Blockage of Glyoxalase I Inhibits Colorectal Tumorigenesis and Tumor Growth via Upregulation of STAT1, p53, and Bax and Downregulation of c-Myc and Bcl-2

Chen, Yuan; Fang, Lei; Zhang, Jiali; Li, Gefei; Ma, Mengni; Li, Changxi; Lyu, Jianxin; Meng, Qing H.

doi:10.3390/ijms18030570

Cited by 20 publications

(21 citation statements)

References 43 publications

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“…Most notably, MYC and B7-H3 were downregulated. Interestingly, miR-29 induced a 500-fold upregulation in STAT1 mRNA expression, a molecule implicated in downregulating MYC expression [36,37]. miR-29 downregulated many pro-angiogenic mRNA’s such as VEGFR2, AKT2, MMP2, MMP9, Zap70, MAP2K5 and HIF-1ɑ, further supporting its anti-angiogenesis role in MB (Figure 5A).…”

Section: Resultsmentioning

confidence: 95%

Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis

Purvis

Janardhan

Guda

et al. 2019

JCM

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Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is highly expressed and is associated with lower overall survival in MYC+ MB’s. Evidence for a direct transcriptional role of MYC on the B7-H3 gene promoter was confirmed by MYC inhibition and anti-MYC antibody ChIP analysis. Interestingly, MYC inhibition not only downregulated the B7-H3 protein expression, but also rescued miR-29 expression, thus indicating a triangular regulatory relationship between MYC, miR-29, and B7-H3 in Group 3 MB cells. From RNA seq and IPAD assay, we observed a negative feedback loop between miR-29 and MYC that may control B7-H3 expression levels in MB cells. Our studies show that B7-H3 expression levels play a crucial role in promoting MB angiogenesis which can be inhibited by miR-29 overexpression via miR-29-mediated B7-H3 downregulation. The tumor suppressor role of miR-29 is mediated by the activation of JAK/STAT1 signaling that further plays a role in MYC-B7-H3 downregulation in MB. This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs.

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Section: Resultsmentioning

confidence: 95%

Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis

Purvis

Janardhan

Guda

et al. 2019

JCM

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“…STAT1 is generally considered as a tumor suppressor, although there are some reports on its tumor promoting functions 23. A correlation of STAT1 expression in tumor cells with good prognosis has been reported in several types of cancers 25, 26. Accumulating evidence indicated that STAT1 acts as a tumor suppressor at multiple levels: tumor-intrinsic growth control and tumor immune environment modulation.…”

Section: Discussionmentioning

confidence: 99%

Cancer/testis Antigen MAGEA3 Interacts with STAT1 and Remodels the Tumor Microenvironment

et al. 2018

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Cancer-testis antigen MAGEA3, being restrictedly expressed in testis and various kinds of tumors, has long been considered as an ideal target for immunotherapy. In this study, we report that MAGEA3 interacts with STAT1 and regulates the expression of tyrosine phosphorylated STAT1 (pY-STAT1) in tumor cells. We show that pY-STAT1 is significantly up-regulated when MAGEA3 is silenced by MAGEA3-specific siRNA. RNA sequencing analysis identified 274 STAT1-related genes to be significantly altered in expression level in MAGEA3 knockdown cells. Further analysis of these differentially expressed genes with GO enrichment and KEGG pathway revealed that they are mainly enriched in plasma membrane, extracellular region and MHC class I protein complex, and involved in the interferon signaling pathways, immune response, antigen presentation and cell chemotaxis. The differentially expressed genes associated with chemokines, antigen presentation and vasculogenic mimicry formation were validated by biological experiments. Matrigel matrix-based tube formation assay showed that silencing MAGEA3 in tumor cells impairs tumor vasculogenic mimicry formation. These data indicate that MAGEA3 expression in tumor cells is associated with immune cells infiltration into tumor microenvironment and anti-tumor immune responses, implying that it may play an important role in tumor immune escape. Our findings reveal the potential impact of MAGEA3 on the immunosuppressive tumor microenvironment and will provide promising strategies for improving the efficacy of MAGEA3-targeted immunotherapy.

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“…In renal cell carcinoma cells, down-regulation of STAT1 expression can slow cell growth ( Ah-Koon et al, 2016 ). Additional research has linked STAT1 with the development of many malignant tumors, including breast cancer, myeloma, and renal cancer ( Suyama et al, 2016 ; Chen et al, 2017 ; Qu et al, 2017 ; Josahkian et al, 2018 ). Specifically, STAT1 was shown to regulate p53 activity by inducing phosphorylation of p53 ( Chen et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…Additional research has linked STAT1 with the development of many malignant tumors, including breast cancer, myeloma, and renal cancer ( Suyama et al, 2016 ; Chen et al, 2017 ; Qu et al, 2017 ; Josahkian et al, 2018 ). Specifically, STAT1 was shown to regulate p53 activity by inducing phosphorylation of p53 ( Chen et al, 2017 ). Through such interaction with p53, STAT1 promotes apoptosis, and STAT1 also interacts with the p53 inhibitor MDM2 ( Chen et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, STAT1 was shown to regulate p53 activity by inducing phosphorylation of p53 ( Chen et al, 2017 ). Through such interaction with p53, STAT1 promotes apoptosis, and STAT1 also interacts with the p53 inhibitor MDM2 ( Chen et al, 2017 ). Therefore, we explored whether the potential effects of Fra-1 on cervical cancer cell growth and the Warburg effect in these cells are mediated by STAT1 regulation of the p53 signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway

Manying

Liang

et al. 2020

Front. Cell Dev. Biol.

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The oncogenesis of cervical cancer is a multi-factor and multi-step process, and major risk factors include oncogene activation with tumor suppressor gene inactivation, viral factors, and immune factors. For example, the human papillomavirus (HPV) has been linked to the occurrence of cervical cancer. At present, the pathogenesis of cervical cancer remains unclear. Fra-1 (Fos-related antigen 1, also known as FOSL1) is a member of the Fos family and an important nuclear transcription factor that regulates normal cell growth, differentiation, and apoptosis. In the present study, we found that Fra-1 inhibited the proliferation of cervical cancer cells while also promoting apoptosis and affecting cell cycle distribution. Moreover, Fra-1 up-regulated STAT1 expression and modulated p53 signal pathway activity in cervical cancer cells. Overexpression of Fra-1 inhibited cell senescence by altering sirtuin 1 (SIRT1) expression in HeLa cells, and Fra-1 overexpression restored mitochondrial disorder and suppressed metabolic reprogramming in HeLa cells. Silencing of STAT1 impaired the inhibitory effect of Fra-1 on cervical cancer cell growth, while knock-down of STAT1 reversed the effect on cell senescence and mitochondrial dysfunction caused by Fra-1 in HeLa cells. Silencing of STAT1 also recovered metabolic reprogramming in cervical cancer cells. In summary, our results show that Fra-1 inhibited cervical cancer cell growth and the Warburg effect via STAT1-mediated regulation of the p53 signaling pathway.

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Blockage of Glyoxalase I Inhibits Colorectal Tumorigenesis and Tumor Growth via Upregulation of STAT1, p53, and Bax and Downregulation of c-Myc and Bcl-2

Cited by 20 publications

References 43 publications

Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis

Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis

Cancer/testis Antigen MAGEA3 Interacts with STAT1 and Remodels the Tumor Microenvironment

Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway

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