Abstract
Background: In addition to exploiting its ribonuclease capacity, Ribonuclease T2 (RNASET2) has been reported to exert anti-angiogenic and anti-tumorigenic effects in several tumors. However, the role of RNASET2 in gastric adenocarcinoma (GAC) remains unclear. The purpose of this study was to explore the expression, location, and clinical implications of RNASET2 in GAC.Methods: Data of RNASET2 mRNA expression in GAC and normal gastric mucosa tissues were extracted from three GSE series and 388 TCGA samples and reanalyzed. Genome-wide CRISPR/Cas9 proliferation screening datasets were used to investigate cell growth changes after RNASET2 knockout in 19 GAC cell lines. The biological processes involved in RNASET2 were studied by the bioinformatics analysis. Furthermore, the corresponding experiments including immunohistochemical staining, clinicopathological features analysis, survival curve, microvessel density detection, cell viability assay, and colony formation assay were performed to validate the expression and function of RNASET2 in GAC.Results: An abundance of RNASET2 was present in the fundus glands and pylorus glands of the normal gastric mucosa. RNASET2 mRNA and protein were down-regulated in GAC compared with adjacent non-cancerous or normal gastric mucosa tissues. The expression of RNASET2 mRNA and protein in early GAC was higher than that in advanced GAC. 79/134 gene sets involved in the early GAC pathway were enriched in the RNASET2 mRNA high expression group. Genome-wide shRNA and CRISPR/Cas9 proliferation screening showed that knockdown or knockout of RNASET2 could not significantly promote GAC cell growth. AlamarBlue cell viability assay and colony formation assay in AGS cells further validated these results. Clinicopathologic features and survival analysis demonstrated that RNASET2 protein was significantly correlated with tumor cell differentiation, Lauren's classification, and TM4SF1 protein expression, but not correlated with lymph nodal metastasis and patient's prognosis. Microvessel density detection indicated that no significant correlation was found between the expression of RNASET2 protein and the angiogenesis of GAC.Conclusions: Down-regulation of RNASET2 in GAC was only the consequence of the GAC, instead of the driver. The expression of RNASET2 could be regarded as a good biomarker for identifying the early stage of GAC.
Highlights
Ribonucleases (RNases) are a large class of hydrolytic enzymes, involving a series of cellular processes such as DNA synthesis, RNA processing, and RNA degradation
The results showed that the expression of ribonuclease T2 (RNASET2) mRNA increased 2.002-fold in fundus glands (35.26 ± 4.209) or 1.899-fold in pylorus glands (33.44 ± 4.837) than that in cardiac glands (17.61 ± 4.826; Figure 1A)
RNASET2 protein was mainly located in the zone of fundus, body (Figure 1C), and part of antral and pylorus mucosa (Figure 1D), while positive staining was hard to find in gastric cardiac mucosa (Figure 1E)
Summary
Ribonucleases (RNases) are a large class of hydrolytic enzymes, involving a series of cellular processes such as DNA synthesis, RNA processing, and RNA degradation. The human ribonuclease T2 (RNASET2) gene, known as RNASE6PL, belongs to the endoribonucleases class [1]. It encodes a secreted glycoprotein (RNase T2) consisting of 256 amino acids and is a novel member of the Rh/T2/S-glycoprotein family [2, 3]. RNASET2, detected in the spermatozoa of male mouse and human, had the ability to inhibit the motility and progressive of sperm by coacting with actin network [6]. It was involved in brain development and myelination through RNA metabolism or angiogenesis [7]. The purpose of this study was to explore the expression, location, and clinical implications of RNASET2 in GAC
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