MicroRNA-21 contributes to renal cell carcinoma cell invasiveness and angiogenesis via the PDCD4/c-Jun (AP-1) signalling pathway
MicroRNA-21 contributes to renal cell carcinoma cell invasiveness and angiogenesis via the PDCD4/c-Jun (AP-1) signalling pathway
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MicroRNA-21 通过 PDCD4/c-Jun (AP-1) 信号通路促进肾细胞癌细胞侵袭和血管生成
DOI：
10.3892/ijo.2019.4928
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发表时间：
2020-01-01
影响因子：
5.2
通讯作者：
Li, Xiancheng
中科院分区：
文献类型：
--
作者：
Fan, Bo;Jin, Yiying;Li, Xiancheng
越来越多的证据表明，microRNAs通过调控靶基因的表达与肿瘤的发生、发展和转移等恶性生物学行为有关。我们以前的研究表明，程序性细胞死亡蛋白4(PDCD4)是一种肿瘤抑制基因，是microRNA-21(miR-21)的靶点，影响肾细胞癌(RCC)细胞的增殖和转化能力。然而，miR-21在肾癌迁移、侵袭和血管生成的分子机制中的作用仍然知之甚少。通过Meta分析和体外对miR-21表达的调节，观察miR-21对肾癌细胞侵袭、迁移和血管生成的影响。在搜索了几个数据库后，6篇文章，包括总共473名患者，符合这项分析的资格标准。Meta分析的综合结果显示，miR-21表达增加与肾癌患者的不良预后显著相关，合并风险比估计为1.740。在体外实验中，我们发现miR-21抑制剂减少了A498和786-O肾癌细胞的迁移和侵袭数量，并减少了PDCD4、c-jun、基质金属蛋白酶(MMP2)和MMP9的表达。此外，抑制miR-21通过影响血管紧张素-1和血管内皮生长因子A的表达来减少血管内皮细胞系HMEC-1的管状形成和管状连接，而PDCD4小干扰RNA对同一细胞具有相反的作用。总体而言，这些发现与循证分子生物学相结合，表明miR-21的表达通过直接靶向PDCD4/c-Jun信号通路促进了肾癌细胞的迁移、侵袭和血管生成能力。这些结果可能有助于阐明肾癌发生发展的分子机制，并为以microRNA为基础的治疗提供一个有前途的靶点。
Accumulating evidence has demonstrated that microRNAs are associated with malignant biological behaviour, including tumorigenesis, cancer progression and metastasis via the regulation of target gene expression. Our previous study demonstrated that programmed cell death protein 4 (PDCD4), which is a tumour suppressor gene, is a target of microRNA-21 (miR-21), which affects the proliferation and transformation capabilities of renal cell carcinoma (RCC) cells. However, the role of miR-21 in the molecular mechanism underlying the migration, invasion and angiogenesis of RCC remains poorly understood. The effects of miR-21 on the invasion, migra tion and angiogenesis of RCC cells was determined through meta-analysis and regulation of miR-21 expression in vitro. After searching several databases, 6 articles including a total of 473 patients met the eligibility criteria for this analysis. The combined results of the meta-analysis revealed that increased miR-21 expression was significantly associated with adverse prognosis in patients with RCC, with a pooled hazard ratio estimate of 1.740. In in vitro experiments, we demonstrated that a miR-21 inhibitor decreased the number of migrating and invading A498 and 786-O RCC cells, along with a decrease in PDCD4, c-Jun, matrix metalloproteinase (MMP)2 and MMP9 expression. Additionally, inhibition of miR-21 was revealed to reduce tube formation and tube junctions in the endothelial cell line HMEC-1 by affecting the expression of angiotensin-1 and vascular endothelial growth factor A, whereas PDCD4 small interfering RNA exerted opposite effects on the same cells. Overall, these findings, along with evidence-based molecular biology, demonstrated that miR-21 expression promoted the migration, invasion and angiogenic abilities of RCC cells by directly targeting the PDCD4/c-Jun signalling pathway. The results may help elucidate the molecular mechanism under lying the development and progression of RCC and provide a promising target for microRNA-based therapy.