Abstract
BackgroundGLYR1 has a high mutation frequency in microsatellite instability colorectal cancer (MSI CRC) and is presumed to be a novel tumor suppressor. However, the role of GLYR1 in tumors has never been studied. In particular, the downregulation of GLYR1 in MSI CRC is worthy of further investigation.MethodsWestern blot and immunohistochemistry analyses were used to detect GLYR1 protein expression in CRC tissues and cell lines, and the clinical significance of GLYR1 was also analyzed. The relationship between GLYR1 and MLH1 was validated by immunofluorescence, immunoprecipitation and bioinformatics analyses. Western blotting, qRT-PCR, CCK-8 assays, colony formation assays, flow cytometry and Hoechst 33258 staining assays were used to assess the effect of GLYR1 on the cell cycle progression, proliferation, differentiation and apoptosis of CRC cells in vitro. The related mechanisms were initially investigated by Western blotting.ResultsGLYR1 was significantly downregulated in MSI CRC and its expression was negatively correlated with tumor size and positively correlated with tumor differentiation in CRC patients. In addition, GLYR1 interacted with MLH1 to regulate its nuclear import and expression. Moreover, downregulation of GLYR1 accelerated G1/S phase transition, promoted proliferation and inhibited differentiation of SW480 and SW620 cells in vitro. Furthermore, downregulation of GLYR1 decreased the sensitivity to 5-fluorouracil (5-FU) by inhibiting the mitochondrial apoptosis pathway in CRC cells. Inhibition of the p38 mitogen-activated protein kinase (p38MAPK) and activation of the phosphatidyl 3-kinase/protein kinase B (PI3K/Akt) signaling pathways were involved in the mechanism by which GLYR1 downregulated p21.ConclusionsOurs is the first study to elucidate the role of GLYR1 in tumors and provide evidence for GLYR1 as a biological marker that reflects the degree of malignancy and sensitivity to 5-FU in MSI CRC.
Highlights
Glyoxylate reductase 1 homolog (GLYR1) has a high mutation frequency in microsatellite instability colorectal cancer (MSI Colorectal cancer (CRC)) and is presumed to be a novel tumor suppressor
15– 20% of CRCs are caused by microsatellite instability (MSI) [1], which usually results from mutation of the mismatch repair (MMR) system genes (MLH1, PMS2, MSH2, and MSH6) or more commonly because of promoter methylation of MLH1 gene [2]
The results confirmed that GLYR1 was downregulated in microsatellite instability colorectal cancer (MSI CRC) cell lines compared with MSS CRC cell lines at the protein level (P = 0.0022, Fig. 1c)
Summary
GLYR1 has a high mutation frequency in microsatellite instability colorectal cancer (MSI CRC) and is presumed to be a novel tumor suppressor. Microsatellite instability colorectal cancer (MSI CRC) is a special subtype of CRC with good prognosis and insensitivity to 5-fluorouracil (5-FU) chemotherapy [2,3,4]. Glyoxylate reductase 1 homolog (GLYR1), known as NP60 and N-PAC, was originally discovered as an oxidoreductase in plant research This protein, which is encoded by a gene located on the 16p13.3 chromosome, contains three domains: PWWP, AT-hook and NAD binding regions. The role of GLYR1 in tumors was first reported in 2012 by Alhopuro et al, who found that GLYR1 had a mutation frequency of 51% in MSI CRC and presumed it to be a novel tumor suppressor [5]
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