The Molecular Mechanism Of PGAM5 Promoting Colorectal Cancer

Colorectal cancer(CRC)is one of the most common cancers in the world.The number of newly diagnosed cases is between one and two million each year.Therefore,CRC has become the third most common cancer in the world and is also a death The cancer with the fourth highest rate causes more than 700,000 deaths each year,second only to lung cancer,liver cancer,and stomach cancer.From a gender perspective,CRC is the second most common cancer in women(9.2%)and the third most common cancer in men(10%).PGAM5 is a phosphatase modified by dephosphorylation at the site of protein serine or threonine(ser / thr).It is involved in the regulation of multiple metabolic pathways and is closely related to the occurrence of tumors,but there are relatively few in-depth studies.Malic enzymes are involved in linking anabolism and catabolism.Malic enzymes use NAD or NADP as essential cofactors to oxidatively decarboxylate malic acid to pyruvate,respectively,thereby generating NADH or NADPH.Several forms of malic enzymes have been found in mammals,including cytoplasmic malic enzyme ME1 and mitochondrial malic enzyme ME2 / 3.Due to the cytoplasmic localization of ME1,it links the glycolytic catabolic pathway and citric acid cycle to the fatty acid and cholesterol biosynthetic pathway through NADPH.In order to study the role of phosphatase in colorectal cancer,we first analyzed the expression of 324 known phosphatases in 382 cases of CRC in the TCGA database.The results showed that 54 phosphatase genes were generally up-regulated in CRC(1.6 times threshold).Next,we analyzed the protein expression of these phosphatases in CRC samples in the Human Protein Atlas Database(HPA).The analysis found that among all tumor samples,only PPM1 G and PGAM5 were significantly overexpressed.Knocked down the expression levels of PGAM5 and PPM1 G in several different CRC cell lines,observed the proliferation of cancer cells,and found that knocking down the expression of PGAM5 significantly inhibited the proliferation of cells,while the expression level of PPM1 G had no significant effect on the phenotype of cancer cells.We analyzed the transcription level and protein expression level of PGAM5 in different tumors in the TCGA database and HPA database,and the analysis results showed that PGAM5 was significantly expressed in CRC.Next,we analyzed the CRC tissue samples in the TCGA database and the GEO database and the matched / unpaired paracancerous tissue samples.The analysis results showed that PGAM5 was highly expressed in colorectal cancer tissues compared to the paracancerous tissues.We collected and analyzed the expression of PGAM5 gene in 31 paired colorectal cancer tissues from Wuhan Union Hospital,Wuhan Huazhong University of Science and Technology,which is consistent with our previous analysis.PGAM5 is highly expressed in colorectal cancer.After analyzing the clinical information of the corresponding samples in the TCGA database,it was found that the expression level of PGAM5 was negatively correlated with the patient's life cycle.We constructed a PGAM5 phosphatase site-inactivating mutant(H105A)as an experimental group,and overexpressed PGAM5-WT / H105 A in PGAM5 knockdown CRC cell lines,and found that overexpression of PGAM5-WT can restore cell proliferation ability However,overexpression of PGAM5-H105 A had no significant effect on cell phenotype.Studies have confirmed that PGAM5 phosphatase activity does affect the proliferation and division of cancer cells.In order to explore the rationality of our conjecture,this study constructed a chemical drug AOM / DSS induced CRC mouse model(AOM / DSS CRC)and a spontaneous CRC mouse model(Apc Min/+ CRC)to simulate induced and spontaneous CRC patient.The experiment detected the expression level of PGAM5 gene in two animal models by q-PCR and Western blot,which is consistent with our previous experimental analysis results.PGAM5 is highly expressed in CRC.In order to explore the scientific nature of PGAM5 as a therapeutic target,we knocked down the expression of PGAM5 in two tumor models,and the experimental results found that knocking down the expression of PGAM5 significantly attenuated lipid metabolism and inhibited the development of colorectal cancer.This study found that PGAM5 is highly expressed in colorectal cancer,and down-regulating the expression of PGAM5 reduces the level of lipid metabolism and inhibits the development of CRC.The experimental results show that PGAM5 may be a potential target for the treatment of CRC patients,providing a molecular basis for the treatment of CRC.