Theranostics 2020; 10(25):11444-11461. doi:10.7150/thno.48469 This issue Cite

Research Paper

Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress

Zhiyong Xiong1,2#, Changfei Yuan1,2#, Jian shi1,2#, Wei Xiong4, Yu Huang1,2, Wen Xiao1,2, Hongmei Yang3✉, Ke Chen1,2✉, Xiaoping Zhang1,2✉

1. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
2. Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
3. Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China.
4. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China.
#These authors contributed equally to this study.

Citation:
Xiong Z, Yuan C, shi J, Xiong W, Huang Y, Xiao W, Yang H, Chen K, Zhang X. Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. Theranostics 2020; 10(25):11444-11461. doi:10.7150/thno.48469. https://www.thno.org/v10p11444.htm
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Abstract

Graphic abstract

Rationale: Tumors have significant abnormalities in various biological properties. In renal cell carcinoma (RCC), metabolic abnormalities are characteristic biological dysfunction that cannot be ignored. Despite this, many aspects of this dysfunction have not been fully explained. The purpose of this study was to reveal a new mechanism of metabolic and energy-related biological abnormalities in RCC.

Methods: Molecular screening and bioinformatics analysis were performed in RCC based on data from The Cancer Genome Atlas (TCGA) database. Regulated pathways were investigated by qRT-PCR, immunoblot analysis and immunohistochemistry. A series of functional analyses was performed in cell lines and xenograft models.

Results: By screening the biological abnormality core dataset-mitochondria-related dataset and the metabolic abnormality core dataset-energy metabolism-related dataset in public RCC databases, PCK2 was found to be differentially expressed in RCC compared with normal tissue. Further analysis by the TCGA database showed that PCK2 was significantly downregulated in RCC and predicted a poor prognosis. Through additional studies, it was found that a low expression of PCK2 in RCC was caused by methylation of its promoter region. Restoration of PCK2 expression in RCC cells repressed tumor progression and increased their sensitivity to sunitinib. Finally, mechanistic investigations indicated that PCK2 mediated the above processes by promoting endoplasmic reticulum stress.

Conclusions: Collectively, our results identify a specific mechanism by which PCK2 suppresses the progression of renal cell carcinoma (RCC) and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. This finding provides a new biomarker for RCC as well as novel targets and strategies for the treatment of RCC.

Keywords: PCK2, renal cell carcinoma (RCC), methylation, endoplasmic reticulum stress, Sunitinib sensitivity


Citation styles

APA
Xiong, Z., Yuan, C., shi, J., Xiong, W., Huang, Y., Xiao, W., Yang, H., Chen, K., Zhang, X. (2020). Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. Theranostics, 10(25), 11444-11461. https://doi.org/10.7150/thno.48469.

ACS
Xiong, Z.; Yuan, C.; shi, J.; Xiong, W.; Huang, Y.; Xiao, W.; Yang, H.; Chen, K.; Zhang, X. Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. Theranostics 2020, 10 (25), 11444-11461. DOI: 10.7150/thno.48469.

NLM
Xiong Z, Yuan C, shi J, Xiong W, Huang Y, Xiao W, Yang H, Chen K, Zhang X. Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. Theranostics 2020; 10(25):11444-11461. doi:10.7150/thno.48469. https://www.thno.org/v10p11444.htm

CSE
Xiong Z, Yuan C, shi J, Xiong W, Huang Y, Xiao W, Yang H, Chen K, Zhang X. 2020. Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. Theranostics. 10(25):11444-11461.

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