Dataset Information

Integrin ?10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival.

ABSTRACT: New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin ?10?1 as a therapeutic target in GBMs. Expression levels and the role of integrin ?10?1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin ?10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin ?10?1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins ?3, ?6, and ?7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin ?10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin ?10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin ?10?1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

SUBMITTER: Munksgaard Thoren M

PROVIDER: S-EPMC6521287 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival.

Munksgaard Thorén Matilda M Chmielarska Masoumi Katarzyna K Krona Cecilia C Huang Xiaoli X Kundu Soumi S Schmidt Linnéa L Forsberg-Nilsson Karin K Floyd Keep Marcus M Englund Elisabet E Nelander Sven S Holmqvist Bo B Lundgren-Åkerlund Evy E

Cancers 20190425 4

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We fo ...[more]

PMID: 31027305

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Project description:Glioblastoma multiformae (GBM) is the most aggressive type of malignant brain tumor with complex molecular profile. Overexpression of Na+/H+ Exchanger isoform 9 (NHE9) promotes tumor progression and correlates positively with insensitivity to radiochemotherapy and poor prognosis. However, molecular mechanisms responsible for increase in NHE9 levels beyond a critical threshold have not been identified.Bioinformatics analysis, luciferase reporter assays, real-time PCR and western blotting were conducted to examine the expression profiles and identify microRNAs (miRNA) that target NHE9. Cell proliferation and migration assays were conducted in U87 glioblastoma cells to determine the consequence of miRNA mediated targeting of NHE9. Endosomal pH measurements, immunofluorescence microscopy and surface biotinylation experiments were conducted to characterize the mechanistic basis of regulation.We show that microRNA 135a (miR-135a) targets NHE9 to downregulate its expression in U87 cells. MiR-135a levels are significantly lower in glioblastoma cells compared to normal brain tissue. Downregulation of NHE9 expression by miR-135a affects proliferative and migratory capacity of U87 cells. Selectively increasing NHE9 expression in these cells restored their ability to proliferate and migrate. We demonstrate that miR-135a takes a two-pronged approach affecting epidermal growth factor receptors (EGFRs) to suppress tumor cell growth and migration. EGFR activity is a potent stimulator of oncogenic signaling. While miR-135a targets EGFR transcripts to decrease the total number of receptors made, by targeting NHE9 it routes the few EGFRs made away from the plasma membrane to dampen oncogenic signaling. NHE9 is localized to sorting endosomes in glioblastoma cells where it alkalinizes the endosome lumen by leaking protons. Downregulation of NHE9 expression by miR-135a acidifies sorting endosomes limiting EGFR trafficking to the glioblastoma cell membrane.We propose downregulation of miR-135a as a potential mechanism underlying the high NHE9 expression observed in subset of glioblastomas. Future studies should explore miR-135a as a potential therapeutic for glioblastomas with NHE9 overexpression.

Dataset Information

Integrin ?10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival.

Publications

Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival.

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