Gene expression analysis of the L-arginine pathway in renal cell carcinoma

School of Bioscience and Medical Engineering, Southeast University, Nanjing, Jiangsu, China

^* Corresponding author: Hongde Liu, liuhongde@seu.edu.cn
Yu Yang: yangyu292347@seu.edu.cn

Abstract

Objective: To explore the key genes and their expression profiles in L-arginine biosynthesis and metabolic pathways in renal cell carcinoma (RCC) using bioinformatics methods. Methods: Differential expression analysis, prediction of upstream transcription factors, and survival analysis were carried out using gene expression data from RCC patients in the TCGA public database and clinical data. Results: Among 64 genes related to L-arginine anabolism, only the gene PYCR1 was up-regulated (P < 0.01); 31 genes were down-regulated (P < 0.05), including argininosuccinate synthase (ASS1), argininosuccinate lyase (ASL), and arginase 2 (ARG2). The transcriptional activators of these three genes, BRD2, EGR1, HNF4A, JUN, NFYA, NFYB, NFYC, SPI1, and TCF7L2, were down-regulated in cancer, whereas the transcriptional repressors c- Myc, ATF4, and ZNF263, were up-regulated. It is hypothesised that the down-regulation of these three genes is associated with changes in the expression of the above transcription factors. In addition, compared to control samples, the correlation between ASL and ASS1 in expression became weaker in clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC), from 0.77, 0.86, and 0.85, respectively, to 0.36, 0.16, and 0.24. Respectively, high expression of ASL corresponded to longer ccRCC patients' overall survival (OS) (P = 0.024), which could be an independent prognostic factor for pRCC (P = 0.04). Conclusions: It is hypothesized that down-regulation of ASL, ASS1 and ARG2 expression leads to inhibition of the L-arginine-related pathway, which in turn correlates with RCC development, and that this down-regulation may be due to changes in transcription factor expression.