PYCR in Kidney Renal Papillary Cell Carcinoma: Expression, Prognosis, Gene Regulation Network, and Regulation Targets.

BACKGROUND

Pyrroline-5-carboxylate reductase (PYCR) includes three human genes encoding three isozymes, , , and (or ), which facilitate the final step in the conversion of glutamine to proline. These genes play important roles in regulating the cell cycle and redox homeostasis as well as promoting growth signaling pathways. Proline is abnormally upregulated in a variety of cancers, and as the last key enzyme in proline production, PYCR plays an integral role in promoting tumorigenesis and cancer progression. However, its role in patients with kidney renal papillary cell carcinoma (KIRP) has not been fully elucidated. In this study, we aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of PYCR in patients with KIRP, elucidate the association between PYCR expression and KIRP, and identify potential new targets for the clinical treatment of KIRP.

METHODS

We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of and in KIRP using multiple online databases including cBioPortal, STRING, MethSurv, GeneMANIA, Gene Expression Profiling Interactive Analysis (GEPIA), Metascape, UALCAN, LinkedOmics, and TIMER.

RESULTS

The expression levels of , and were considerably upregulated in patients with KIRP based on sample type, sex, age, and individual cancer stage. and transcript levels were markedly upregulated in females than in males, and patients aged 21-40 years had higher and transcript levels than those in other age groups. Interestingly, transcript levels gradually decreased with age. In addition, the expressions of and were notably correlated with the pathological stage of KIRP. Patients with KIRP with low and expression had longer survival than those with high and expression. , and were altered by 4%, 7%, and 6%, respectively, in 280 patients with KIRP. The methylation levels of cytosine-phosphate-guanine (CpG) sites in PYCR were markedly correlated with the prognosis of patients with KIRP. , , and their neighboring genes form a complex network of interactions. The molecular functions of the genes, as demonstrated by their corresponding Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, included calcium channel activity, phospholipid binding, RNA polymerase II-specificity, and kinase and GTPase-regulatory activities. , , and targeted miR-21, miR-221, and miR-222, resulting in a better prognosis of KIRP. We analyzed mRNA sequencing data from 290 patients with KIRP and found that , , and were positively associated with expression; , , and were positively correlated with expression; , , and were positively correlated with expression; was positively correlated with B cell and CD8+ T-cell infiltration levels; macrophage infiltration was negatively correlated with expression; and expression was negatively correlated with B-cell, CD8+ T cell, and dendritic cell infiltration levels.

CONCLUSIONS

, and may be potential therapeutic and prognostic biomarkers for patients with KIRP. The regulation of microRNAs (miRNAs), including miR-21, miR-221, and miR-222, may prove an important strategy for KIRP treatment.