PARP inhibitor increases chemosensitivity by upregulating miR-664b-5p in BRCA1-mutated triple-negative breast cancer.
PARP inhibitor increases chemosensitivity by upregulating miR-664b-5p in BRCA1-mutated triple-negative breast cancer.
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PARP 抑制剂通过上调 BRCA1 突变三阴性乳腺癌中的 miR-664b-5p 来增加化疗敏感性。
DOI：
10.1038/srep42319
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发表时间：
2017-02-08
影响因子：
4.6
通讯作者：
Guan X
中科院分区：
文献类型：
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作者：
Song W;Tang L;Xu Y;Xu J;Zhang W;Xie H;Wang S;Guan X
新出现的证据表明，在BRCA 1突变的三阴性乳腺癌（TNBC）患者中，在化疗方案中添加聚（ADP-核糖）聚合酶（PARP）抑制剂上级优于单独的对照方案，但其潜在机制尚未完全阐明。在这项研究中，使用两种BRCA 1突变的TNBC细胞系的miRNA微阵列分析，我们发现在卡铂（CBP）加吉西他滨（GEM）治疗方案中加入PARP抑制剂奥拉帕尼后，miR-664 b-5 p表达增加。功能分析显示miR-664 b-5 p过表达抑制BRCA 1突变的TNBC细胞的增殖、迁移和侵袭。CCNE 2被鉴定为miR-664 b-5 p的新的功能靶点，并且CCNE 2敲除揭示了与miR-664 b-5 p过表达所观察到的效应相似的效应。CCNE 2敲低和miR-664 b-5 p过表达均显著增加BRCA 1突变TNBC细胞的化疗敏感性。此外，体内研究表明，与肿瘤异种移植模型中的对照相比，miR-664 b-5 p抑制肿瘤生长，并且我们还发现，在90个TNBC患者样本中，CCNE 2表达与miR-664 b-5 p表达呈负相关。总之，miR-664 b-5 p作为肿瘤抑制因子发挥作用，并在PARP抑制剂的调节中发挥重要作用，通过靶向CCNE 2来增加化疗敏感性。这可能是PARP抑制剂增加BRCA 1突变TNBC化疗敏感性的可能机制之一。
Emerging evidence has shown that adding poly(ADP-ribose) polymerase (PARP) inhibitors to chemotherapy regimens is superior to the control regimens alone in BRCA1-mutated triple-negative breast cancer (TNBC) patients, but their underlying mechanisms have not been fully elucidated. In this study, using miRNA microarray analysis of two BRCA1-mutated TNBC cell lines, we found that miR-664b-5p expression was increased after adding a PARP inhibitor, olaparib, to a carboplatin (CBP) plus gemcitabine (GEM) therapy regimen. Functional assays showed miR-664b-5p overexpression inhibited proliferation, migration and invasion in BRCA1-mutated TNBC cells. CCNE2 was identified as a novel functional target of miR-664b-5p, and CCNE2 knockdown revealed effects similar to those observed with miR-664b-5p overexpression. Both CCNE2 knockdown and miR-664b-5p overexpression significantly increased the chemosensitivity of BRCA1-mutated TNBC cells. In addition, in vivo studies indicated that miR-664b-5p inhibited tumour growth compared with the control in tumour xenograft models, and we also found that CCNE2 expression was inversely correlated with miR-664b-5p expression in 90 TNBC patient samples. In conclusion, miR-664b-5p functions as a tumour suppressor and has an important role in the regulation of PARP inhibitors to increase chemosensitivity by targeting CCNE2. This may be one of the possible mechanisms by which PARP inhibitors increase chemosensitivity in BRCA1-mutated TNBC.