Clinical Significance And Functional Validation Of Inorganic Pyrophosphatase In Diffuse B-cell Lymphoma In Humans

Diffuse large B-cell lymphoma(DLBCL),the most common type of non-Hodgkin's lymphoma,displays marked heterogeneity in clinical manifestations,genetic characteristics and therapeutic responses for different subtypes.R-CHOP is the standard solution for DLBCL.Although it is usually curable,30-50%of patients die due to refractory treatment or cancer relapse.Development of tumor is a complex process involved multiple abnormal expression of polygene and abnormal regulation after transcription.It is known that all biological changes in tumor development may associated with changes in the energy.Therefore,revealing energy dysregulation in the development of tumor attracts more and more attention researchers.Metabolic change is considered to be a new feature of tumors,which maintain their high rate of reproduction through metabolic changes.PPA1,one of the family members of the inorganic pyrophosphatase,is thought to play a role in catalyzing the hydrolysis of PPi molecule into inorganic phosphates(Pi),which also releases energy and can also make H~+into the membrane from the cytoplasm acting as a proton pump.It can be used as an energy donor and ATP substitute in certain conditions,and also plays an important role in cell growth and development.Recently,PPA1was found to be overexpressed in different types of solid cancer in humans,which was related to the rapid proliferation and high invasiveness of cells,contributing to tumorigenesis by supplying the tumor with an enormous energy source.However,the role of PPA1 in blood tumors,especially in highly heterogeneous DLBCL,has not been reported.Here,we localized PPA1 in 65 patients with DLBCL and 20 patients with reactive hyperplasia of the lymph nodes(control).The PPA1expression was significantly higher in patients with DLBCL than in control subjects(p<0.05),and it closely associated with B symptoms(i.e.,fever,night sweats,and weight loss)and the IPI score(p<0.05).Furthermore,PPA1 mRNA and protein levels were higher in most DLBCL cell lines than in the control HMy2.CIR cell line.Then,we investigated the effects of PPA1 knockdown on the proliferation and survival of the DLBCL cell line.We found that p53 and p21 expression increased in PPA1-silenced DLBCL cells.Taken together,DLBCL cell proliferation had been suppressed and the apoptosis had been increased significantly.In mechanism,PPA1 may enhance cell viability through JNK-p53 signaling pathways,and it may prevent cell apoptosis by inhibiting Caspase-3 cleavage.Taken together,PPA1 is a novel molecule that may be useful in the development and prognosis of DLBCL in the future.