Alterations in Gene Expression of Renin-Angiotensin System Components and Related Proteins in Colorectal Cancer

Abstract

Materials and methods: Quantitative expression of the RNA of these 17 genes in normal and cancerous tissues obtained using chip arrays from the public functional genomics data repository, Gene Expression Omnibus (GEO) application, was compared statistically.

Results: Expression of four genes, AGT (angiotensinogen), ENPEP (aminopeptidase A) MME (neprilysin), and PREP (prolyl endopeptidase), was significantly upregulated in CRC specimens. Expression of REN (renin), THOP (thimet oligopeptidase), NLN (neurolysin), PRCP (prolyl carboxypeptidase), ANPEP (aminopeptidase N), and MAS1 (Mas receptor) was downregulated in CRC specimens.

Conclusions: Presuming gene expression parallel protein expression, these results suggest that increased production of the angiotensinogen precursor of angiotensin (ANG) peptides, with the reduction of the enzymes that metabolize it to ANG II, can lead to accumulation of angiotensinogen in CRC tissues. Downregulation of THOP, NLN, PRCP, and MAS1 gene expression, whose proteins contribute to the ACE2/ANG 1-7/Mas axis, suggests that reduced activity of this RAS branch could be permissive for oncogenicity. Components of the RAS may be potential therapeutic targets for treatment of CRC.

Figure 1

Current understanding of the renin-angiotensin system 2021. Black font indicates the classical RAS circa 1990. Red font indicates additional metabolic and signaling pathways that have been incorporated into the RAS since 1990. Proteins, enzymes, and receptors indicated in gray boxes are the proteins whose genes were evaluated in this analysis. Dotted lines indicate hypothetical pathways. ^??Uncharacterized enzymatic mediators.

Figure 2

RAS components that showed highly significant differences in gene expression between normal and tumor tissues. (a, b) Describe angiotensinogen gene (AGT) expression, (c, d) describe renin gene (REN) expression, and (e, f) describe Mas receptor gene (MAS1) expression. (a, c, and e) Show pairing of samples with connecting lines. (b, d, and f) Show mean, SEM, and individual data points. All of these comparisons were significant at the p < 0.01 level after correction for multiple comparisons.

Figure 3

RAS-related enzymes that showed highly significant differences in gene expression between normal and tumor tissues. (a–j) Describe neprilysin gene (MME) expression, thimet oligopeptidase gene (THOP) expression, neurolysin gene (NLN) expression, prolyl endopeptidase gene (PREP) expression, and aminopeptidase N gene (ANPEP) expression. (a, c, e, g, and i) Show pairing of samples with connecting lines. (b, d, f, h, and j) Show mean, SEM, and individual data points. All of these comparisons were significant at the p < 0.01 level after correction for multiple comparisons.

Figure 4

RAS-related components that showed significant (p < 0.05) differences in gene expression between normal and tumor tissues. (a, b) Describe prorenin receptor gene (ATP6AP2) expression, and (c, d) describe aminopeptidase A gene (ENPEP) expression. (a, c) Show pairing of samples with connecting lines. (b, d) Show mean, SEM, and individual data points. All of these comparisons wesssre significant at the p < 0.05 level after correction for multiple comparisons.