Function And Mechanism Of ANT2 In The Development And Progression Of Familial Gastric Cancer

Gastric cancer is the most common malignancy of the digestive system,both morbidity and mortality rank at the top of all malignancies.It poses a great threat to the physical and mental health of the patients and also consumes a great deal of health resources and puts a heavy burden on society.China is a high-risk area for gastric cancer,new cases and deaths of gastric cancer account for about 40%of the world total every year.In recent years,the overall incidence and mortality of gastric cancer have declined slightly,however,the incidence of early-onset gastric cancer and familial gastric cancer(FGC)has increased.Most of the gastric cancers are sporadic cases,about 10%of them show family clustering.Familial gastric cancer has the characteristics of early onset,poor prognosis,and poor tumor differentiation.There is still a lack of specific and sensitive diagnostic methods.With the development of molecular biology and genetics,genetic factors are considered to play a more important role in the development of familial gastric cancer.Thus,exploring the pathogenic factors of familial gastric cancer and its role and mechanism in the development and progression of familial gastric cancer has important social and economic significance.Constrained by factors such as the search for familial gastric cancer family,China's research on familial gastric cancer started late.Apart from E-cadherin(CDH1),there is few report about other susceptibility genes.The previous period of the study collected sixteen familial gastric cancer families nationwide that met the diagnostic criteria.After high-throughput full-exon sequencing,missense mutation occurred in Adenine nucleotide translocator 2(ANT2)on the X chromosome in 6 families.And according to the Mendelian inheritance law,there is a possibility of hereditary X chromosomes in all six families.This is not particularly consistent with the previous report that familial gastric cancer is mostly autosomal dominant.Therefore,the role and mechanism of this gene in familial gastric cancer have great research significance.Adenine nucleotide translocator 2(ANT2)is a member of the mitochondrial transporter family.In normal differentiated tissues,the expression is low,while the expression is high in undifferentiated and proliferative tissues and cells.Under normal physiological conditions,it acts as an ADP/ATP antiporter between the cytosol and mitochondrial matrix and plays a key role in maintaining mitochondrial membrane potential and inhibiting apoptosis.Previously,it was reported that the abnormal expression of ANT2 played an important role in the development and drug resistance of various malignant tumors such as breast cancer,non-small cell lung cancer,and hepatocellular carcinoma,but direct reports of the role of gastric cancer were rare.We further validated the possibility of ANT2 as a susceptibility gene for familial gastric cancer through multi-level experimental methods such as molecular experiments,cell experiments,tissue experiments,and animal experiments.According to a series of functional tests and clinical pathological data results:The expression level of ANT2 has an important influence on the malignant biological behavior of gastric cancer cell lines,down-regulation of ANT2 expression can inhibit the proliferation and metastasis of gastric cancer cells in vitro,and inhibit tumorigenicity in nude mice,and there is a certain correlation between the expression level of ANT2 and the prognosis of clinical patients.In addition,we used GSEA to analyze the expression profile of gastric cancer in TCGA database and found that ANT2 has a high correlation with apoptosis and related P53-mediated signaling pathways,and it is likely to interact with several key genes.We speculate that ANT2 influences the pathogenesis of gastric cancer by regulating apoptosis and P53 signaling pathway.Thus,we believe that ANT2 may be a susceptibility gene for familial gastric cancer.Through this study and subsequent studies,we hope to provide a theoretical basis for the risk assessment and clinical guidance of familial gastric cancer patients in China.