Restoration of expression of transforming growth factor-β Type II receptor in murine renal cell carcinoma (renca) cells by 5-Aza-2′-deoxycytidine

Zhang, Qiang; Rubenstein, Jonathan N.; Liu, Victoria C.; Park, Irwin; Jang, Thomas L.; Lee, Chung

doi:10.1016/j.lfs.2004.10.021

Cited by 16 publications

(14 citation statements)

References 18 publications

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“…The present data observed in gingival fibroblasts confirm this observation for IL11. Moreover, our findings that 5-aza increased TGF-βRII expression in gingival fibroblasts are supported by data from renal cell carcinoma [26]. However, it cannot be concluded that 5-aza affects all TGF-β target genes, as only IL11, but not PRG4 and NOX4, was enhanced by the demethylation reagent.…”

Section: Discussionsupporting

confidence: 70%

“…Impaired oral wound healing may involve methylation, decreasing the responsiveness of cells to growth factors. In particular, the TGF-β1 target genes [21][22][23][24] and their respective TGF-β receptors [25,26] can be subjected to methylation, thus altering the respective cellular response. Because TGF-β1 is a key player in wound healing, we studied the impact of 5-aza, a DNMTs inhibitor, on the expression of three major TGF-β1 target genes in oral fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, 5-aza has been found to decrease the expression of TGF-β1 target genes, such as α-smooth muscle actin in kidney epithelial cells [22], lung fibroblasts [23], and hepatic stellate cells [24]. In addition to changes in the methylation pattern of the promoters of the target genes, 5-aza increased TGF-βRII https://doi.org/10.5051/jpis.2017.47.2.66 DNA demethylation and TGF-β signaling signaling in human gastric cancer cell lines [25] and TGF-βRII in renal cell carcinoma [26], changing cell sensitivity to TGF-β. Thus, it is reasonable to suggest that 5-aza may also make periodontal fibroblasts more responsive to TGF-β1.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of DNA methylation support TGF-β1-induced IL11 expression in gingival fibroblasts

Șufaru

Beikircher

Weinhäusel

et al. 2017

J Periodontal Implant Sci

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Purpose: Oral wound healing requires gingival fibroblasts to respond to local growth factors. Epigenetic silencing through DNA methylation can potentially decrease the responsiveness of gingival fibroblasts to local growth factors. In this study, our aim was to determine whether the inhibition of DNA methylation sensitized gingival fibroblasts to transforming growth factor-β1 (TGF-β1). Methods: Gingival fibroblasts were exposed to 5-aza-2'-deoxycytidine (5-aza), a clinically approved demethylating agent, before stimulation with TGF-β1. Gene expression changes were evaluated using quantitative polymerase chain reaction (PCR) analysis. DNA methylation was detected by methylation-sensitive restriction enzymes and PCR amplification. Results: We found that 5-aza enhanced TGF-β1-induced interleukin-11 (IL11) expression in gingival fibroblasts 2.37-fold (P=0.008). 5-aza had no significant effects on the expression of proteoglycan 4 (PRG4) and NADPH oxidase 4 (NOX4). Consistent with this, 5-aza caused demethylation of the IL11 gene commonly next to a guanosine (CpG) island in gingival fibroblasts. The TGF-β type I receptor kinase inhibitor SB431542 impeded the changes in IL11 expression, indicating that the effects of 5-aza require TGF-β signaling. 5-aza moderately increased the expression of TGF-β type II receptor (1.40-fold; P=0.009), possibly enhancing the responsiveness of fibroblasts to TGF-β1. As part of the feedback response, 5-aza increased the expression of the DNA methyltransferases 1 (DNMT1) (P=0.005) and DNMT3B (P=0.002), which are enzymes responsible for gene methylation. Conclusions: These in vitro data suggest that the inhibition of DNA methylation by 5-aza supports TGF-β-induced IL11 expression in gingival fibroblasts.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibitors of DNA methylation support TGF-β1-induced IL11 expression in gingival fibroblasts

Șufaru

Beikircher

Weinhäusel

et al. 2017

J Periodontal Implant Sci

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“…Silencing of the T␤RII gene has been reported to result from histone deacetylation and/or promoter methylation in cancers, such as lung, breast, prostate, pancreatic, renal cell carcinoma, and B-cell lymphoma. 40,50,53,54,[63][64][65][66] We found that in PEL cell lines both methylation and histone deacetylation play a role in T␤RII transcriptional repression.The promoter of the T␤RII gene has previously been characterized. 49 It lacks a TATA box near its transcription initiation site and contains 4 regulatory elements: 2 positive regulatory elements, For personal use only.…”

mentioning

confidence: 99%

KSHV LANA inhibits TGF-β signaling through epigenetic silencing of the TGF-β type II receptor

