c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma

Liu, Zhi Gang; Jiang, Guanmin; Tang, Jiao; Wang, Hui; Feng, Guokai; Chen, Fu‐Rong; Tu, Ziwei; Liu, Guiyun; Zhao, Yu; Peng, Ming; He, Zheng Wen; Chen, Xiao Yan; Lindsay, Holly; Xia, Yun; Li, Xiao Nan

doi:10.18632/oncotarget.11779

Cited by 43 publications

(34 citation statements)

References 38 publications

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“…Although TMZ is considered to be one of the most effective chemotherapeutic agents to prolong GBM patient survival [2] , these SOC treatments, including TMZ, have not provided any long-term survival, and reoccurrence is very common. The recurrence for high-grade gliomas, particularly GBM, is due to difficulty in achieving a gross surgical section coupled with resistance to chemo- (mainly TMZ) [3] , [4] and radiotherapies [5] , [6] . Glioma-initiating cells that have stem-like properties have been linked with resistance to therapy and progression [7] , [8] .…”

Section: Introductionmentioning

confidence: 99%

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

Towner

Smith

Saunders

et al. 2019

Translational Oncology

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Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007–treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-β1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients.

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Section: Introductionmentioning

confidence: 99%

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

Towner

Smith

Saunders

et al. 2019

Translational Oncology

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“…However, overexpression of c-Jun and c-Fos also promoted the malignant transformation of cells ( 19 ). Previous investigations revealed that silencing of c-Fos sensitized glioma cells to radiation and c-Fos overexpression was correlated with poor prognosis in malignant glioma patients ( 20 ). c-Fos transcriptionally controled MMP10 and S100A15 expression in keratinocytes in skin squamous cell carcinoma, promoting epidermal hyperplasia ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

c-Fos mediates α1, 2-fucosyltransferase 1 and Lewisï¿½y expression in response to TGF-β1 in ovarian cancer

et al. 2017

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FUT1 is a key rate-limiting enzyme in the synthesis of Lewis y, a membrane-associated carbohydrate antigen. The aberrant upregulation of FUT1 and Lewis y antigen is related to proliferation, invasion and prognosis in malignant epithelial tumors. A c-Fos/activator protein-1 (AP-1) binding site was found in the FUT1 promoter. However, the mechanisms of transcriptional regulation of FUT1 remain poorly understood. TGF-β1 is positively correlated to Lewis y. In the present study, we investigated the molecular mechanism of FUT1 gene expression in response to TGF-β1. We demonstrated that c-Fos was highly expressed in 77.50% of ovarian epithelial carcinoma cases and was significantly correlated with Lewis y. Using luciferase activity and chromatin immunoprecipitation (ChIP) assay, we further revealed that c-Fos interacted with the FUT1 promoter in ovarian cancer cells and transcriptional capacity of the heterodimer formed by c-Fos and c-Jun was stronger than that of the c-Fos or c-Jun homodimers. Then, we demonstrated that TGF-β1 induced dose-dependent c-Fos expression, which was involved in TGF-β1-induced ovarian cancer cell proliferation. In addition, inhibition of MAPK activation or TGF-β1 receptor by pharmacological agents prevented TGF-β1-induced c-Fos and Lewis y expression. Silencing of c-Fos prevented TGF-β1-induced Lewis y expression. Collectively, the results of these studies demonstrated that TGF-β1 regulated FUT1 and Lewis y expression by activating the MAPK/c-Fos pathway.

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“…c-FOS, as a major component of activator protein (AP)-1 complex, has been involved in cell differentiation, proliferation, angiogenesis, invasion, and metastasis [45,46]. Here, we found that c-FOS was an important target gene positively regulated by miR-744, which mediated the promotion of miR-744 on the malignant phenotype of NSCLC cells.…”

Section: Discussionmentioning

confidence: 87%

MiR-744 facilitates non-small cell lung cancer progression by direct transcriptional regulation and indirect MAPK pathway activation mediated upregulation of C-FOS

Zhu

2020

Preprint

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Background: Metastasis is the leading cause of lung cancer associated death. Here, we focused on the function and molecular mechanism of miR-744 and its potential clinical application in lung carcinoma. Methods: The clinical cohort and data from TCGA were analyzed for the correlation of miR-744 and outcomes. Multiple NSCLC cell lines and a xenograft model were applied for the functional studies. Reporter assays were explored for transcriptional regulatory mechanism.Results: It was confirmed that the overexpression of miR-744 was significantly correlated with lymph node metastasis and poor prognosis in NSCLC. Both in vitro and in vivo studies revealed that miR-744 overexpression aggravated the growth, invasion and metastasis of NSCLC cells. MiR-744 enhanced the resistance of lung cancer cells to radiotherapy and paclitaxel. MiR-744 positively regulated C-FOS by directly binding to the promoter of C-FOS and -1195 to -1227 and -298 to -323 bp upstream of C-FOS gene were the direct and efficient miR-744 binding sites. MiR-744 could also indirectly upregulate c-FOS protein by activating MAPK pathway.Conclusion: Our findings uncover the function and a novel mechanism of miR-744 in mediating growth and metastasis of NSCLC cells. Our data suggests that miR-744 may serve as a possible therapeutic target for NSCLC.

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c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma

Cited by 43 publications

References 38 publications

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

c-Fos mediates α1, 2-fucosyltransferase 1 and Lewisï¿½y expression in response to TGF-β1 in ovarian cancer

MiR-744 facilitates non-small cell lung cancer progression by direct transcriptional regulation and indirect MAPK pathway activation mediated upregulation of C-FOS

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