PinX1 represses renal cancer angiogenesis via the mir-125a-3p/VEGF signaling pathway
PinX1 represses renal cancer angiogenesis via the mir-125a-3p/VEGF signaling pathway
复制标题
PinX1 通过 mir-125a-3p/VEGF 信号通路抑制肾癌血管生成
DOI：
10.1007/s10456-019-09675-z
复制
发表时间：
2019-11-01
期刊：
影响因子：
9.8
通讯作者：
Bai, Jin
中科院分区：
文献类型：
--
作者：
Hou, Pingfu;Li, Hailong;Bai, Jin
研究背景：PIN 2/TRF 1相互作用的端粒酶抑制因子1（PinX 1）是多种肿瘤的抑癌基因。然而，PinX 1在癌症发展和进展中作用的分子机制仍不清楚。本研究旨在揭示PinX 1在肾细胞癌（renal cell carcinoma，RCC）发生发展中的新的分子机制和作用。采用染色质免疫沉淀和荧光素酶报告基因分析方法，探讨PinX 1调控mir 125 - 3 p的分子机制。采用组织芯片原位杂交技术检测肾癌组织中mir-125 a-3 p的表达。采用卡方检验分析mir-125 a-3 p表达水平与临床病理特征的相关性。结果本研究发现PinX 1通过转录激活mir-125 a-3 p的表达，从而抑制mir-125 a-3 p靶基因血管内皮生长因子（VEGF）的表达，这是PinX 1在肾细胞癌血管生成中的一种新的分子机制。PinX 1还通过增加肾癌中mir-125 a-3 p的表达来抑制肿瘤血管生成。结论PinX 1通过mir-125 a-3 p/VEGF信号通路抑制肾癌血管生成。miR-125 a-3 p可能是肾细胞癌的一个候选临床预后标志物和一个新的治疗靶点。
Background PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) is a tumor suppressor in various tumors. However, the molecular mechanism underlying PinX1's role in cancer development and progression remains unclear. In this study, we aimed to uncover the new molecular mechanism and role of PinX1 in renal cell carcinoma (RCC) progression.Methods We used miRNA microarray to detect the different expressed miRNAs upon PinX1 knockdown. Chromatin immunoprecipitation and Luciferase reporter assays were taken to identify the molecular mechanism of PinX1 in regulating mir125-3p. In situ hybridization was performed to analyze the expression of mir-125a-3p in RCC using tissue microarray. The correlations between the mir-125a-3p expression level and clinicopathological features were evaluated using the chi(2) test. The role and molecular mechanism of PinX1 in RCC angiogenesis were investigated through a series of in vitro and in vivo experiments.Results In this study, we discovered a new molecular mechanism of PinX1, in which PinX1 transcriptionally activated mir-125a-3p expression, thereby inhibiting the expression of vascular endothelial growth factor (VEGF), which is the target gene of mir-125a-3p. PinX1 also repressed tumor angiogenesis by increasing the mir-125a-3p expression in renal cancer. Moreover, the loss of mir-125a-3p expression was manifested in patients with RCC, and low miR-125a-3p levels correlated with poor survival of these patients.Conclusions PinX1 represses renal cancer angiogenesis through mir-125a-3p/VEGF signal pathway. The miR-125a-3p may be a candidate clinical prognostic marker and a novel therapeutic target in RCC.