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.
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.