Bartolo

Cannon

Liu

et al. 2008

Blood

115

117

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IntroductionKaposi sarcoma herpesvirus (KSHV) is associated with the pathogenesis of primary effusion lymphoma (PEL), Kaposi sarcoma (KS), and some forms of multicentric Castleman disease (MCD). [1][2][3] Its genome contains an extensive number of pirated cellular homologs involved in subverting critical cellular regulatory processes. 4,5 As a member of the ␥-herpesvirus family, KSHV is characterized by a prolonged latency during which only a subset of its genes are expressed. These latently expressed gene products play important roles in immune evasion, cell proliferation, and inhibition of apoptosis.One of these latently expressed proteins, latency-associated nuclear antigen (LANA), is involved in several cellular processes. It is considered an oncogenic protein because of its ability to dysregulate tumor suppressor pathways associated with p53 and pRb and to transform primary rat embryo fibroblasts in cooperation with the cellular oncogene H-ras. 6,7 Its association with GSK-3␤, an important modulator of the Wnt signaling pathway, leads to accumulation of ␤-catenin and subsequent up-regulation of Tcf/Lefregulated genes. 8 LANA inhibits expression of the reactivation transcriptional activator (RTA/Lyta), which is critical for the switch from latency to lytic reactivation. 9,10 It tethers the viral episome to host chromatin during mitosis, ensuring KSHV DNA gets replicated and episomes are not lost during cellular division. 11-14 LANA also regulates viral as well as cellular gene expression. [6][7][8][15][16][17] Although some of the changes mediated by LANA occur indirectly via activation of ␤-catenin and E2F target genes, direct binding of LANA to DNA also results in transcriptional repression. 18,19 Interactions with corepressors mSin3, SAP30, and CIR, the methyl CpG-binding protein MeCP2, and the histone methyltransferase SUV39H1 are consistent with a direct role for LANA in transcriptional repression. 14,20,21 LANA has been shown to inhibit in vitro histone acetyltransferase activity of CREB-binding protein (CBP) and, more recently, to associate with Dnmt3a, a DNA methyltransferase involved in de novo DNA methylation, supporting a role for LANA in epigenetic gene regulation. 16,22 Transforming growth factor-beta (TGF-␤) is a multifunctional cytokine involved in diverse biologic processes, which include embryonic development, regulation of cell growth, differentiation, hematopoiesis, angiogenesis, immune function, and apoptosis (reviewed by Roberts and Sporn 23 and Massague 24 ). There are 3 isoforms of TGF-␤, each of which binds to the same heterotetrameric complex of type I (T␤RI) and type II (T␤RII) serine/ threonine kinase receptors. Initially, TGF-␤ binds to T␤RII, which leads to the recruitment and activation of T␤RI. Receptor-activated Smads (R-Smads), Smad2 and Smad3, are then phosphorylated by T␤RI and translocate into the nucleus in a complex with Smad4. In the nucleus, the Smad complex binds its cognate binding site as well as several transcription factors, transcriptional activators, or transcri...

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“…This phenomenon may be attributable to the TGF-b, because wild-type RENCA cells secrete significant amounts of this cytokine. 43 In addition, RENCA tumors may attract naturally occurring Treg via secretion of various chemokines. 44 In contrast there were only few Tregs infiltrating RENCA-H6 administration site.…”

Section: Discussionmentioning

confidence: 99%

Gene-modified tumor vaccine secreting a designer cytokine Hyper-Interleukin-6 is an effective therapy in mice bearing orthotopic renal cell cancer

et al. 2010

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Although Renal Cell Cancer (RCC) is known to be immunogenic, clinical efficacy of various immunotherapeutic approaches remains unsatisfactory. Novel targeted therapies showing cytostatic rather than cytotoxic activity are unable to cure RCC patients. In our studies, we evaluated the therapeutic efficacy of whole-cell vaccine based on irradiated murine RENCA cells genetically modified to secrete designer cytokine-Hyper-IL6 (H6)-comprising IL-6 and soluble IL-6 receptor. An orthotopic RCC model based on a subcapsular implantation of RENCA cells into kidneys of Balb/C mice was employed. The efficacy of RENCA-H6 vaccine was compared with control vaccine (RENCA-wt) in relation to naive (non-immunized) animals. Three sets of vaccination experiments were carried out in a (i) protective, (ii) palliative and (iii) adjuvant (following nephrectomy) setting. The influence of vaccination on survival of RCC-bearing animals was analyzed. Specificity of vaccine-induced immune response was studied using model antigen-GFP. RCC-bearing animals immunized with RENCA-H6 vaccine showed prolonged survival compared with other groups. In palliative and adjuvant settings the survival RENCA-H6-immunized animals exceeded 75%. Administration of RENCA-H6 inhibited formation and recruitment of Treg cells (CD4 þ CD25 þ Foxp3 þ ) and increased maturation of DCs. RENCA tumors in RENCA-H6-vaccinated animals contained large populations of NK cells and activated CD4 þ , CD8 þ T cells. In addition, in mice vaccinated with RENCA-H6 cells large population of CD4 þ and CD8 þ memory cells (CD62Llow) were detected. In the orthotopic RCC model, RENCA-H6 vaccine showed high therapeutic potential, which resulted from modulation of numerous immunological mechanisms.

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Restoration of expression of transforming growth factor-β Type II receptor in murine renal cell carcinoma (renca) cells by 5-Aza-2′-deoxycytidine

Cited by 16 publications

References 18 publications

Inhibitors of DNA methylation support TGF-β1-induced IL11 expression in gingival fibroblasts

Inhibitors of DNA methylation support TGF-β1-induced IL11 expression in gingival fibroblasts

KSHV LANA inhibits TGF-β signaling through epigenetic silencing of the TGF-β type II receptor

Gene-modified tumor vaccine secreting a designer cytokine Hyper-Interleukin-6 is an effective therapy in mice bearing orthotopic renal cell cancer

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