The Biological Behavior Of SDF2L1 And Potential Mechanism In Pancreatic Cancer

Objective:Chemotherapy resistance of pancreatic cancer is the main reason for the poor prognosis of patients.Abnormal regulation of metabolism is an important factor of chemotherapy resistance.It is important to find a key molecular regulating chemotherapy resistance in pancreatic cancer and clarifying its mechanism,which can significantly improve the prognosis of pancreatic cancer patients.We have used Patient-Derived Pancreatic Cancer Xenograft(PDTX model)that can truly reflect the patient’s chemotherapy sensitivity to get the histology specimens to distinguish the chemotherapy-resistant group.The following high-throughput transcriptome sequencing was performed on the chemotherapy-resistant group and sensitive group separately to screen out the SDF2L1 gene.Previous studies have shown that stromal cell-derived factor 2 like protein 1(SDF2L1)plays an important role in maintaining the stability of the endoplasmic reticulum.It was found that cancer cells can upregulate SDF2L1 to inhibit apoptosis caused by ER stress,leading to further proliferation of cancer cells.This research intends to study the effects of targeted inhibition of SDF2L1 expression on invasion and metastasis of pancreatic cancer cells and chemotherapy resistance through in vivo/external experiments.This topic is expected to provide a new therapeutic target for chemotherapy resistance in pancreatic cancer.Method:Based on the data of PDTX model,the chemotherapy-resistant group and sensitive group were sequenced by high-throughput transcriptome After data analyzation,it was found that compared with chemotherapy-sensitive pancreatic cancer cell,in pancreatic cancer chemotherapy-resistant cells,SDF2L1 was significantly overexpressed.In this experiment,standard pancreatic cancer cell lines(panc-1,bxpc-3)with moderate expression of SDF2L1 were selected to construct pancreatic cancer cell lines with SDF2L1 gene knockdown.The effect of SDF2L1 knockdown on the biological behavior of pancreatic cancer cell lines(invasion,metastasis,proliferation,etc.)will be observed.Furthermore,after treated with gemcitabine according to time gradient concentration,the survival of knockdown cells and control cells under treatment conditions will be also observed.At the same time,based on the TCGA database,bioinformatics will be used to analyze the possible signaling pathways of the SDF2L1 gene in pancreatic cancer.Results:1.SDF2L1 was highly expressed in the gemcitabine resistant group of PDTX model.Transcriptome sequencing of 15 cases in the gemcitabine sensitive group and 13 cases of drug resistance group in the PDTX model revealed that SDF2L1 was significantly overexpressed in the drug resistance group.2.SDF2L1 can promote pancreatic cancer cell proliferation and chemotherapy resistance.Knockdown of SDF2L1 with siRNA found that the proliferation of pancreatic cancer was inhibited,and the inhibitory rate of gemcitabine on tumor cells increased,suggesting that SDF2L1 can promote tumor proliferation and reduce the sensitivity of cells to gemcitabine.3.Gemcitabine can induce up-regulation of SDF2L1 expression.Adding different concentrations of gemcitabine to the culture medium of pancreatic cancer cell lines to simulate stress stimulation,collecting live cells,extracting total RNA and using fluorescence quantitative PCR detection,it was found that the expression level of SDF2L1 in cells increased significantly after adding gemcitabine.Conclusion:SDF2L1 gene is differentially expressed in drug-resistant pancreatic cancer cells.Knocking down SDF2L1 can inhibit the proliferation of pancreatic cancer cells,and at the same time increase the inhibition rate of gemcitabine on tumor cells.Gemcitabine can also induce up-regulation of SDF2L1 expression.It indicates that SDF2L1 is one of the potential factors affecting the chemotherapy resistance of pancreatic cancer...