Overexpression Of IGFBP2 MRNA And Its Clinical Implication In Glioblastoma

Background:Glioma,originated in neuroepithelial cells,is the most common primary intracranial tumors.In which the high-grade glioma,glioblastoma(GBM),accounts for approximately 50%of all gliomas.Although giving operation,radiotherapy,chemotherapy and other treatments,the prognosis is still poor.Patients suffering from GBM have a dismal prognosis with a median survival of 15–17 months.At present,in the field of nervous system tumors research,molecular biomarkers have become an integral part of the tumor evaluation and guide the clinical decision-making of certain tumor subtypes.Some have been used for the clinical pathological classification of glioma such as TERT promoter mutation,IDH1/2 mutation and chromosomal loss of combined 1p/19q.Insulin like growth factor binding protein-2(IGFBP2),is a member of the secreted IGFBP family that functions by interacting with circulating Insulin-like growth factors(IGFs)to modulate IGF-mediated signaling.It has been observed that overexpression of IGFBP2 promoted an upregulation of migration and invasion.Increased IGFBP2 expression has conferred chemotherapy resistance in multiple types of malignancies including breast cancer,colon cancer and lung cancer.In glioblastoma,IGFBP2 is involved in the activation of related pathways such as PTEN and AKT,overexpression significantly increased the invasive capability of tumor cells.Analysis has showed that high IGFBP2 transcript level is associated with malignant clinical features of GBM cells.However,the studies of IGFBP2 transcript expression in GBM specimen detected by in situ method are limited.Based on the above research background,we asked the questions:Could the expression of IGFBP2 mRNA in glioblastoma tissues be detected in an in situ method?Could we treat IGFBP2 mRNA as an potential biomarker in predicting the survival of GBM?Methods:1.Collect GBM tissues and make Tissue microarrays(TMA);2.Nested PCR and Sanger sequencing were used in detecting the TERT promoter mutation in GBM tissues;3.Immunocytochemistry(IHC)was used in detecting the expression of protein such as Hsp27 and IDH1;4.RNAscope in situ hybridization(RISH)was used in detecting the expression of IGFBP2 mRNA of GBM sample;5.Analyze the relationship of expression of IGFBP2 in GBMs and clinical parameters.Results:1.RISH detection showed that IGFBP2 was of overexpression in 23.9%of the tested GBMs,including the anatomical types of cellular tumor(CT),cellular tumor pseudopalisading cells around necrosis(CT-pan)and microvascular proliferation (MVP).IGFBP2 mRNA was significantly higher expressed in primary than that in secondary GBMs(29.3%vs 2.5%,P=0.001);2.The high expression of IGFBP2 mRNA predicts a shorter survival than the low IGFBP2(mOS=11.6 vs 16.9 months,P=0.005).Multivariate Cox regression analysis demonstrated that IGFBP2 mRNA expression was an independent shorter survival indicator in GBMs(P=0.001);3.IGFBP2 expression was positively correlated with the expression of Hsp27,TERT promoter mutation(P=0.015 and 0.016),but negatively correlated with IDH1 mutation(P=0.013);4.By combining IGFBP2 mRNA expression and TERT promoter mutation,all GBMs can be divide into there subgroups with significantly difference of survival time,TERTp~-,TERTp~+/IGFBP2~-,TERTp~+/IGFBP2~+(mOS=19.6,14.8,9.8 months,P=0.001).Conclusion:1.Overexpression of IGFBP2 mRNA predicts poor survival in patients with glioblastoma;2.Together with TERT status,IGFBP2 mRNA might serve as a potential prognostic indicator in patients with glioblastoma.