miR-342 overexpression results in a synthetic lethal phenotype in BRCA1-mutant HCC1937 breast cancer cells.
miR-342 overexpression results in a synthetic lethal phenotype in BRCA1-mutant HCC1937 breast cancer cells.
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DOI：
10.18632/oncotarget.7617
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发表时间：
2016-04-05
期刊：
影响因子：
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通讯作者：
Gariboldi M
中科院分区：
文献类型：
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作者：
Crippa E;Folini M;Pennati M;Zaffaroni N;Pierotti MA;Gariboldi M
miR-342的表达与乳腺癌中的雌激素受体（ER）状态密切相关，其中在ER阳性肿瘤中最高，在三阴性肿瘤中最低。我们研究了miR-342转染在三阴性乳腺癌细胞系MDA-MB-231和HCC 1937中的作用，后者携带生殖系BRCA 1突变。miR-342的重组仅在HCC 1937细胞中导致半胱天冬酶依赖性的凋亡诱导，而野生型BRCA 1在HCC 1937细胞中的过表达抵消了miR-342介导的凋亡诱导，表明miR-342过表达和功能性BRCA 1的缺乏导致合成致死表型。此外，siRNA介导的BRCA 1在表达野生型蛋白的MDA-MB-231细胞中的耗竭导致miR-342转染后的细胞凋亡。使用计算机模拟方法和荧光素酶报告系统，我们鉴定并功能验证了杆状病毒IAP重复序列6基因（BIRC 6），该基因编码抗凋亡因子Apollon/布鲁斯，作为miR-342的靶标。在我们的模型中，BIRC 6可能是BRCA 1突变型HCC 1937细胞中miRNA依赖性诱导凋亡的决定因素。总之，我们的研究结果表明，miR-342的肿瘤抑制功能可以用于治疗BRCA 1突变遗传性乳腺癌的一个子集。
Expression of miR-342 has been strongly correlated with estrogen receptor (ER) status in breast cancer, where it is highest in ER-positive and lowest in triple-negative tumors. We investigated the effects of miR-342 transfection in the triple-negative breast cancer cell lines MDA-MB-231 and HCC1937, the latter carrying a germ-line BRCA1 mutation. Reconstitution of miR-342 led to caspase-dependent induction of apoptosis only in HCC1937 cells, while overexpression of wild-type BRCA1 in HCC1937 cells counteracted miR-342-mediated induction of apoptosis, suggesting that miR-342 overexpression and the lack of functional BRCA1 result in a synthetic lethal phenotype. Moreover, siRNA-mediated depletion of BRCA1 in MDA-MB-231 cells expressing the wild-type protein led to apoptosis upon transfection with miR-342. Using an in silico approach and a luciferase reporter system, we identified and functionally validated the Baculoviral IAP repeat-containing 6 gene (BIRC6), which encodes the anti-apoptotic factor Apollon/BRUCE, as a target of miR-342. In our model, BIRC6 likely acts as a determinant of the miRNA-dependent induction of apoptosis in BRCA1-mutant HCC1937 cells. Together, our findings suggest a tumor-suppressive function of miR-342 that could be exploited in the treatment of a subset of BRCA1-mutant hereditary breast cancers.