The Role And Mechanism Of UPF1 In Different Stages Of Pancreatic Ductal Adenocarcinoma

Background and ObjectivePancreatic cancer is a highly malignant and invasive tumor of digestive system.Only20% of patients can get the opportunity of direct surgery after dignose.Although chemotherapy,radiotherapy and immunotherapy have been widely used in pancreatic cancer,the prognosis of pancreatic cancer is still unsatisfactory.The poor therapeutic effect of pancreatic cancer may be related to insufficient understanding of its pathogenesis and mechanism.The occurrence and development of tumor is a complex process,involving many aspects,including DNA and RNA levels.Therefore,the research on the pathogenesis and mechanism of pancreatic cancer needs continuous exploration to reveal the mystery of tumor occurrence.UPF1 is a key factor in a variety of m RNA decay pathways,of which nonsense mediated m RNA degradation is widely concerned.Nowadays,UPF1 has been reported in many different cancers.And the evidence shows that UPF1 disorder plays important roles respectively in these cancers.In our past research,it was found that UPF1 has gene mutation in pancreatic adenosquamous carcinoma,suggesting that there is a link between UPF1 and pancreatic cancer.Therefore,this study aims to explore the role and mechanism of UPF1 in three different stages of pancreatic ductal adenocarcinoma.Methods:This study explored the role and mechanism of UPF1 in pancreatic ductal adenocarcinoma in three different stages.At the stage of tumorigenesis,mice with pancreatic specific UPF1 overexpression were made.Relevant experiments were carried out on mice and their pancreas to explore the role of UPF1 in the growth and development of mouse pancreas and whether tumor would occur.At the stage of tumor progression,through sequencing the samples of patients,it was found that UPF1 experienced an RNA editing event,and this UPF1 sample was transfected into pancreatic cancer cell lines to figure out the impact of its function on tumor cells.In the stage of tumor recurrence,a preliminary study was conducted on 15 recurrent samples,and it was found that UPF1 was downregulated in 8 cases,and NMD pathway was damaged.At the same time,the possible mechanism of tumor recurrence was preliminarily explored.Results:Part I: In the stage of tumorigenesis,pancreatic specific UPF1 overexpression mice were made.The results showed that the overexpression of UPF1 caused the increase of blood glucose in all male mice,and also caused ADM,Pan IN and IPMN.At the same time,IHC test was carried out on 52 collected samples of IPMN patients.It was found that UPF1 was highly expressed in male IPMN patients with diabetes,which proved that UPF1 played a key role in the progress of IPMN.Part II: In the stage of tumor progression,UPF1 was found to have RNA editing in PDAC by sequencing the samples of PDAC patients.Through the determination of known substrates,it was proved that NMD pathway was over-activated and increased the production of asparagine synthetase,resulting in dysregulations in tumor metabolism,and accelerating tumor proliferation and metastasis.Part III: In the stage of tumor recurrence,through the detection of 15 recurrent samples,it was found that the expression of UPF1 was decreased in 8 of them,resulting in the disorder of NMD pathway and the production of abnormal MDM2 transcripts and corresponding proteins.At the same time,the expression of P53 and P21 in the samples was detected,and it was found that their overexpression was associated with abnormal MDM2.This will increase the number of tumor cells staying in G1 phase,help them escape treatment and survive,and become the molecular basis for the next tumor recurrence.Conclusion:The content of this study proves that UPF1 plays important roles in different stages of pancreatic ductal adenocarcinoma.In the stage of tumorigenesis,it affects the development of pancreas and the function of pancreatic islets,causing precancerous lesions.In the stage of tumor progression,the metabolic function of tumor is dysregulated,and the ability of tumor proliferation,invasion and metastasis is enhanced,leading to the progression and deterioration of tumor disease.In the stage of tumor recurrence,NMD pathway disorder was caused,producing abnormal proteins and accumulates,helping tumor cells escape treatment.UPF1 affects the occurrence and development of pancreatic ductal adenocarcinoma in many ways.There are still shortcomings in this study.The complete mechanism between UPF1 and pancreatic ductal adenocarcinoma has not been explored,which will encourage us to continue to study the mechanism of UPF1 and pancreatic cancer.