Enforced expression of hsa |
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Enforced expression of hsa
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Epigenetic gene inactivation by microRNAs (miRNAs) plays a key role in malignant transformation, prevention of apoptosis, drug resistance and metastasis. It has been shown that miR-125a is down-regulated in HER2-amplified and HER2-overexpressing breast cancers (BCa), and this miRNA is believed to serve as an important tumor suppressor. miR-125a has two mature forms: hsa-miR-125a-3p and hsa-miR-125a-5p. However, the functional details of these miRNAs in BCa, particularly during pathogenesis of drug resistance, remain largely unexplored. Herein, we reported that hsa-miR-125a-3p expression was significantly reduced in chemoresistant BCa tissues and in experimentally established chemoresistant BCa cells. hsa-miR-125a-3p knockdown promoted cell proliferation and compromised docetaxel (Dox)-induced cell death, whereas overexpression of hsa-miR-125a-3p attenuated Dox chemoresistance in BCa cells. From a mechanistic standpoint, hsa-miR-125a-3p directly targeted 3'-untranslated regions (3'-UTRs) of breast cancer early onset gene 1 (BRCA1) and inhibits its protein expression via translational repression mechanism. In addition, suppression of BRCA1 expression by siRNA treatment effectively improved hsa-miR-125a-3p deficiency-triggered chemoresistance in BCa cells. Collectively, these findings suggest that hsa-miR-125a-3p may function as a tumor suppressor by regulating the BRCA1 signaling, and reintroduction of hsa-miR-125a-3p analogs could be a potential adjunct therapy for advanced/chemoresistant BCa.
中文翻译：
microRNA（miRNA）使表观遗传基因失活在恶性转化，预防细胞凋亡，耐药性和转移中起着关键作用。已经显示，miR-125a在HER2扩增和HER2过表达的乳腺癌（BCa）中被下调，并且该miRNA被认为是重要的肿瘤抑制因子。miR-125a具有两种成熟形式：hsa-miR-125a-3p和hsa-miR-125a-5p。然而，这些miRNA在BCa中的功能细节，特别是在耐药性发病机理中，仍未得到很好的探讨。在本文中，我们报道了hsa-miR-125a-3p表达在耐化学性BCa组织和实验建立的耐化学性BCa细胞中显着降低。hsa-miR-125a-3p敲低可促进细胞增殖，并损害多西他赛（Dox）诱导的细胞死亡，而过表达的hsa-miR-125a-3p减弱了BCa细胞的Dox化学耐药性。从机理的角度来看，hsa-miR-125a-3p直接靶向乳腺癌早期发病基因1（BRCA1）的3'-非翻译区（3'-UTR），并通过翻译抑制机制抑制其蛋白质表达。另外，通过siRNA处理抑制BRCA1表达可有效改善BCa细胞中hsa-miR-125a-3p缺乏触发的化学耐药性。总的来说，这些发现表明，hsa-miR-125a-3p可能通过调节BRCA1信号传导而起抑癌作用，而重新引入hsa-miR-125a-3p类似物可能是晚期/耐化学性BCa的潜在辅助疗法。-UTRs）是乳腺癌的早发基因1（BRCA1），并通过翻译抑制机制抑制其蛋白表达。另外，通过siRNA处理抑制BRCA1表达可有效改善BCa细胞中hsa-miR-125a-3p缺乏触发的化学耐药性。总的来说，这些发现表明，hsa-miR-125a-3p可能通过调节BRCA1信号传导而起抑癌作用，而重新引入hsa-miR-125a-3p类似物可能是晚期/耐化学性BCa的潜在辅助疗法。-UTRs）是乳腺癌的早发基因1（BRCA1），并通过翻译抑制机制抑制其蛋白表达。另外，通过siRNA处理抑制BRCA1表达可有效改善BCa细胞中hsa-miR-125a-3p缺乏触发的化学耐药性。总的来说，这些发现表明，hsa-miR-125a-3p可能通过调节BRCA1信号传导而起抑癌作用，而重新引入hsa-miR-125a-3p类似物可能是晚期/耐化学性BCa的潜在辅助疗法。 |
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