Overexpression of AMPD2 indicates poor prognosis in colorectal cancer patients via the Notch3 signaling pathway

Abstract

Background: AMPD2 is a critical enzyme catalyzing smooth muscle energy supply and metabolism; however, its cellular biological function and clinical implication in colorectal cancer (CRC) are largely unknown.

Aim: To clarify the role of AMPD2 in CRC and study the pathway and prognostic value of its role.

Methods: AMPD2 expression was analyzed by integrated bioinformatics analysis based on TCGA data sets and immunohistochemistry in tissue microarrays, and the correlation between AMPD2 expression and clinicopathological parameters, Notch3 expression, and prognostic features was assessed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were then performed to investigate the regulatory pathway involved. The effects of AMPD2 expression on CRC cells and Notch3 protein expression were investigated by downregulation and overexpression of AMPD2.

Results: AMPD2 mRNA was significantly overexpressed in tumor tissue when compared with normal tissue in a cohort of the TCGA-COAD data set. Biological function enrichment analysis indicated that the Notch pathway strongly correlated with AMPD2 expression, and that the expression of Notch3 and JAG2 mRNA was positively associated with AMPD2 in CRC tissues. In vitro, AMPD2 overexpression markedly reduced Notch3 protein expression in CRC cells, while knockdown of AMPD2 showed the opposite findings. In addition, protein expression was significantly up-regulated in our CRC cohort as indicated by tissue microarray analysis. High expression of AMPD2 protein correlated with advanced depth of tumor and poor differentiation. Furthermore, high AMPD2 expression in CRC tissues was an indicator of poor outcome for CRC patients.

Conclusion: AMPD2 is commonly overexpressed in CRC, and acts as a metabolism oncogene to induce CRC progression through the Notch signaling pathway. Thus, AMPD2 may be a novel prognostic biomarker for CRC.

Keywords: AMPD2; Biomarkers; Colorectal cancer; Notch3; Poor prognosis; Tumor metabolism.