G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

Zhang, Qiao; Han, Qiaoqiao; Yang, Zhe; Ni, Yueli; Agbana, Yannick Luther; Bai, Honggang; Yi, Zihan; Yi, Xiaojia; Kuang, Yingmin; Zhu, Yuechun

doi:10.3892/ijo.2020.5041

Cited by 24 publications

(45 citation statements)

References 63 publications

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“…ROS interacts with numerous oncogenic signaling pathways, such as the STAT3 and MAPK pathways, to favor the development of human cancers. Moreover, proliferation and metastasis related genes, such as cyclins and MMPs, were found to be involved in this mechanisms of action [9,12]. These implies that ROS might be involved in the G6PDmediated upregulation of Cyclin E1 and MMP9 in our study.…”

Section: Discussionsupporting

confidence: 55%

“…When most of the cell fell off, fresh culture medium containing serum was added and transferred to new culture bottles by 1:3. G6PD-overexpressing or G6PD-knocked down stable cells establishment were conducted as described before [9,12]. h. Cells were harvested and cell cycle analysis were performed as described in a previous report by a PARTEC CyFlow Space flow cytometer and ModFit software [12].…”

Section: Cell Culture and Stable Cell Constructionmentioning

confidence: 99%

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G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

Yang¹,

Zhang²,

Ni³

et al. 2020

Preprint

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Background: Clear cell renal cell carcinoma (ccRCC) is a cell metabolic disease with high metastasis rate and poor prognosis. Our previous studies demonstrate that glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is highly expressed in ccRCC and predicts poor outcomes of ccRCC patients. The aims of this study were to confirm the oncogenic role of G6PD in ccRCC and unravels novel mechanisms involving Cyclin E1 and MMP9 in G6PD-mediated ccRCC progression. Methods: Real-time RT-PCR, Western blot and immunohistochemistry were used to determine the expression patterns of G6PD, Cyclin E1 and MMP9 in ccRCC. TCGA dataset mining was used to identify Cyclin E1 and MMP9 correlations with G6PD expression, relationships between clinicopathological characteristics of ccRCC and the genes of interest, as well as the prognosis of ccRCC patients. The role of G6PD in ccRCC progression and the regulatory effect of G6PD on Cyclin E1 and MMP9 expression were investigated by using a series of cytological function assays in vitro. To verify this mechanism in vivo, xenografted mice models were established. Results: G6PD, Cyclin E1 and MMP9 were overexpressed and positively correlated in ccRCC, and they were associated with poor prognosis of ccRCC patients. Moreover, G6PD changed cell cycle dynamics, facilitated cells proliferation, promoted migration in vitro, and enhanced ccRCC development in vivo, more likely through enhancing Cyclin E1 and MMP9 expression. Conclusion: These findings present G6PD, Cyclin E1 and MMP9, which contribute to ccRCC progression, as novel biomarkers and potential therapeutic targets for ccRCC treatment.

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Section: Discussionsupporting

confidence: 55%

Section: Cell Culture and Stable Cell Constructionmentioning

confidence: 99%

G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

Yang¹,

Zhang²,

Ni³

et al. 2020

Preprint

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“…Previous studies from our laboratory demonstrated that G6PD overexpression lead to the increment of G6PD-NADPH-NOX4-dependent ROS accumulation and then pSTAT3 and MAKP signaling over-activation in ccRCC [19,20]. However, several problems, such as alterations in ROS-triggered signaling pathways or other relevant regulators responsible for G6PD high expression, remained to be clarified.…”

Section: Discussionmentioning

confidence: 92%

“…A further investigation descripted that the overexpressed G6PD positively regulated reactive oxygen species (ROS) generation by facilitating NADPH oxidase 4 activity, increased phosphorylated signal transducer and activator of transcription 3 (pSTAT3) activation and enhanced RCC development [19]. Moreover, G6PD could stimulate ccRCC invasion through facilitating ROS-MAPK-MMP2 axis pathway [20]. The aforementioned results suggested that how G6PD regulated the downstream target, influenced ROS production, and promoted RCC growth and invasion had partially been revealed, but why G6PD was aberrantly overexpressed during ccRCC tumorigenesis was still not completely known.…”

Section: Introductionmentioning

confidence: 99%

NF-κB and pSTAT3 synergistically drive G6PD overexpression and facilitate sensitivity to G6PD inhibition in ccRCC

