| Objective: To explore the expression of HIFs hypoxic induction pathway key factors HIFs,VHL and PHDs in adult diffuse glioma at all levels,and to study their expression correlation and prognostic correlation in this tumor,so as to provide potential biomarkers and theoretical basis for the treatment of glioma.Methods: Glioma samples were collected from Pathology Department of Affiliated Hospital of Southwest Medical University according to WHO classification standard 2016 edition.All samples were reclassified according to the WHO 5th Edition classification standard,and the homozygous deletion of CDKN2A/B gene was detected by fluorescence in situ hybridization.The expressions of HIF-1α,HIF-2α,HIF-1β,VHL,PHD1,PHD2 and PHD3 in all levels of adult diffuse glioma were detected by immunohistochemistry,and their correlation among all levels was analyzed.Combined with clinicopathologic data and follow-up records,comprehensive analysis was conducted.Results:1.HIF-1α was mainly expressed in cytoplasm of adult diffuse glioma tumor cells,and there was no significant difference in expression among different levels(P>0.05).In glioblastoma,IDH wild type,grade 4,HIF-1αwas correlated with PHD1 expression(P<0.05).HIF-1α was associated with PHD1 in astrocytoma,IDH mutant,grade 2(P<0.05);HIF-1α was associated with PHD3 both in astrocytoma,IDH mutant,grade 3,and glioblastoma,IDH wild type,grade 4(P<0.05).In oligodendroglioma,IDH mutation combined with 1p/19 q co-deletion,grade 2,HIF-1α was correlated with PHD2 expression(P<0.05).The expression of HIF-1α was related to tumor size and tumor cell origin(P<0.05).HIF-1α was correlated with the expression of ATRX,1p/19 q,TERT and MGMT(P<0.05),but had no significant correlation with IDH,Ki67 and P53(P>0.05).There was no significant correlation between HIF-1α and PFS by Cox regression analysis(P>0.05).2.HIF-2α was only expressed in the nucleus,and there was no significant difference in expression among different levels(P>0.05).3.HIF-1β was only expressed in the nucleus,and there were significant difference respectively among astrocytoma,IDH mutant,and glioblastoma,IDH wild type,grade 4(P<0.01),oligodendroglioma,IDH mutation with 1p/19 q deletion,grade 2(P<0.01),oligodendroglioma,IDH mutation with 1p/19 q deletion,grade 3(P<0.01).In astrocytoma,IDH mutant,grade 3,HIF-1β expression was correlated with PHD1 expression(P<0.05).In astrocytoma,IDH mutant,grade 4,HIF-1β was correlated with VHL expression(P<0.05).The expression of HIF-1β was correlated with tumor size and tumor cell origin(P<0.05).HIF-1β was significantly correlated with the expression of IDH,ATRX,1p/19 q,TERT,Ki67 and P53(P<0.05),but had no significant correlation with MGMT(P>0.05).HIF-1βmay be an independent prognostic factor by Cox regression analysis.4.VHL was only expressed in cytoplasm,and there were significant differences between VHL in astrocytoma,IDH mutant,grade 3 and 4 and glioblastoma,IDH wild type,grade 4,respectively(P<0.05).In astrocytoma,IDH mutant,grade 2,VHL was correlated with PHD3(P<0.05);In astrocytoma,IDH mutant,grade 4,HIF-1β was correlated with VHL expression(P<0.01).VHL was correlated with tumor size(P<0.05).VHL was significantly correlated with the expressions of IDH,ATRX,1p/19 q,TERT and Ki67(P<0.05),but had no significant correlation with MGMT and P53(P>0.05).There was a correlation between VHL and PFS in univariate Cox regression analysis(P<0.05),but no significant correlation between VHL and PFS in multivariate Cox regression analysis(P>0.05).5.PHD1 was only expressed in cytoplasm,and there were significant differences in astrocytoma,IDH mutant,grade 4 and oligodendroglioma,IDH mutation with 1p/19 q co-deletion,grade 3 respectively compared with glioblastoma,IDH wild type,and grade 4(P<0.05),but no differences in the others(P>0.05).In astrocytoma,IDH mutant,grade 2,HIF-1α was correlated with PHD1 expression(P<0.05);In astrocytoma,IDH mutant,grade 3,PHD1 was correlated with HIF-1β expression(P<0.05).In glioblastoma,IDH wild type,grade 4,the expressions of PHD1 and PHD2 were correlated(P<0.01).PHD1 was correlated with sex and tumor size(P<0.05).PHD1 was significantly correlated with the expressions of IDH,MGMT and Ki67(P<0.05),but had no significant correlation with ATRX,1p/19 q,TERT and P53(P>0.05).There was a correlation between PHD1 and PFS in univariate Cox regression analysis(P<0.05),but no significant correlation between PHD1 and PFS in multivariate Cox regression analysis(P>0.05).6.PHD2 was mainly expressed in the cytoplasm.In oligodendroglioma with IDH mutation and 1p/19 q co-deletion,a few samples were expressed in the nucleus,and there was no significant difference in the expression of PHD2 among all levels(P>0.05).In glioblastoma,IDH wild type,the expression of PHD2 was correlated with PHD1 in grade 4(P<0.05).In oligodendroglioma,IDH mutation combined with 1p/19 q co-deletion,and PHD2 was correlated with HIF-1α expression in grade 2(P<0.05).There was no significant correlation between PHD2 and clinical features(P>0.05).7.PHD3 was expressed in cytoplasm and nucleus,mainly in cytoplasm,and its expression in astrocytoma,IDH mutant,grade 2 and 3 were significantly different from that in glioblastoma,IDH wild type,grade 4 and oligodendroglioma,IDH mutation with 1p/19 q co-deletion,with significant differences between grade 2 and grade 3(P<0.05).There was no significant difference among other grades(P>0.05).In astrocytoma,IDH mutant,grade 2,VHL was correlated with PHD3(P<0.05);In astrocytoma,IDH mutant,grade 3,HIF-1α was correlated with PHD3expression(P<0.05).In glioblastoma,IDH wild type,grade 4,HIF-1α was correlated with PHD3 expression(P<0.01).PHD3 was correlated with age,tumor size,tumor cell source and tumor location(P<0.05).PHD3 was significantly correlated with the expressions of IDH,1p/19 q,TERT,MGMT,Ki67 and P53(P<0.05),but had no significant correlation with ATRX(P>0.05).There was no significant correlation between PHD3 and PFS by Cox regression analysis(P>0.05).8.Homozygous deletion of CDKN2A/B was found in 3 cases(6.7%)by Fluorescence In Situ Hybridization.Conclusions:1.The expressions of HIF-1β,VHL,PHD1 and PHD3 in adult diffuse glioma were different at different levels.2.HIF-1β may be an independent prognostic factor for adult diffuse glioma.3.There may be different metabolic pathways of HIFs,VHL and PHDs among all levels of adult diffuse glioma. |
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