Deregulation of a STAT3-Interleukin 8 Signaling Pathway Promotes Human Glioblastoma Cell Proliferation and Invasiveness

Abstract

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 PTENregulated tumor suppressive function in mouse astrocytes. Here, we report that STAT3 plays a critical tumor suppressive role in PTENdeficient 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.

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

“…The results of a recent study (26), similar to our findings, showed that IFN-β induces the phosphorylation of STAT3 in glioma cells and thereby activates STAT3-mediated miR-21 transcription in a luciferase reporter gene system. Our findings support the hypothesis that STAT3 activation exerts a cytostatic or antiproliferative effect in some types of cells (34)(35)(36)(37); however, the role of STAT3 activation is debatable because its overactivation has been reported to be oncogenic in some cell lines (38,39). Loffler et al showed that IL-6-dependent STAT3 activates the transcription of miR-21 in multiple myeloma cells.…”

STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma

“…Moreover, these results might be influenced by genetic background of GBM tumors. It has been shown that STAT3 may play in some tumors, a pro-or an anti-oncogenic role, depending on the mutational status of PTEN (18). We showed here that, STAT3 status in turn can influence tumor responsiveness to a chemical treatment (Gö6976) and to irradiation.…”

Identification of candidate colon cancer biomarkers by applying a random forest approach on microarray data

“…There are 1,182 studies describing the gene function of IL8, including the biological mechanism in progress of most kinds of human cancer such as: glioblastoma, gastric carcinoma, small cell lung cancer, prostate cancer, esophageal squamous cell carcinoma, acute myelogenous leukemia, and colon cancer (23)(24)(25)(26)(27)(28)(29). It was confirmed that IL8 is differentially expressed in colon cancer, and is associated with proliferation, migration, angiogenesis and chemosensitivity in colon cancer cell line models (30).…”