miR-93-5p targets Smad7 to regulate the transforming growth factor-β1/Smad3 pathway and mediate fibrosis in drug-resistant prolactinoma
miR-93-5p targets Smad7 to regulate the transforming growth factor-β1/Smad3 pathway and mediate fibrosis in drug-resistant prolactinoma
复制标题
miR-93-5p靶向Smad7调节转化生长因子-β1/Smad3通路并介导耐药催乳素瘤的纤维化
DOI：
10.1016/j.brainresbull.2019.03.013
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发表时间：
2019-07-01
影响因子：
3.8
通讯作者：
Wang, Haijun
中科院分区：
文献类型：
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作者：
Hu, Bin;Mao, Zhigang;Wang, Haijun
催乳素瘤是垂体瘤的一种常见亚型。多巴胺受体激动剂是催乳素瘤的首选治疗方法；然而，这种治疗方法经常会产生耐药性。在我们以前的工作中，我们发现部分耐药的催乳素瘤表现出纤维化的增加，并且转化生长因子-β1/Smad3信号通路介导了纤维化并参与了耐药。此外，众所周知，手术的成功在很大程度上受垂体腺瘤的一致性影响。因此，在本研究中，我们旨在阐明催乳素瘤纤维化的机制。使用高通量测序分析microRNAs，我们发现miR-93-5p在高度纤维化的催乳素瘤标本中显著上调，而在无纤维化的标本中则显著上调。此外，我们还发现miR-93-5p与临床催乳素瘤中Smad7的相对表达呈负相关，与转化生长因子-β1的相对表达呈正相关。此外，荧光素酶报告分析显示，miR-93-5p可以下调转化生长因子-β1/Smad3信号通路的重要抑制物Smad7基因，并在前馈循环中激活转化生长因子-β1/Smad3信号介导的纤维化。此外，miR-93-5p可通过调节依赖于转化生长因子-β1/Smad3的纤维化来增强催乳素瘤细胞的耐药性。综上所述，我们的研究结果表明miR-93-5p可能是抑制催乳素瘤细胞纤维化和降低耐药性的潜在治疗靶点。
Prolactinoma is a common subtype of pituitary tumors. Dopamine receptor agonists are the preferred treatment for prolactinoma; however, with this therapy, drug resistance often occurs. In our previous work, we found that partial resistant prolactinomas showed increased fibrosis and that the transforming growth factor (TGF)-beta 1/Smad3 signaling pathway mediated fibrosis and was involved in drug resistance. Additionally, the success of surgery is known to be heavily influenced by the consistency of the pituitary adenoma. Therefore, in this study, we aimed to clarify the mechanisms of fibrosis in prolactinoma. Using high-throughput sequencing for analysis of microRNAs, we found that miR-93-5p was significantly upregulated in prolactinoma samples with a high degree of fibrosis compared with that in samples without fibrosis. Furthermore, we found that miR-93-5p was negatively correlated with the relative expression of Smad7 and positively correlated with the relative expression of TGF-beta 1 in clinical prolactinoma samples. In addition, luciferase reporter assays showed that miR-93-5p could downregulate the Smad7 gene, an important inhibitor of the TGF-beta 1/Smad3 signaling pathway, and activate TGF-beta 1/Smad3 signaling-mediated fibrosis in a feed-forward loop. Moreover, miR-93-5p could enhance the drug resistance of prolactinoma cells by regulation of TGF-beta 1/Smad3-dependent fibrosis. Taken together, our findings demonstrated that miR-93-5p may be a potential therapeutic target for inhibiting fibrosis and reducing drug resistance in prolactinoma cells.