The Role And The Possible Molecular Mechanism Of TK1 In Pancreatic Cancer

Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive digestive malignancies and is the fourth most common cause of cancer-related death in the United States.Patients diagnosed with PDAC have a poor prognosis with an overall 5 year survival rate of only 8% and a median survival of 6 months.Although the morbidity of this malignant tumor has been increased over the last several years,there is no obvious improvem ent in the survival rate.Surgical resection may prolong survival and provide a unique curative option.Unfortunately,the surgical resection rate is <20% because of difficulty for diagnosis at early stage.Therefore,an increasing understanding of the complex molecular basis of PDAC and exploring novel therapeutic targets may contribute to the clinical treatment of this aggressive malignancy.It is reported that wide distribution and overexpression of TK1 are found in most neoplastic cells.Progression and development of cancer are complex biological processes.Although the causes and exact mechanisms are still unknown,the anomaly of the cell cycle and abnormal regulation of cell proliferation are recognized to be elementary events in any malignant transformation.To further identify the role of TK1 in PDAC,we evaluated the expression patterns in PDAC cell lines and tissues and investigated the possible molecular mechanism.Objectives: 1、To investigate the expression of TK1 protein on pancreatic cancer samples,and further to analyze the association between TK1 expression and chinicopathological factors of pancreatic cancer,as well as the prognosis.To study the expression of TK1 in pancreatic cancer cell lines,and to investigate the effects of TK1 on cancer cell proliferation,invasion,and migration,as well as the potential regulatory mechanisms.To investigate the upstream regulatory mechanisms of TK1,and further to analyze the correlation between TK1 expression and upstream regulatory factors expression in samples.Methods: TK1 expression was analyzed by immunohistochemistry,RT-PCR,western-blot,and its relationship with clinical and pathological characteristics of PDAC patients was further investigated.To verify the function of TK1 and potential mechanism,TK1 Si-RNA was used to transfect PDAC cells and perform a series of assays in cell and animal models.Results: The level of TK1 expression was higher in cancerous tissues compared to matched adjacent tissues.TK1 overexpression was associated with progression of PDAC and poor prognosis.Knockdown of TK1 could suppress cell proliferation via inducing S phase arrest mediated by upregulation of P21.Further mechanism investigation suggest that transcription factor E2F-1 can directly regulate the TK1 and promote tumor proliferation.Conclusions: TK1 might be involved in progression of PDAC and might work as a promising therapeutic target.