Regulation And Mechanism Of Pin1 In Multiple Myeloma

BackgroundMultiple myeloma is a hematological malignancy derived from abnormal monoclonal plasma cells.The main symptoms of untreated multiple myeloma are anemia,infections,bone lesions and renal failure.Multiple myeloma is more likely to occur in middle-aged elderly men and its median survival time is about six years.According to statistics,the incidence of MM has been increasing year by year and becoming the second common hematological malignancy,which surpasses acute leukemia.Recently,current therapies including high-dose chemotherapy,hematopoietic stem cell transplantation,proteasome inhibitors and immunomodulators,such as bortezomib and lenalidomide,have improved the complete response rate and overall survival.However,nearly all MM patients eventually die due to relapse and progression of the disease.Therefore,it is of great clinical significance to explore novel therapeutic targets for multiple myeloma.Pinl is an evolutionarily conserved member of peptidyl-prolyl cis/trans isomerase family.The Pinl protein is composed of 163 amino acid residues with a relative molecular weight of 18 KD.The Pinl protein could specifically bind to and isomerize the peptidyl-prolyl bond in specific phosphorylated Ser/Thr-Pro motifs and thereby induces conformational changes in its target proteins.It changes the nature and subcellular localization of substrate proteins and regulates the function of substrates after phosphorylation.Pinl plays a pivotal regulatory role in the process of cell development and various cell signals.In the recent years,numerous studies have shown that Pinl is a molecular marker which is highly expressed in many human tumor tissues,such as liver cancer,breast cancer and nasopharyngeal carcinoma etc.Pinl is involved in the regulation of intracellular signal transduction in different types of malignant cancer cells,and it’s a molecular switch in the development of human tumor cells.Therefore,Pinl is of great use in the molecular diagnosis,disease progression,clinical therapy and prognostic evaluation of human tumors.Up to date,there is no report about the function of Pin1 in multiple myeloma.Our study reveals the tumor-promoting role of Pinl in MM,thus providing molecular evidence that targeting Pinl could be a promising therapeutic strategy for MM.MethodsAnalysis of the differential expression of Pinl in healthy donors and multiple myeloma patients and its clinical prognostic value using GEO database.The effect of Pinl mutation and copy number on the expression of Pinl in myeloma cells was explored using the CCLE database.The cell proliferation,migration and invasion after Pinl overexpression and knockdown were explored in vitro and in vivo.The transcriptional activity and expression of NF-κB and Wnt/β-catenin pathway were explored by the dual luciferase reporter assay and immunoblotting.The anti-myeloma effect of Pin1 inhibitor,API-1,was further explored.ResultsPinl expression is much higher in myeloma patients than that in healthy donors with analysis using GEO database(p<0.05).The expression of Pin1 increased with the progression of the plasma cell diseases,the highest level in plasma cell leukemia patients,followed by myeloma patients and lower in MGUS patients.The overall survival and progression free survival in patients with high level of Pin1 was significantly lower than that in patients with low level of Pinl(p<0.05).The proliferation,migration,invasion,transcriptional activity of NF-κB and Wnt/β-catenin pathway were enhanced by overexpression of Pin1 in myeloma cells(p<0.05).The proliferation,migration,invasion,transcriptional activity of NF-κB and Wnt/β-catenin pathway were decreased by inhibition of Pinl in myeloma cells(p<0.05).The Pinl inhibitor,API-1,inhibits the proliferation,migration,invasion and tumorigenesis of myeloma cells(p<0.05).ConclusionIn conclusion,this study shows that Pinl is highly expressed in multiple myeloma patients and is closely related to its poor prognosis.Pin1 promotes the malignant biological behavior of myeloma cells and is a potential therapeutic target for the treatment of multiple myeloma.