Defective Expression of Transforming Growth Factor β Receptor Type II Is Associated with CpG Methylated Promoter in Primary Non-Small Cell Lung Cancer

Zhang, Hongtao; Chen, Xiaofeng; Wang, Minghua; Wang, Jiucun; Qi, Qing-Yuan; Zhang, Rongmei; Xu, Weiqing; Fei, Qingyan; Wang, Fei; Cheng, Qiqun; Chen, Feng; Zhu, Chengsong; Tao, Shiheng; Luo, Zewei

doi:10.1158/1078-0432.ccr-0959-3

Cited by 69 publications

(53 citation statements)

References 27 publications

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“…Interestingly, CITED2 expression was inhibited by TGF-b in both A549 and H1975 cell lines, which responded to TGF-b-induced cellular quiescence (Figures 4a and c). As defective expression of TGF-b receptors (TGFBRI and TGFBRII) is found in cells from patients with lung cancer, 5,6 expression of TGFBRI and TGFBRII messenger RNA (mRNA) was investigated in these cells. Absolute Q-PCR analysis and western blot indicated loss of TGFBRII in CL1-0 cells (Figure 4d).…”

Section: Resultsmentioning

confidence: 99%

“…3 In contrast, TGF-b induces quiescence of lung epithelial cells. 4 TGF-b signaling is mediated through the TGF-b type II (TGFBRII) and type I (TGFBRI) receptors; methylation silencing of TGFBRII is observed in some NSCLC cancer cells, 5 rendering tumor cells refractory to TGF-b-induced growth arrest. 6 Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), which was originally identified from the studies of differential gene expression by cytokine stimulation, encodes a transcriptional modulator without DNA-binding domains.…”

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confidence: 99%

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CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

Chou

Hsieh

et al. 2012

Cell Death Differ

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Transforming growth factor-a (TGF-a)-induced proliferation and transforming growth factor-b (TGF-b)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYCinteracting transcriptional modulator, responds to TGF-a induction and TGF-b suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-a induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21 CIP1 . CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC-HDAC1 complex formation. TGF-b stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21 CIP1 suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/ p21 CIP1 signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF-a and TGF-b-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

Chou

Hsieh

et al. 2012

Cell Death Differ

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“…The methylation and non-methylation-specific PCR primers were annotated E-cadherin-MF/E-cadherin-MR and E-cadherin-UF/Ecadherin-UR, respectively. SssI enzyme-treated genomic DNA from normal blood served as a positive control for methylation analysis, while unmodified DNA from normal blood served as a negative control for methylation analysis (Zhang et al, 2004).…”

Section: Nested Methylation-specific Pcr (Msp)mentioning

confidence: 99%

Clinical Outcomes of Downregulation of E-cadherin Gene Expression in Non-small Cell Lung Cancer

Zheng

Hou²,

Zhao³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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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.…”

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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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Defective Expression of Transforming Growth Factor β Receptor Type II Is Associated with CpG Methylated Promoter in Primary Non-Small Cell Lung Cancer

Abstract: ABSTRACT

Cited by 69 publications

References 27 publications

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

Clinical Outcomes of Downregulation of E-cadherin Gene Expression in Non-small Cell Lung Cancer

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

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