G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS-MAPK axis pathway
G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS-MAPK axis pathway
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G6PD 通过 ROS-MAPK 轴通路增强 MMP2 表达促进透明细胞肾细胞癌侵袭
DOI：
10.3892/ijo.2020.5041
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发表时间：
2020-07-01
影响因子：
5.2
通讯作者：
Zhu, Yuechun
中科院分区：
文献类型：
--
作者：
Zhang, Qiao;Han, Qiaoqiao;Zhu, Yuechun
葡萄糖-6-磷酸脱氢酶（G6PD）是戊糖磷酸途径（PPP）的关键限速酶。G6PD失调已在各种类型的人类癌症中被报道，并且G6PD在癌症进展中的作用已在许多研究中得到证实。我们实验室之前的一项研究描述了G6PD在透明细胞肾细胞癌（ccRCC）中的预后意义，并通过信号转导和转录激活因子磷酸化形式的正反馈调节3证明了其增殖作用。然而，G6PD在ccRCC侵袭中的作用尚不清楚。本研究通过细胞模型、异种移植小鼠模型和人体标本的逆转录定量（RT-q） PCR、western blotting、酶活性测定、transwell测定和免疫组织化学分析来评价G6PD在ccRCC侵袭中的作用。本研究结果表明，G6PD可能通过提高体内外基质金属蛋白酶2 (matrix metalloproteinase 2, MMP2) mRNA和蛋白的表达，促进ccRCC细胞侵袭能力。此外，RT-qPCR和western blotting在20对ccRCC肿瘤标本和匹配的邻近正常组织中证实G6PD与MMP2表达呈正相关。此外，G6PD在ccRCC细胞中促进活性氧（ROS）的产生，激活MAPK信号通路。此外，ROS显著促进MAPK信号通路的激活，进而导致MMP2在ccRCC细胞中过表达。综上所述，本研究表明G6PD可能通过ROS-MAPK轴通路增强MMP2的表达，从而促进ccRCC细胞的侵袭能力。
Glucose-6-phosphate dehydrogenase (G6PD) is crucial rate-limiting enzyme of the pentose phosphate pathway (PPP). G6PD dysregulation has been reported in various types of human cancer, and the role of G6PD in cancer progression was demonstrated in numerous studies. A previous study from our laboratory described the prognostic significance of G6PD in clear cell renal cell carcinoma (ccRCC), and demonstrated its proliferative role through positive feedback regulation of the phosphorylated form of signal transducer and activator of transcription 3. However, the role of G6PD in ccRCC invasion remains unclear. In the present study, reverse transcription-quantitative (RT-q) PCR, western blotting, enzyme activity assay, transwell assay and immunohistochemistry analysis in cell model, xenograft mice model and human specimen studies were performed to evaluate the role of G6PD in ccRCC invasion. The results from the present study demonstrated that G6PD may promote ccRCC cell invasive ability by increasing matrix metalloproteinase 2 (MMP2) mRNA and protein expression both in vitro and in vivo. In addition, a positive correlation between G6PD and MMP2 expression was demonstrated by RT-qPCR and western blotting in twenty pairs of ccRCC tumor specimens and matched adjacent normal tissues. Furthermore, G6PD promoted reactive oxygen species (ROS) generation and activated the MAPK signaling pathway in ccRCC cells. In addition, ROS significantly promoted the MAPK signaling pathway activation, which in turn contributed to MMP2 overexpression in ccRCC cells. In conclusion, the present study demonstrated that G6PD may facilitate ccRCC cell invasive ability by enhancing MMP2 expression through ROS-MAPK axis pathway.