective strategy for overcoming chemo-resistance.
Additional file 1: Table S1. The sequences of PCR primers used in this study. (DOCX 13 kb)13048_2017_321_MOESM1_ESM.docx
Additional file 2: Figure S1. Influence of let-7e inhibitor on the mRNA levels of RFX6, CASP3, MMP9 and EZH2. Student’s t-test, *P < 0.05, **P < 0.01, ***P < 0.001. Figure S2. qRT-PCR analysis of let-7e expression in SKOV3 cells after transfection with let-7e inhibitor. Student’s t-test, *** P < 0.001. Figure S3. Associations of Rad51 and BRCA1 expression with prognosis of ovarian cancer patients in publically available datasets. (DOCX 202 kb)13048_2017_321_MOESM2_ESM.docx
Cavallo F, Graziani G, Antinozzi C, Feldman DR, Houldsworth J, Bosl GJ, et al. Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to Cisplatin and poly (adp-ribose) polymerase inhibition. PLoS One. 2012;7(12):e51563. CrossRefPubMedPubMedCentral
Sharbati J, Lewin A, Kutz-Lohroff B, Kamal E, Einspanier R, Sharbati S. Integrated microRNA-mRNA-analysis of human monocyte derived macrophages upon Mycobacterium avium subsp. hominissuis infection. PLoS One. 2011;6(5):e20258.
Ventayol M, Vinas JL, Sola A, Jung M, Brune B, Pi F, et al. miRNA let-7e targeting MMP9 is involved in adiposederived stem cell differentiation toward epithelia. Cell Death Dis. 2014;5:e1048.
Liu G, Yang D, Rupaimoole R, Pecot CV, Sun Y, Mangala LS, et al. Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers. J Natl Cancer Inst. 2015;107(7):djv108.
Tian N, Han Z, Li Z, Zhou M, Fan C. Lin28/let-7/Bcl-xL pathway: the underlying mechanism of drug resistance in Hep3B cells. Oncol Rep. 2014;32(3):1050–6. PubMed
- Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair
- BioMed Central
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