Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

Zeng, Huijun; Zhao, Yang; Xu, Ningbo; Liu, Boyang; Zhao, Fen; Lian, Changlin

doi:10.1038/cddis.2017.248

Cited by 43 publications

(35 citation statements)

References 49 publications

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“…Additionally, it is addressed that KDM3A, a demethylase of histone H3K9me1/2, can promote the expression of CTGF by facilitating H3K27ac on the enhancers of CTGF [22]. While CTGF promotes drug-resistance in glioblastoma cells and facilitates the progression of glioblastoma [23]. Based on what has been discussed above, it was indicated that miR-27a-3p secreted from glioblastoma-EVs could downregulate EZH1 expression, elevate expression of KDM3A and further upregulate CTGF to polarize M2 macrophage.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

Zhao

Ding

et al. 2020

Preprint

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Background: M2 macrophage polarization has been found to be correlated with malignancy of glioblastoma. In this study, we investigated the potential role of microRNA (miRNA) derived from extracellular vesicles of glioblastoma (glioblastoma-EVs) in M2 macrophage polarization.Methods: After isolation of human glioblastoma-EVs, transmission electron microscopy (TEM) and Nano-particle tracking analysis (NTA) were performed to identify the EVs. Besides, the proliferation, migration and invasion of glioma cells were analyzed by CCK8 and Transwell assays, respectively. The target genes of miR-27a-3p were predicted through bioinformatics analysis and verified by dual-luciferase reporter gene assay. ChIP assay was applied to detect the binding of enhancer of zeste homologue 1 (EZH1) to lysine-specific demethylase 3A (KDM3A) promoter region and the interaction between KDM3A and connective tissue growth factor (CTGF). Glioblastoma mouse models were established followed by the implement of hematoxylin-eosin (HE) and ELISA staining on pathological changes of mouse brain tissues.Results: Human glioblastoma-EVs were successfully isolated. The high expression of miR-27a-3p was found in glioblastoma tissues as well as glioblastoma-EVs, which could induce M2 polarization, thus promoting glioblastoma cell proliferation, migration and invasion. It was also shown that miR-27a-3p targeted EZH1 and promoted KDM3A expression to elevate the expression of CTGF. Glioblastoma-EVs delivered miR-27a-3p to promote the KDM3A-upregulated CTGF by downregulating EZH1, thereby promoting M2 macrophage polarization and development of glioblastoma in vivo.Conclusion: These findings highlight that EV miR-27a-3p may promote M2 macrophage polarization, which is associated with the progression of tumors.

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

Zhao

Ding

et al. 2020

Preprint

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“…CTGF has been shown to regulate the MET of head and neck cancer cells ( 177 ) and drug resistance in glioblastoma ( 178 ), both via a mechanism involving the re-expression of pluripotency genes. Furthermore, CTGF inhibition reduces the growth of metastatic melanoma in an animal model ( 179 ).…”

Section: Molecular Regulators Of the Ecm That Influence Cancer Cell Pmentioning

confidence: 99%

The Role of the Extracellular Matrix and Its Molecular and Cellular Regulators in Cancer Cell Plasticity

et al. 2018

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The microenvironment encompasses all components of a tumor other than the cancer cells themselves. It is highly heterogenous, comprising a cellular component that includes immune cells, fibroblasts, adipocytes, and endothelial cells, and a non-cellular component, which is a meshwork of polymeric proteins and accessory molecules, termed the extracellular matrix (ECM). The ECM provides both a biochemical and biomechanical context within which cancer cells exist. Cancer progression is dependent on the ability of cancer cells to traverse the ECM barrier, access the circulation and establish distal metastases. Communication between cancer cells and the microenvironment is therefore an important aspect of tumor progression. Significant progress has been made in identifying the molecular mechanisms that enable cancer cells to subvert the immune component of the microenvironment to facilitate tumor growth and spread. While much less is known about how the tumor cells adapt to changes in the ECM nor indeed how they influence ECM structure and composition, the importance of the ECM to cancer progression is now well established. Plasticity refers to the ability of cancer cells to modify their physiological characteristics, permitting them to survive hostile microenvironments and resist therapy. Examples include the acquisition of stemness characteristics and the epithelial-mesenchymal and mesenchymal-epithelial transitions. There is emerging evidence that the biochemical and biomechanical properties of the ECM influence cancer cell plasticity and vice versa. Outstanding challenges for the field remain the identification of the cellular mechanisms by which cancer cells establish tumor-promoting ECM characteristics and delineating the key molecular mechanisms underlying ECM-induced cancer cell plasticity. Here we summarize the current state of understanding about the relationships between cancer cells and the main stromal cell types of the microenvironment that determine ECM characteristics, and the key molecular pathways that govern this three-way interaction to regulate cancer cell plasticity. We postulate that a comprehensive understanding of this dynamic system will be required to fully exploit opportunities for targeting the ECM regulators of cancer cell plasticity.

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“…3.2 | CCN2 increases ABCG2 expression via the α6β1 integrin receptor in human osteosarcoma cells CCN2 is capable of binding various growth factors or integrins and modifying their activity in certain carcinoma cells (Jun & Lau, 2017;Yang et al, 2016;Zeng et al, 2017). The most researched CCNbinding receptors are the integrins αvβ3, αvβ5, α5β1, and α6β1 (Lau, 2016).…”

Section: Ccn2 Enhances Abcg2 Expression and Increases Osteosarcoma mentioning

confidence: 99%

“…Around 27 human cancers have been linked to aberrant CCN2 expression (Zeng et al, 2017). CCN2 is a multifunctional signaling protein involved in a wide variety of biological and pathological processes (Bornstein & Sage, 2002;Pan et al, 2002), with some studies reporting that CCN2 promotes cell progression by supporting tumor cell survival and correlating with chemotherapeutic resistance in a variety of cancers (Corvaisier et al, 2016;Cui et al, 2011;Yin et al, 2010;Zeng et al, 2017).…”

mentioning

confidence: 99%

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

Tsai

Chang

Tsai

et al. 2018

Journal Cellular Physiology

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In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP‐binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6β1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR‐519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6β1 integrin receptor, whereas CCN2 downregulates miR‐519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.

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Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

Cited by 43 publications

References 49 publications

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

The Role of the Extracellular Matrix and Its Molecular and Cellular Regulators in Cancer Cell Plasticity

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

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