LDLRAD2 Promotes Pancreatic Cancer Progression Through AKT/mTOR Signaling Pathway

Objective:Pancreatic cancer(PC)is one of the most fatal human cancers and also a main cause of cancer-related death worldwide.LDLRAD2,located on chromosome1p36.12,was unregulated in gastric cancer tissues and cell lines,and the increased expression of LDLRAD2 was associated with unfavorable prognosis of gastric cancer patients.Moreover,LDLRAD2 promoted gastric cancer development through activating Wnt/ β-catenin pathway.However,the expression,biological roles,and molecular mechanism of LDLRAD2 in other malignancies including PC have never been explored.Methods:(1)Quantitative real-time PCR was used to test the gene expression.And western blot analysis was applied to test the protein expression.(2)The short-hairpin RNA(sh-RNA)interference was performed to steadily suppress LDLRAD2.(3)Cell Counting Kit-8,wound-healing scratch assay,cell invasion assay and mouse xenograft were adopted to determine the cell proliferation,migration,invasion in vitro and metastasis in vivo,respectively.(4)ECAR(extracellular acidifcation rate)was used to reflect the glycolytic capacity of pancreatic cancer cells.Lactate production and glucose uptake were used to imply the warburg effect.(5)Intracellular signaling arrays were adopted to compare cell signaling changes in pancreatic cancer cells before and after LDLRAD2 knockdown.Results:(1)LDLRAD2 expression was examined in PC tissue,adjacent normal pancreatic tissue,PC cell lines,and a normal pancreatic cell line.The results showed that LDLRAD2 was up-regulated in PC tissues and cell lines(P<0.01).(2)LDLRAD2 knockdown significantly inhibited PC cells proliferation,migration,invasion in vitro,and tumor growth,metastasis in vivo(P<0.01).(3)LDLRAD2 silence suppressed the Warburg effect and EMT(epithelial-tomesenchymal transition)(P<0.01).(4)Intracellular signaling array and western blot analysis demonstrated that silencing of LDLRAD2 inhibited Akt/m TOR signaling pathway(P<0.01).Conclusion:In summary,LDLRAD2 was up-regulated in PC and promoted PC cell proliferation,invasion,and Warburg effect involved Akt/m TOR signaling pathway.Our work shed new light on the utilization of LDLRAD2 as a potential novel diagnostic biomarker and therapeutic target for PC.