The Role Of Tumor Suppressor Gene FHIT In The Early Stage Of Gastric Carcinogenesis

The fragile histidine triad(FHIT)is a tumor suppressor gene discovered more than20 years ago,which contains the most common chromosomal fragile site FRA3 B,and its expression is lost or silenced in more than 50% of human tumors including gastric cancer.However,the mechanism of its tumor suppression is still unclear,particularly in the early stage of tumorgenesis.Based on our previous experiments,we found that STAT3 signaling activation was implicated in FHIT depletion in cell malignant transformation induced by N-nitrosamines compounds chemical carcinogens(NOCs).Activated STAT3 transactivated the DNA methyltransferase 3B(DNMT3B)and recruited it to FHIT promoter region.This complex increased the methylation level of FHIT promoter and inhibited FHIT expression.In order to further study the function and role of FHIT in the process of chemical carcinogen-induced cell malignancy,we confirmed that the DNA damage response pathway ATR and p38 MAPK singaling pathway played an important role in STAT3 signaling pathway continuously activation in cell malignant transformation and in gastric carcinogenesis model both induced by NOCs.In the phenotypic experiments we confirmed that the anti-apoptotic ability of malignant transformed cells down-regulated FHIT was enhanced,and knockdown ofFHIT promoted the proliferation in normal gastric epithelial cells(GES1).In recent years,FHIT has been newly identified as a scavenger-decapping enzyme which can degrade the methylguanosine(m7Gppp N)dinucleotides generated by 3’-5’ degradation of m RNAs,and it may be involved in post-transcriptional regulation of gene.Therefore we performed Polysome profiling and Ribosome profiling assay to investigate the effect of FHIT expression on translation of gastric adenocarcinoma cells.Preliminary results suggested that overexpression of FHIT affected translation of AGS and regulated the translation of certain tumor-associated m RNA:APOA1、FADS2、SIX4、IHH、SEMA3、PTPRR、ST3GAL5、AQP1、CALB1、DMBT1、SEMA6A、NR4A3.In addition,the combination of the drug STAT3 pathway inhibitor(AZD1480)and DNA methylation inhibitor(5AZA)was used to intervene in the mouse gastric cancer model induced by NOCs.The preliminary results showed that the combination of drugs significantly inhibited the development of gastric cancer in mice.The analysis of clinical tissue research further confirmed that the abnormal expression of FHIT mediated by STAT3 played an important regulatory role in the occurrence and development of gastric cancer.In conclusion,our study found that in the early stage of gastric cancer induced by chemical carcinogens,the tumor suppressor gene FHIT can undergo DNA methylation modification-mediated downregulation,and may play the role of scavenger-decapping enzyme involved in the regulation of tumor-related m RNA translation,thereby affecting the occurrence and development of gastric cancer.Our results also provide new insights and evidences to help us understand the mechanism of FHIT in the early stage of gastric carcinogenesis and to find effective early interventions of cancer.