CpG methylation at promoter site −140 inactivates <i>TGFβ2</i> receptor gene in prostate cancer

Zhao, Hong; Shiina, Hìroaki; Greene, Kirsten L.; Li, Long-Cheng; Tanaka, Yuichiro; Kishi, Hirofumi; Igawa, Mikio; Kane, Christopher J.; Carroll, Peter R.; Dahiya, Rajvir

doi:10.1002/cncr.21135

Cited by 40 publications

(54 citation statements)

References 55 publications

(59 reference statements)

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“…tion, and tested whether AR expression profiles in the three types of stem/progenitor cell are changed but found no significant differences (data not shown). We next investigated whether the AR expression difference is due to the methylation difference in the AR promoter-associated CpG island region because numerous studies demonstrated that the methylation of these CpG islands interferes with transcription, resulting in an absence of mRNA and protein expression (41,42).…”

Section: Differential Ar Expression In Different Types Of Stem/progenmentioning

confidence: 99%

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

Tian

Lee

Liang

et al. 2012

Journal of Biological Chemistry

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Background: There is a specific silencing of AR gene expression in prostate stem cells. Results:The induction of AR gene expression inhibited the self-renewal of the prostate stem cells. Conclusion:The induction of AR expression suppressed PCa stem cell-mediated tumorigenicity. Significance: This is the first attempt to suppress prostate cancer growth via epigenetic modification of AR genes in PCa stem cells.

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Section: Differential Ar Expression In Different Types Of Stem/progenmentioning

confidence: 99%

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

Tian

Lee

Liang

et al. 2012

Journal of Biological Chemistry

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“…Most research in the prostate concerns TGF1. TGF synthesis is enhanced in CaP, but not in PIN or BPH (Zhao et al, 2005). As CaP progresses, the cancer cells become refractory to the growth inhibitory effects of TGF1.…”

Section: 2a Transforming Growth Factor  (Tgf)mentioning

confidence: 96%

“…TGF receptors-1 and -2 mediate signalling. In CaP, TGF receptor-2 is progressively M a n u s c r i p t 6 lost due to promoter methylation leading to decreased growth inhibitory effects (Zhao et al, 2005). Treatment with demethylating agents, such as 5-aza-2'-deoxycytidine, can restore expression of receptor-2 and sensitivity to TGF.…”

Section: 2a Transforming Growth Factor  (Tgf)mentioning

confidence: 99%

Androgen receptor signalling in prostate: Effects of stromal factors on normal and cancer stem cells

Berry

Maitland

Collins

2008

Molecular and Cellular Endocrinology

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Please cite this article as: Berry, P.A., Maitland, N.J., Collins, A.T., Androgen receptor signalling in prostate: effects of stromal factors on normal and cancer stem cells, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe prostate gland is the most common site for cancer in males within the developed world. Androgens play a vital role in prostate development, maintenance of tissue function and pathogenesis of prostate disease. The androgen receptor signalling pathway facilitates that role in both the epithelial compartment and in the underlying stroma. Stroma is a key mediator of androgenic effects upon the epithelium and can regulate both the fate of the epithelial stem cell and potentially the initiation and progression of prostate cancer. Different groups of growth factors are expressed by stroma, which control proliferation, and differentiation of prostate epithelium demonstrating a critical role for stroma in epithelial growth and homeostasis. Paracrine stromal proteins may offer the possibility to control tumour stem cell growth and could permit prostate-specific targeting of both therapies and of androgenresponsive proteins. The effect of 5-dihydrotestosterone, the more potent metabolite of testosterone, on expression of androgen regulated genes in stroma from benign prostatic hyperplasia is a key mediator of epithelial cell fate. Global gene expression arrays have recently identified new candidate genes in androgen responsive stroma, some of which have androgen receptor binding sites in their promoter regions. Some of these genes have direct androgen receptor binding ability.

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Section: Tgfbr2 Expression In Hccsmentioning

confidence: 99%

“…Epigenetic silencing of TGFBR2 by promoter methylation occurs in stomach, lung, and prostate cancers. [25][26][27] Considering that mutations or loss of the TGFBR2 gene are rare in HCCs, epigenetic silencing may be involved in reduced TGFBR2 expression in HCC.Progression of HCC often leads to vascular invasion and IM, which correlate with recurrence after treatment, and completely abolished in the cell with reduced TGFBR2 expression. Reduced TGFBR2 expression correlated with portal vain invasion in HCC cases, and poorly differentiated HCC cells showed lower TGFBR2 expression compared with well-differentiated cells.…”

mentioning

confidence: 99%

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

Mamiya

Yamazaki

Masugi

et al. 2010

Laboratory Investigation

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Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-b (TGF-b) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-b signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-b signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-b receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-b. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (Po0.001), poor differentiation (Po0.001), portal vein invasion (P ¼ 0.002), intrahepatic metastasis (IM) (Po0.001), and shorter recurrence-free survival (P ¼ 0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC. Hepatocellular carcinoma (HCC) is a common cause of death from cancer worldwide. 1 Prolonged infection with hepatitis virus often causes chronic hepatitis, followed by liver cirrhosis. 2 During the development of these liver diseases, transforming growth factor-b (TGF-b) has an important role in fibrosis of the lesions. 3 HCCs mainly occur in those injured livers with activated TGF-b signaling, although TGF-b inhibits hepatocyte cell growth in the normal liver. 4,5 TGF-b signaling is activated when a TGF-b ligand binds to its receptor on the cell membrane. The downstream effectors, SMAD2 and SMAD3, together with SMAD4, translocate to the nucleus and regulate the expression of various genes, including cyclin-dependent kinase inhibitor 1A (CDKN1A), which is involved in cell growth arrest. 6,7 TGF-b signaling is also suggested to be involved in the malignant progression of tumors. TGF-b can induce epithelial-mesenchymal transition and promote tumor cell invasion, and may also have angiogenic and immunosuppressive effects on the tumor microenvironment, all of which promote metastasis. 8 Mutations in the TGF-b superfamily genes have been found in various cancers. The TGF-b receptor II (TGFBR2) gene is frequently mutated in colon cancers, 9,10 gastric cancers, 10,11 and in gliomas 12 with microsatellite instability. SMAD4 mutations occur mainly in pancreatic cancers, in which the SMAD4 gene was first identified as a tumorsuppressor gene. 13 In HCCs, however, mutations in TGF-b superfamily genes are rare, 14,15 and alteration of TGF-b signaling is still unclear and controversial. To investigate alterations of TGF-b signaling in HCC progression, we compared the expression profiles of TGF-b signalingrelated genes in HCC cells exhibiting different metastatic potential. We...

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CpG methylation at promoter site −140 inactivates TGFβ2 receptor gene in prostate cancer

Cited by 40 publications

References 55 publications

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

Androgen receptor signalling in prostate: Effects of stromal factors on normal and cancer stem cells

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

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