Insulin-like growth factor binding protein-2 and glucose-regulated protein 78 kDa: Potential biomarkers affect prognosis in IDH-wildtype glioblastoma patients

Harland, Abigail J; Perks, Claire M; White, Paul; Kurian, Kathreena M; Barber, Hannah R

Abstract

Background: The overall survival of IDH-wildtype glioblastoma patients is poor despite best available treatments. There is an urgent need for new biomarkers to inform more precise disease stratification. Previous studies have identified insulin-like growth factor binding protein-2 (IGFBP-2) as a potential biomarker for glioblastoma diagnosis and therapeutic targeting. Other studies have indicated links between the insulin-like growth factor (IGF) axis and tumorigenic functions of a molecular chaperone glucose related protein of 78 kDa (GRP78). We aimed to interrogate the oncogenic effects of IGFBP-2 and GRP78 in our glioma stem cell (GSC) lines and clinical cohort. Methods: Immunoblotting, reverse transcription quantitative real-time PCR were used to quantify protein and mRNA levels derived from GSCs and non-malignant neural stem cells (NSCs). Microarray analysis was used to compare the differences in IGFBP-2 (IGFBP-2) and GRP78 (HSPA5) transcript expression between NSCs, GSCs and adult human cortex samples. Immunohistochemistry was used to quantify IGFBP-2 and GRP78 expression in IDH-wildtype glioblastoma tissue sections (n = 92) and clinical implications assessed using survival analysis. Finally, the relationship between IGFBP-2 and GRP78 was further explored molecularly using coimmunoprecipitation. Results: Here, we demonstrate that IGFBP-2 and HSPA5 mRNA is overexpressed in GSCs and NSCs in comparison to non-malignant brain tissue. We also determined a relationship in which G144 and G26 GSCs expressed higher IGFBP-2 protein and mRNA than GRP78, and this was reversed in mRNA isolated from adult human cortex samples. Clinical cohort analysis revealed that Glioblastomas with high IGFBP-2 protein expression paired with low GRP78 protein expression were significantly associated with a much shorter survival time (Median = 4 months, p = 0.019) compared with 12-14 months for any other combination of high/low protein expression. Conclusions: Inverse levels of IGFBP-2 and GRP78 may be adverse clinical prognostic markers in IDH-wildtype glioblastoma. Further interrogation of the mechanistic link between IGFBP-2 and GRP78 may be important for rationalisation of their potential as biomarkers and therapeutic targets.

• Journal Article Type: Article
• Acceptance Date: Apr 28, 2023
• Online Publication Date: May 22, 2023
• Publication Date: Jul 31, 2023
• Deposit Date: Apr 28, 2023
• Publicly Available Date: Aug 17, 2023
• Journal: Cancer Medicine
• Electronic ISSN: 2045-7634
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 13
• Pages: 14426-14439
• DOI: https://doi.org/10.1002/cam4.6071
• Keywords: Insulin, growth factor, binding protein-2 , binding protein, glucose regulated protein 78kDa, 78kDa, biomarkers, prognosis, IDH-wildtype glioblastoma, glioblastoma
• Public URL: https://uwe-repository.worktribe.com/output/10722133