Dataset Information

High-Concentration Metformin Reduces Oxidative Stress Injury and Inhibits the Growth and Migration of Clear Cell Renal Cell Carcinoma.

ABSTRACT:

Objective

To explore the mechanism of metformin in treating CCRCC.

Methods

Prospective cohort study was conducted. SOD and cyclin D in six CCRCC samples donated by volunteers were detected to compare the degree of oxidative stress injury and the status of cell proliferation. 786-0 CCRCC cells were cultured in vitro with different concentrations of metformin, and MTT assay and Transwell cell migration and wound healing assay were used to detect their proliferation and migration. After culture, SOD and cyclin D in 786-0 CCRCC cells were also detected.

Results

In the edge tissue, SOD was lower than in the tumor nest and normal tissue, and cyclin D was highly expressed. In grade II CCRCC, SOD was higher than in grade IV CCRCC, but cyclin D was also highly expressed in grade IV CCRCC. The cell proliferation rate and density of the metformin group were lower than the control group, while in the high-concentration metformin group, it was lower than medium- and low-concentration groups. After culture, the migration of 786-0 cells in the metformin group was significantly lower than that in the control group, the wound healing rate was decreased, and the migration and wound healing rates in the high-concentration metformin group were significantly lower than those in the medium- and low-concentration groups. However, the SOD of the metformin group was higher than the control group, but the cyclin D was lower, while the SOD was higher than medium- and low-concentration groups in the high-concentration group, but the cyclin D was lower after cultured.

Conclusion

High-concentration metformin can reduce oxidative stress injury, increase the expression of SOD in CCRCC, and reduce cyclin D in CCRCC to inhibit proliferation and migration, which has optimistic prospects and application value in controlling the progression of CCRCC.

SUBMITTER: Liu Y

PROVIDER: S-EPMC9113878 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

High-Concentration Metformin Reduces Oxidative Stress Injury and Inhibits the Growth and Migration of Clear Cell Renal Cell Carcinoma.

Liu Yang Y Li Jianwei J Song Miaomiao M Qi Guisong G Meng Lingling L

Computational and mathematical methods in medicine 20220510

<h4>Objective</h4>To explore the mechanism of metformin in treating <i>CCRCC</i>.<h4>Methods</h4>Prospective cohort study was conducted. <i>SOD</i> and <i>cyclin D</i> in six <i>CCRCC</i> samples donated by volunteers were detected to compare the degree of oxidative stress injury and the status of cell proliferation. <i>786-0 CCRCC</i> cells were cultured <i>in vitro</i> with different concentrations of metformin, and <i>MTT</i> assay and <i>Transwell</i> cell migration and wound healing assay w ...[more]

PMID: 35592685

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Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1's carcinogenic effects in ccRCC.MethodsExpression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways.ResultsThe expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05).ConclusionsThis study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC.

Dataset Information

High-Concentration Metformin Reduces Oxidative Stress Injury and Inhibits the Growth and Migration of Clear Cell Renal Cell Carcinoma.

Objective

Methods

Results

Conclusion

Publications

High-Concentration Metformin Reduces Oxidative Stress Injury and Inhibits the Growth and Migration of Clear Cell Renal Cell Carcinoma.

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