| Backgroud and ObjectiveIn recent years,more and more molecular markers have been found as indicators of glioma typing,prognosis and treatment.The 2016 version of the WHO Central Nervous System Tumor Classification Update officially introduced important molecular markers such as IDH,ATRX and 1p/19q.Compared with the traditional histological classification,this revision provides a new molecular typing of gliomas and proposes the concept of integrated diagnosis.Unfortunately,this revision still lacks data from China.In addition,malignant glioma is the most common primary intracranial malignant tumor.Although the latest molecular classification combined with surgery and chemoradiotherapy,the treatment effect is still not satisfactory.The study found that highly invasive characteristic and immune escape were the two main reasons for its high recurrence rate and poor prognosis.Therefore,it is necessary to find new immune-related molecules as the basis for future accurate diagnosis and treatment.MethodsThe molecular markers in glioma were detected by IHC,PCR,Sanger sequencing,and FISH.By up-regulating or interfering the expression of IL4I1 in glioma cells,the effects of IL4I1 on the invasion and immune escape of glioma cells in vitro were observed by MTT,plate cloning,flow cytometry,scratch healing,transwell invasion assay,and cytokine microarray.RNA-seq and Western Blot were used to verify the tumor related signaling pathway regulated by IL4I1.Bioinformatics and IHC methods were used to study the role of LGALS3 in the immune microenvironment and prognosis of glioma and its correlation with the important molecular markers of glioma.ResultsThe frequency of IDH1 mutations in WHO grade Ⅱ astrocytomas was 68.7%(79/115)in our cohort,while "triple negative gliomas" were 23.8%(82/344),and we found 7 cases of new molecular phenotypes presented as "IDH wild-type and lp/19q co-deletion".We found that IL4I1 was mainly expressed in GBM and IDH wild-type LGG.Stratification analysis showed that IL4I1 was a significant indicator of poor prognosis in all LGG,GBM and IDH wild-type glioma.We found that IL4I1 was mainly expressed by glioma cells for the first time and it could promote the invasion and migration of glioma cell lines and secretion of cytokines associated with immunosuppression.IL4I1 activated Toll-like receptor 2 and its downstream MYD88-mediated classical NF-κB signaling pathway.In addition,we found that glioblastoma had a large amount of CD163+TAM,and it was closely related to LGALS3.Database analysis revealed that LGALS3 was involved in important inflammatory responses and immune pathways,including cytokine signaling,NF-κB,NOD receptors and TNF signaling pathways.ConclusionOur data indicate that the frequency of IDH mutations in Chinese is relatively low compared with the American and European,and the prevalence of triple-negative gliomas is high,suggesting that there may be ethnic and geographic differences in certain molecular changes.In addition,the new molecular phenotype "IDH wild-type and 1p/19q co-deletion" deserves special attention.We found that IL4I1 was expressed and secreted in glioma cells for the first time.IL4I1 promoted glioma invasion and immune escape by activating the Toll-like receptor/NF-κB signaling pathway.We found that LGALS3 was related to the poor prognosis of diffuse invasive glioma,and it was also one of the important prognostic markers in LGG and GBM,and it was closely related to tumor-associated macrophages in glioma.These results will help to explore the potential of IL4I1 and LGALS3 as diagnostic targets,and provide new insights and ideas for glioma treatment strategies. |
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