The Role And Mechanism Of ALDOA And ALDOB In The Development Of Colorectal Cancer

I:Aldolase A overexpression is associated with poor prognosis and promotes tumor progression by the epithelial-mesenchymal transition in colon cancerThere is increasing evidence that glycolysis is involved in cancer progression.Aldolase is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate.Disruption of the aldolase genes also plays a role in the progression of multiple types of cancer.However,the underlying mechanism of the action of aldolases in colon cancer progression remains elusive.In this study,aldolase A expression was investigated and found to be upregulated along with human colon cancer progression and metastasis at both the mRNA and protein levels in human colon cancer tissues.In addition,silencing aldolase A suppressed colon cancer cell proliferation and invasion and inhibited the EMT phenotype.Aldolase A protein expression in colon cancer was related to tumor location,tumor clinical stage and survival.KaplaneMeier analysis showed that high aldolase A protein expression was associated with an unfavorable outcome.Moreover,aldolase A affected the development of colon cancer not only by affecting the glucose metabolism but also by interacting with the HIF-1 and other EMT-related signaling pathways;silencing aldolase A resulted in the reduced activity of these signaling pathways.These results indicate that aldolase A has additional nonglycolytic functions in transcriptional EMT regulation and may therefore have potential as a therapeutic target or a biomarker for identifying patients at risk for poorer survival.II:ALDOB impairs DNA mismatch repair and induces apoptosis in colon cancerDNA lesions are repaired primarily by the base excision repair(BER)and mismatch repair(MMR)pathways.Published evidence suggests that individual DNA repair capacity(DRC)may affect a patient’s prognosis.Aldolase B(ALDOB)is well known for its role in metabolism and glycolysis.The expression characteristics of ALDOB in colon cancer and its influence on colon cancer prognosis remain elusive and controversial,and its role in DNA MMR has not yet been reported.In this study,we identified a cluster of DNA repair-related proteins that interact with ALDOB in the colon cell line HCT116.Expression analysis of TCGA-COAD data(n=551)indicated that ALDOB mRNA expression was significantly higher in specimens that manifested microsatellite instability(MSI)than in specimens that manifested microsatellite stability(MSS).Regarding prognosis,colon cancer patients with high ALDOB mRNA expression had longer overall survival.Higher expression of ALDOB protein was significantly correlated with MMR deficiency(d-MMR)in formalin-fixed paraffin-embedded(FFPE)patient specimens.The expression of ALDOB was significantly elevated in colon cancer cell lines.Further evidence indicated that rather than affecting proliferation,ALDOB overexpression induced the functional loss of MMR proteins and further caused irreversible DNA damage and cell apoptosis.Overall,our study demonstrates that high ALDOB expression impairs DNA MMR and induces apoptosis in colon cancer.ALDOB may be a new biomarker associated with d-MMR and an independent factor to predict prognosis.