Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
Int J Oncol. 2020 Jan;56(1):178-192. doi: 10.3892/ijo.2019.4928. Epub 2019 Dec 2.
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, migration 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 underlying the development and progression of RCC and provide a promising target for microRNA‑based therapy.
越来越多的证据表明，microRNAs 与恶性生物学行为有关，包括肿瘤发生、癌症进展和转移，其通过调节靶基因表达来实现。我们之前的研究表明，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）的靶基因，miR-21 可影响肾细胞癌（RCC）细胞的增殖和转化能力。然而，miR-21 在 RCC 细胞迁移、侵袭和血管生成的分子机制中的作用仍知之甚少。通过体外分析 microRNA-21 的表达调控，研究了 miR-21 对 RCC 细胞侵袭、迁移和血管生成的影响。在搜索了几个数据库后，共有 6 篇文章（共纳入 473 例患者）符合本分析的纳入标准。荟萃分析的综合结果表明，miR-21 表达增加与 RCC 患者的不良预后显著相关，合并风险比估计值为 1.740。在体外实验中，我们证实 miR-21 抑制剂可减少 A498 和 786-O RCC 细胞的迁移和侵袭数量，同时降低 PDCD4、c-Jun、基质金属蛋白酶（MMP）2 和 MMP9 的表达。此外，miR-21 的抑制作用通过影响血管紧张素-1 和血管内皮生长因子 A 的表达，减少内皮细胞系 HMEC-1 的管形成和管结，而 PDCD4 小干扰 RNA 对同一细胞产生相反的作用。总的来说，这些发现以及基于证据的分子生物学表明，miR-21 表达通过直接靶向 PDCD4/c-Jun 信号通路促进 RCC 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 RCC 发生和进展的分子机制，并为基于 microRNA 的治疗提供有希望的靶点。
