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The Journal of Neuroscience, June 4, 2008, 28(23):5870-5878; doi:10.1523/JNEUROSCI.5385-07.2008

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Neurobiology of Disease
Deregulation of a STAT3–Interleukin 8 Signaling Pathway Promotes Human Glioblastoma Cell Proliferation and Invasiveness

Núria de la Iglesia,^1 * Genevieve Konopka,^1,2 * Kah-Leong Lim,¹ Catherine L. Nutt,⁴ Jacqueline F. Bromberg,⁵ David A. Frank,⁵ Paul S. Mischel,⁶ David N. Louis,⁴ and Azad Bonni^1,2

¹Department of Pathology, ²Program in Neuroscience, and ³Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, ⁴Department of Pathology and Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, ⁵Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and ⁶Department of Molecular and Medical Pharmacology and Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Azad Bonni at the above address. Email: azad_bonni{at}hms.harvard.edu

Inactivation of the tumor suppressor phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN) is recognized as a major event in the pathogenesis of the brain tumor glioblastoma. However, the mechanisms by which PTEN loss specifically impacts the malignant behavior of glioblastoma cells, including their proliferation and propensity for invasiveness, remain poorly understood. Genetic studies suggest that the transcription factor signal transducers and activators of transcription 3 (STAT3) harbors a PTEN-regulated tumor suppressive function in mouse astrocytes. Here, we report that STAT3 plays a critical tumor suppressive role in PTEN-deficient human glioblastoma cells. Endogenous STAT3 signaling is specifically inhibited in PTEN-deficient glioblastoma cells. Strikingly, reactivation of STAT3 in PTEN-deficient glioblastoma cells inhibits their proliferation, invasiveness, and ability to spread on myelin. We also identify the chemokine interleukin 8 (IL8) as a novel target gene of STAT3 in human glioblastoma cells. Activated STAT3 occupies the endogenous IL8 promoter and directly represses IL8 transcription. Consistent with these results, IL8 is upregulated in PTEN-deficient human glioblastoma tumors. Importantly, IL8 repression mediates STAT3 inhibition of glioblastoma cell proliferation, invasiveness, and spreading on myelin. Collectively, our findings uncover a novel link between STAT3 and IL8, the deregulation of which plays a key role in the malignant behavior of PTEN-deficient glioblastoma cells. These studies suggest that STAT3 activation or IL8 inhibition may have potential in patient-tailored treatment of PTEN-deficient brain tumors.

Key words: STAT3; IL8; astrocyte; astroglia; gliogenesis; glioma; tumor

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Received Dec. 5, 2007; revised April 9, 2008; accepted April 9, 2008.

Correspondence should be addressed to Azad Bonni at the above address. Email: azad_bonni{at}hms.harvard.edu

This article has been cited by other articles:

				J. Wanninger, M. Neumeier, J. Weigert, S. Bauer, T. S. Weiss, A. Schaffler, C. Krempl, C. Bleyl, C. Aslanidis, J. Scholmerich, et al. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-{kappa}B, and STAT3 signaling pathways Am J Physiol Gastrointest Liver Physiol, September 1, 2009; 297(3): G611 - G618. [Abstract] [Full Text] [PDF]

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