Circadian Gene PER2 Promotes The Development Of Pancreatic Cancer By Activating RAS/MAPK Signaling Pathway

As one kind of malignant tumors in the digestive tract,pancreatic cancer has the features of occult clinical manifestation,rapid development,and poor prognosis.At present,gemcitabine(GEM)-based chemotherapy remains the main treatment option for pancreatic cancer,especially for patients with advanced pancreatic cancer or as adjuvant therapy after surgical resection.However,long-term chemotherapy can lead to drug resistance and side effects,which may result in poor compliance and tolerance among patients.So there is an urgent need for new treatments or means to improve the situation.A large number of studies have demenstrated that circadian genes are closely related to the occurrence and development of tumors,and they can indirectly or directly regulate the related signaling pathways in the process of tumor occurrence and development.However,only rare study was able to show an association between circadian genes and the development of pancreatic cancer.Circadian oscillation,provides a new idea for the clinical treatment of pancreatic cancer.The use of certain chemotherapy drugs in PDAC patients at a specific time,may increase drug efficacy,decrease drug resistance and improve patient compliance.Therefore,in this study,we explore PER2 gene targeting RAS / MAPK signaling pathway in pancreatic cancer,and Chrono chemotherapy was used to treat PDAC model mice.Bioinformatics analysis have investigated the relationship between the expression of related genes and survival time of PDAC patients;The expression of PER2 gene in human pancreatic cancer cell lines and normal human pancreatic cell line was compared by RT-PCR.The PDAC model mouse was established by injecting pancreatic cancer cells in situ.The expression of PER2 gene in mouse pancreatic tumor and normal pancreas was compared to verify the phenotype of PER2 gene.The PER2 gene was knocked down in mouse pancreatic cancer cell line,and the effect of PER2 gene on RAS / MAPK signaling pathway related genes was detected by RT-PCR.The ability of proliferation and migration have been detected to verify the function of PER2 gene.The circadian oscillation curves of PER2 and RAS / MAPK signaling pathway-related genes in normal mice and PDAC model mice were drawn;The model mice were treated with Chrono chemotherapy at a specific time.The results showed that in the clinical PDAC patients,the expression levels of PER2 gene and RAS / MAPK signaling pathway-related genes were higher than those of the control group.The survival time of patients with high expression of RAS / MAPK signaling pathway related genes was shorter;The expression of PER2 gene in human pancreatic cancer cell lines was higher than that in normal pancreatic cell line;The expression level of PER2 in PDAC model mice was higher than that in normal mice;In mouse pancreatic cancer cell line,the expression of RAS / MAPK signaling pathway-related genes was down regulated after PER2 gene knockdown,and the proliferation and migration ability of mouse pancreatic cancer cell line with PER2 gene knockdown were decreased;The mice in CT0 and CT12 group were treated with Chrono chemotherapy,and the mice in CT12 group got better drug efficacy.Through the database research and in vivo and in vitro experiments,it is proved that PER2 gene can promote the occurrence and development of pancreatic cancer by activating RAS /MAPK signaling pathway in pancreatic cancer,and the efficacy of Chrono chemotherapy in the treatment of pancreatic cancer get better.