Inhibition of STAT3 and ErbB2 Suppresses Tumor Growth, Enhances Radiosensitivity, and Induces Mitochondria-Dependent Apoptosis in Glioma Cells

Gao, Ling; Li, Fengsheng; Dong, Bo; Junquan, Zhang; Rao, Yalan; Cong, Yue; Bingzhi, Mao; Chen, Xiaohua

doi:10.1016/j.ijrobp.2009.12.036

Cited by 59 publications

(41 citation statements)

References 18 publications

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“…Among these five hub miRNAs, miR-16 and miR-15a were found to be dysregulated in glioma [42]; moreover, they have performed cooperative regulatory functions in other cancers [43], [44]. Some genes in this survival module were similarly implicated in the occurrence and development of glioma, such as ERBB2 , ITGB3 , EGFR , and MET [45], [46], [47], [48]. As illustrated in Figure 2, all genes in the survival module were divided into 13 classes (12 pathways and 1 multi-pathway) according to the KEGG pathway classification.…”

Section: Resultsmentioning

confidence: 99%

Identification of miRNA-Mediated Core Gene Module for Glioma Patient Prediction by Integrating High-Throughput miRNA, mRNA Expression and Pathway Structure

Zhang

et al. 2014

PLoS ONE

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The prognosis of glioma patients is usually poor, especially in patients with glioblastoma (World Health Organization (WHO) grade IV). The regulatory functions of microRNA (miRNA) on genes have important implications in glioma cell survival. However, there are not many studies that have investigated glioma survival by integrating miRNAs and genes while also considering pathway structure. In this study, we performed sample-matched miRNA and mRNA expression profilings to systematically analyze glioma patient survival. During this analytical process, we developed pathway-based random walk to identify a glioma core miRNA-gene module, simultaneously considering pathway structure information and multi-level involvement of miRNAs and genes. The core miRNA-gene module we identified was comprised of four apparent sub-modules; all four sub-modules displayed a significant correlation with patient survival in the testing set (P-values≤0.001). Notably, one sub-module that consisted of 6 miRNAs and 26 genes also correlated with survival time in the high-grade subgroup (WHO grade III and IV), P-value = 0.0062. Furthermore, the 26-gene expression signature from this sub-module had robust predictive power in four independent, publicly available glioma datasets. Our findings suggested that the expression signatures, which were identified by integration of miRNA and gene level, were closely associated with overall survival among the glioma patients with various grades.

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Section: Resultsmentioning

confidence: 99%

Identification of miRNA-Mediated Core Gene Module for Glioma Patient Prediction by Integrating High-Throughput miRNA, mRNA Expression and Pathway Structure

Zhang

et al. 2014

PLoS ONE

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“…Therefore, STAT3 is considered to be a target molecule in patients with glioma (31). In addition, STAT3 activation in tumor cells is considered to cause tumor cell resistance to anti-cancer therapies, such as chemotherapy and radiotherapy (32). We also previously demonstrated that the STAT3 inhibitor CA enhanced the efficacy of chemotherapeutic agents against glioblastoma cells.…”

Section: Discussionmentioning

confidence: 97%

Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3

Komohara

2011

Oncol Rep

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Abstract. Tumor-associated macrophages (TAMs) polarized to the M2 phenotype promote tumor cell proliferation and are associated with a poor prognosis in patients with high grade glioma. We previously revealed that corosolic acid, a triterpenoid compound, inhibits the M2 polarization of human monocyte-derived macrophages (HMDM). In the present study, we examined whether oleanolic acid (OA), a triterpenoid compound whose structure is similar to corosolic acid, also shows inhibitory effects on M2 polarization in HMDM. OA significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, as well as suppressed the secretion of IL-10, one of the anti-inflammatory cytokines preferentially produced by M2 macrophages, thus suggesting that OA suppresses the M2 polarization of macrophages. Furthermore, OA inhibited the proliferation of U373 human glioblastoma cells, and the activation of signal transducer and activator of transcription-3 (STAT3) in both human macrophages and glioblastoma cells. These results indicate that OA suppresses the M2 polarization of macrophages and tumor cell proliferation by inhibiting STAT3 activation. Therefore, OA may be a potentially new agent that can be used for the prevention and treatment of various malignant tumors, including glioma.

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“…Another indication that the antitumorigenic effect of microglia is due to their specific glioma associated phenotype came from experiments interfering with the signaling pathway involving signal transducers and activators of transcription 3 (Stat3). Inactivation of Stat3 in experimental gliomas by siRNA resulted in microglial activation and tumor growth inhibition (Gao et al, 2010). Cyclosporin A at clinically relevant concentrations impairs the protumorigenic phenotype of microglia when studying the glioma migration in organotypic brain slices.…”

Section: Microglia Promote Glioma Migration and Tumor Growthmentioning

confidence: 99%

The brain tumor microenvironment

Charles

Holland

Gilbertson

et al. 2011

Glia

693

327

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High-grade brain tumors are heterogeneous with respect to the composition of bona fide tumor cells and with respect to a range of intermingling parenchymal cells. Glioblastomas harbor multiple cell types, some with increased tumorigenicity and stem cell-like capacity. The stem-like cells may be the cells of origin for tumor relapse. However, the tumor-associated parenchymal cells such as vascular cells, microglia, peripheral immune cells, and neural precursor cells also play a vital role in controlling the course of pathology. In this review, we describe the multiple interactions of bulk glioma cells and glioma stem cells with parenchymal cell populations and highlight the pathological impact as well as signaling pathways known for these types of cell-cell communication. The tumor-vasculature not only nourishes glioblastomas, but also provides a specialized niche for these stem-like cells. In addition, microglial cells, which can contribute up to 30% of a brain tumor mass, play a role in glioblastoma cell invasion. Moreover, non-neoplastic astrocytes can be converted into a reactive phenotype by the glioma microenvironment and can then secrete a number of factors which influences tumor biology. The young brain may have the capacity to inhibit gliomagenesis by the endogenous neural precursor cells, which secrete tumor suppressive factors. The factors, pathways, and interactions described in this review provide a new prospective on the cell biology of primary brain tumors, which may ultimately generate new treatment modalities. However, our picture of the multiple interactions between parenchymal and tumor cells is still incomplete. V

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Inhibition of STAT3 and ErbB2 Suppresses Tumor Growth, Enhances Radiosensitivity, and Induces Mitochondria-Dependent Apoptosis in Glioma Cells

Cited by 59 publications

References 18 publications

Identification of miRNA-Mediated Core Gene Module for Glioma Patient Prediction by Integrating High-Throughput miRNA, mRNA Expression and Pathway Structure

Identification of miRNA-Mediated Core Gene Module for Glioma Patient Prediction by Integrating High-Throughput miRNA, mRNA Expression and Pathway Structure

Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3

The brain tumor microenvironment

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