Research Papers:

TRAF3IP2, a novel therapeutic target in glioblastoma multiforme

Eckhard U. Alt, Zahra Barabadi, Andreas Pfnür, Joana E. Ochoa, Fatemeh Daneshimehr, Lea M. Lang, Dong Lin, Stephen E. Braun, Bysani Chandrasekar and Reza Izadpanah _

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Oncotarget. 2018; 9:29772-29788. https://doi.org/10.18632/oncotarget.25710

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Eckhard U. Alt1,*, Zahra Barabadi1,*, Andreas Pfnür1, Joana E. Ochoa2, Fatemeh Daneshimehr1, Lea M. Lang1, Dong Lin1, Stephen E. Braun3, Bysani Chandrasekar4 and Reza Izadpanah1,2

1Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA

2Department of Surgery, Tulane University Health Science Center, New Orleans, Louisiana, USA

3Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, Louisiana, USA

4Department of Medicine, University of Missouri School of Medicine and Harry S. Truman Veterans Memorial Hospital, Columbia, Missouri, USA

*These authors contributed equally to this work

Correspondence to:

Reza Izadpanah, email: [email protected]

Keywords: TRAF3IP2; glioblastoma multiforme; tumor microenvironment; cancer stem cells; inflammation

Received: April 04, 2018     Accepted: June 13, 2018     Published: July 03, 2018


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.

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