The Role And Molecular Mechanism Of CYLD In Pancreatic Cancer

Pancreatic cancer is the most common cancer among all malignant tumors,and the incidence of pancreatic cancer is increasing rapidly.At present,with the development of medical standards,the incidence and mortality of other common cancers continue to decline,but the mortality and deaths caused by pancreatic cancer are still gradually increasing,and the survival of most patients with pancreatic cancer is less than 5 years.Surgical resection is the best way to cure pancreatic cancer.However,because the early symptoms of pancreatic cancer are not obvious,most patients are diagnosed in the late stage of cancer,which leads to missed the best time for surgical resection.In addition,patients with pancreatic cancer respond poorly to most of the chemotherapeutic agents used clinically.The high mortality rate of pancreatic cancer also shows that the current medical level cannot meet the needs of human beings,so it is urgent to improve the clinical detection level to prevent the development of pancreatic cancer.Early prevention and treatment of pancreatic cancer is essential for improving patient survival.Most patients with pancreatic cancer have almost no detectable symptoms at the beginning of the disease,so many patients are diagnosed after the cancer has metastasized to other organs.At present,there is still no effective biomarker detection index for early diagnosis of pancreatic cancer.Therefore,in-depth understanding of the pathogenesis of pancreatic cancer,identification of biomarkers in the development of pancreatic cancer,is of great significance for the early prevention and treatment of pancreatic cancer.In this study,we found that the tumor suppressor cylindromatosis(CYLD)plays an important role in the development of pancreatic cancer.CYLD is a microtubule-binding protein with deubiquitination,which is widely distributed in human body and is a key regulator of various cellular processes such as immune response,cell proliferation and inflammation.At the same time,the function of CYLD as a tumor suppressor has been reported for different types of cancer.In this study,we found that CYLD expression was significantly down-regulated in multiple pancreatic cancer samples by immunohistochemistry experiments on human pancreatic cancer tissue samples,whereas in samples adjacent to pancreatic cancer tissue,CYLD The level of expression is elevated.We detected the expression of CYLD by real-time fluorescent quantitative PCR(RT-PCR),and the mRNA expression level of CYLD was significantly decreased in all samples of pancreatic cancer compared with normal pancreatic samples.At the same time,the loss of gene copy number is a mechanism that can promote the down-regulation of mRNA expression.The gene copy number loss of CYLD is the main reason for the down-regulation of CYLD protein expression by gene copy number analysis.In addition,we analyzed the correlation between CYLD expression and clinicopathological parameters of pancreatic cancer,and found that the down-regulation of CYLD expression and various clinical pathological parameters(including tissue grade,lymph node metastasis,pathological tumor lymph node metastasis,CA19-9 level,etc.)were negative.Correlatively,at the same time,less lymph node(LN)metastasis was observed in samples with high levels of CYLD expression.In vitro studies have shown that overexpression of CYLD significantly inhibits the number of colonies formed in soft agar.In contrast,CYLD knockdown significantly promoted the number of colonies formed in soft agar,suggesting that CYLD deficiency promotes colony formation in vitro,and mouse tumorigenicity experiments also indicate that CYLD deficiency promotes the development of pancreatic cancer in vivo.Overexpression of CYLD significantly inhibited the proliferation of pancreatic cancer cells PANC-1 and EPP85 by BrdU incorporation assay.Related mechanisms have shown that CYLD is critical for cell division.Taken together,these data suggest that CYLD plays a key role in the inhibition of pancreatic cancer and may be a potential biomarker and prognostic indicator for early detection of pancreatic cancer.