Zhang

Yang

et al. 2020

Cancer Cell Int

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Background Glucose 6-phosphate dehydrogenase (G6PD) serves key roles in cancer cell metabolic reprogramming, and has been reported to be involved in certain carcinogenesis. Previous results from our laboratory demonstrated that overexpressed G6PD was a potential prognostic biomarker in clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer. G6PD could stimulate ccRCC growth and invasion through facilitating reactive oxygen species (ROS)-phosphorylated signal transducer and activator of transcription 3 (pSTAT3) activation and ROS-MAPK-MMP2 axis pathway, respectively. However, the reasons for ectopic G6PD overexpression and the proliferation repressive effect of G6PD inhibition in ccRCC are still unclear. Methods The impact of ROS accumulation on NF-κB signaling pathway and G6PD expression was determined by real-time RT-PCR and Western blot in ccRCC cells following treatment with ROS stimulator or scavenger. The regulatory function of NF-κB signaling pathway in G6PD transcription was analyzed by real-time RT-PCR, Western blot, luciferase and ChIP assay in ccRCC cells following treatment with NF-κB signaling activator/inhibitor or lentivirus infection. ChIP and Co-IP assay was performed to demonstrate protein-DNA and protein–protein interaction of NF-κB and pSTAT3, respectively. MTS assay, human tissue detection and xenograft model were conducted to characterize the association between NF-κB, pSTAT3, G6PD expression level and proliferation functions. Results ROS-stimulated NF-κB and pSTAT3 signaling over-activation could activate each other, and exhibit cross-talks in G6PD aberrant transcriptional regulation. The underlying mechanism was that NF-κB signaling pathway facilitated G6PD transcription via direct DNA–protein interaction with p65 instead of p50. p65 and pSTAT3 formed a p65/pSTAT3 complex, occupied the pSTAT3-binding site on G6PD promoter, and contributed to ccRCC proliferation following facilitated G6PD overexpression. G6PD, pSTAT3, and p65 were highly expressed and positively correlated with each other in ccRCC tissues, confirming that NF-κB and pSTAT3 synergistically promote G6PD overexpression. Moreover, G6PD inhibitor exhibited tumor-suppressor activities in ccRCC and attenuated the growth of ccRCC cells both in vitro and in vivo. Conclusion ROS-stimulated aberrations of NF-κB and pSTAT3 signaling pathway synergistically drive G6PD transcription through forming a p65/pSTAT3 complex. Moreover, G6PD activity inhibition may be a promising therapeutic strategy for ccRCC treatment.

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Section: Discussionmentioning

confidence: 92%

NF-κB and pSTAT3 synergistically drive G6PD overexpression and facilitate sensitivity to G6PD inhibition in ccRCC

Zhang

Yang

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Glucose 6-phosphate dehydrogenase (G6PD) serves key roles in cancer cell metabolic reprogramming, and has been reported to be involved in certain carcinogenesis. Previous results from our laboratory demonstrated that overexpressed G6PD was a potential prognostic biomarker in clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer. G6PD could stimulate ccRCC growth and invasion through facilitating reactive oxygen species (ROS)-phosphorylated signal transducer and activator of transcription 3 (pSTAT3) activation and ROS-MAPK-MMP2 axis pathway, respectively. However, the reasons for ectopic G6PD overexpression and the proliferation repressive effect of G6PD inhibition in ccRCC are still unclear. Methods: The impact of ROS accumulation on NF-κB signaling pathway and G6PD expression was determined by real-time RT-PCR and Western blot in ccRCC cells following treatment with ROS stimulator or scavenger. The regulatory function of NF-κB signaling pathway in G6PD transcription was analyzed by real-time RT-PCR, Western blot, luciferase and ChIP assay in ccRCC cells following treatment with NF-κB signaling activator/inhibitor or lentivirus infection. ChIP and Co-IP assay was performed to demonstrate protein-DNA and protein-protein interaction of NF-κB and pSTAT3, respectively. MTS assay, human tissue detection and xenograft model were conducted to characterize the association between NF-κB, pSTAT3, G6PD expression level and proliferation functions.Results: ROS-stimulated NF-κB and pSTAT3 signaling over-activation could activate each other, and exhibit cross-talks in G6PD aberrant transcriptional regulation. The underlying mechanism was that NF-κB signaling pathway facilitated G6PD transcription via direct DNA–protein interaction with p65 instead of p50. p65 and pSTAT3 formed a p65/pSTAT3 complex, occupied the pSTAT3-binding site on G6PD promoter, and contributed to ccRCC proliferation following facilitated G6PD overexpression. G6PD, pSTAT3, and p65 were highly expressed and positively correlated with each other in ccRCC tissues, confirming that NF-κB and pSTAT3 synergistically promote G6PD overexpression. Moreover, G6PD inhibitor exhibited tumor-suppressor activities in ccRCC and attenuated the growth of ccRCC cells both in vitro and in vivo. Conclusion: ROS-stimulated aberrations of NF-κB and pSTAT3 signaling pathway synergistically drive G6PD transcription through forming a p65/pSTAT3 complex. Moreover, G6PD activity inhibition may be a promising therapeutic strategy for ccRCC treatment.

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G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

Cited by 24 publications

References 63 publications

G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

NF-κB and pSTAT3 synergistically drive G6PD overexpression and facilitate sensitivity to G6PD inhibition in ccRCC

NF-κB and pSTAT3 synergistically drive G6PD overexpression and facilitate sensitivity to G6PD inhibition in ccRCC

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