GLI2 Regulates TGF-β1 in Human CD4+ T Cells: Implications in Cancer and HIV Pathogenesis

Furler, Robert L.; Uíttenbogaart, Christel H.

doi:10.1371/journal.pone.0040874

Cited by 33 publications

(31 citation statements)

References 57 publications

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“…In this tumor, as well as in one HCC tumor, we detected HBV S protein transcripts integrated into GLI2, generally considered a marker of activation of the sonic hedgehog signaling pathway, which has been shown to play a role in aggressive types of renal cell carcinoma (30)(31)(32) and in HCC (33,34).…”

Section: Resultsmentioning

confidence: 93%

Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq

Khoury¹,

Tannir

Williams³

et al. 2013

J Virol

198

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Elucidation of tumor-DNA virus associations in many cancer types has enhanced our knowledge of fundamental oncogenesis mechanisms and provided a basis for cancer prevention initiatives. RNA-Seq is a novel tool to comprehensively assess such associations. We interrogated RNA-Seq data from 3,775 malignant neoplasms in The Cancer Genome Atlas database for the presence of viral sequences. Viral integration sites were also detected in expressed transcripts using a novel approach. The detection capacity of RNA-Seq was compared to available clinical laboratory data. Human papillomavirus (HPV) transcripts were detected using RNA-Seq analysis in head-and-neck squamous cell carcinoma, uterine endometrioid carcinoma, and squamous cell carcinoma of the lung. Detection of HPV by RNA-Seq correlated with detection by in situ hybridization and immunohistochemistry in squamous cell carcinoma tumors of the head and neck. Hepatitis B virus and Epstein-Barr virus (EBV) were detected using RNA-Seq in hepatocellular carcinoma and gastric carcinoma tumors, respectively. Integration sites of viral genes and oncogenes were detected in cancers harboring HPV or hepatitis B virus but not in EBV-positive gastric carcinoma. Integration sites of expressed viral transcripts frequently involved known coding areas of the host genome. No DNA virus transcripts were detected in acute myeloid leukemia, cutaneous melanoma, low-and high-grade gliomas of the brain, and adenocarcinomas of the breast, colon and rectum, lung, prostate, ovary, kidney, and thyroid. In conclusion, this study provides a large-scale overview of the landscape of DNA viruses in human malignant cancers. While further validation is necessary for specific cancer types, our findings highlight the utility of RNA-Seq in detecting tumor-associated DNA viruses and identifying viral integration sites that may unravel novel mechanisms of cancer pathogenesis.

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Section: Resultsmentioning

confidence: 93%

Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq

Khoury¹,

Tannir

Williams³

et al. 2013

J Virol

198

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“…In one case, GLI2 was found to regulate the expression of TGFβ1 in human CD4+ cells. Researchers have shown the presence of GLI2-binding sites in the TGFβ1 promoter in CD4+ cells [76] . Reporter and ChIP assays showed that GLI2 was able to bind to two of these sites to promote transcriptional activation of TGFβ1 [76] .…”

Section: Gli2 and Disease: Congenital Malformations And Cancermentioning

confidence: 99%

“…Researchers have shown the presence of GLI2-binding sites in the TGFβ1 promoter in CD4+ cells [76] . Reporter and ChIP assays showed that GLI2 was able to bind to two of these sites to promote transcriptional activation of TGFβ1 [76] . Since regulatory T cells are associated with a poor prognosis in many tumors, understanding their regulation and function for the purposes of aiding in cancer therapy may be important.…”

Section: Gli2 and Disease: Congenital Malformations And Cancermentioning

confidence: 99%

From Normal Development to Disease: The Biochemistry and Regulation of GLI2

McCleary‐Wheeler¹

2014

Med Epigenet

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GLI2 is an oncogene encoding a unique transcription factor with both repressor and activator functions. Vitally important in development, it is also thought to be necessary for homeostasis of adult cells. However, deregulation of the GLI2 protein can result in detrimental effects to an organism, such as congenital defects or cancer. Historically deemed an activator and effector molecule of the Hedgehog signaling pathway, GLI2 has since been shown to be a critical effector of other signaling pathways, thus positioning itself as a potent mediator of signaling crosstalk. While GLI2 activity can be modulated by a variety of signaling influences, its regulation at the gene level is less understood. Indeed, gene mutations in GLI2 have been reported, but these generally led to developmental defects and are less commonly identified in tumors as being a cause of its deregulation. While the biological importance of GLI2 overexpression in a multitude of unrelated cancers has been well established, questions about the mechanisms leading to aberrant expression have remained largely unanswered. Furthering our understanding of both the transcriptional regulation of the GLI2 gene and the target genes regulated by GLI2 may identify novel therapeutic targets for cancer treatment.

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“…Previous studies have shown that GLI2 can modulate the expression of TGF-β(28). Furthermore, we have shown that GLI2 modulates the expression and secretion of IL-6 and IL-6R(4, 29).…”

Section: Discussionmentioning

confidence: 99%

Novel Molecular Mechanism of Regulation of CD40 Ligand by the Transcription Factor GLI2

Han

Jackson

Matissek

et al. 2017

The Journal of Immunology

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The interaction between tumor cells and their surrounding microenvironment is essential for the growth and persistence of cancer cells. This interaction is mediated in part, by cytokines. Although the role of cytokines in normal and malignant cell biology is well established, many of the molecular mechanisms regulating their expression remain elusive. Here, we provide evidence of a novel pathway controlling the transcriptional activation of CD40 ligand (CD40L) in bone marrow-derived stromal cells. Using a PCR-based screening of cytokines known to play a role in the biology of bone marrow malignancies we identified CD40L as a novel GLI2 target gene in stromal cells. CD40L plays an important role in malignant B cell biology and we found increased Erk phosphorylation and cell growth in malignant B cells co-cultured with CD40L expressing stromal cells. Further analysis indicated that GLI2 overexpression induced increased CD40L expression, and conversely, GLI2 knockdown reduced CD40L expression. Using luciferase and chromatin immunoprecipitation assays, we demonstrate that GLI2 directly binds and regulates the activity of the CD40L promoter. We found that the CCR3-PI3K-AKT signaling modulates GLI2-CD40L axis and GLI2 is required for CCR3-PI3K/AKT mediated regulation of CD40L promoter. Finally, co-culture of malignant B cells with cells stably expressing human CD40L, results in increased Erk phosphorylation and increased malignant B cell growth indicating CD40L in the TME promotes malignant B cell activation. Therefore, our studies identify a novel molecular mechanism of regulation of CD40L by the transcription factor GLI2 in the tumor microenvironment downstream of CCR3 signaling.

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GLI2 Regulates TGF-β1 in Human CD4+ T Cells: Implications in Cancer and HIV Pathogenesis

Cited by 33 publications

References 57 publications

Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq

Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq

From Normal Development to Disease: The Biochemistry and Regulation of GLI2

Novel Molecular Mechanism of Regulation of CD40 Ligand by the Transcription Factor GLI2

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