Abstract
Glioblastoma multiforme (glioblastoma) remains one of the deadliest cancers. Pro-inflammatory and pro-tumorigenic mediators present in tumor microenvironment (TME) facilitate communication between tumor cells and adjacent non-malignant cells, resulting in glioblastoma growth. Since a majority of these mediators are products of NF-κB- and/or AP-1-responsive genes, and as TRAF3 Interacting Protein 2 (TRAF3IP2) is an upstream regulator of both transcription factors, we hypothesized that targeting TRAF3IP2 blunts tumor growth by inhibiting NF-κB and pro-inflammatory/pro-tumorigenic mediators. Our in vitro data demonstrate that similar to primary glioblastoma tumor tissues, malignant glioblastoma cell lines (U87 and U118) express high levels of TRAF3IP2. Silencing TRAF3IP2 expression inhibits basal and inducible NF-κB activation, induction of pro-inflammatory mediators, clusters of genes involved in cell cycle progression and angiogenesis, and formation of spheroids. Additionally, silencing TRAF3IP2 significantly increases apoptosis. In vivo studies indicate TRAF3IP2-silenced U87 cells formed smaller tumors. Additionally, treating existing tumors formed by wild type U87 cells with lentiviral TRAF3IP2 shRNA markedly regresses their size. Analysis of residual tumors revealed reduced expression of pro-inflammatory/pro-tumorigenic/pro-angiogenic mediators and kinesins. In contrast, the expression of IL-10, an anti-inflammatory cytokine, was increased. Together, these novel data indicate that TRAF3IP2 is a master regulator of malignant signaling in glioblastoma, and its targeting modulates the TME and inhibits tumor growth by suppressing the expression of mediators involved in inflammation, angiogenesis, growth, and malignant transformation. Our data identify TRAF3IP2 as a potential therapeutic target in glioblastoma growth and dissemination.
Highlights
Glioblastoma multiforme (GBM/glioblastoma) is the most aggressive and diffuse brain tumor of astrocytic lineage
The expression of IL-10, an anti-inflammatory cytokine, was increased. These novel data indicate that TRAF3IP2 is a master regulator of malignant signaling in glioblastoma, and its targeting modulates the tumor microenvironment (TME) and inhibits tumor growth by suppressing the expression of mediators involved in inflammation, angiogenesis, growth, and malignant transformation
In order to demonstrate the clinical relevance of TRAF3IP2 in glioblastoma, we analyzed its expression by IHC using a commercially available brain glioblastoma tissue array that contains tissue sections from 10 different glioblastoma patients of both genders and different ages
Summary
Glioblastoma multiforme (GBM/glioblastoma) is the most aggressive and diffuse brain tumor of astrocytic lineage. In addition to malignant cells, glioblastoma lesions contain non-malignant cells that include endothelial cells, inflammatory cells, cells with stem-like properties, and cells with neural, glial, or myeloid markers. These cells, together with soluble inflammatory mediators, form the tumor microenvironment (TME). Non-tumor cell-derived TNF-α, IL-6, IL-8, and IL-1β stimulate tumor cell proliferation, invasion, and metastasis via paracrine signaling [6,7,8,9,10] These inflammatory mediators possess chemotactic properties and recruit various immune cells to the TME. Many of these inflammatory mediators are NF-κB- and/or AP-1-responsive genes
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