The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells

Zhu, Geng; Lenzi, Michelle L.; Schwartz, Edward L.

doi:10.1038/sj.onc.1206030

Cited by 64 publications

(44 citation statements)

References 51 publications

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“…In the tumor microenvironment, TNFa mediates cancer-related inflammation, and may promote tumor progression by increasing angiogenesis and metastasis. [1][2][3]25 The levels of TNFa [6][7] and its downstream genes c-FLIP 18,29 and thymidine phosphorylase [19][20][21][22] are known to be elevated in nasopharyngeal carcinoma tumor tissues. Here, we used Affymetrix chips to identify the 10 TNFa-inducible genes showing the highest upregulation in nasopharyngeal carcinoma tissues vs normal adjacent tissues.…”

Section: Discussionmentioning

confidence: 99%

“…We analyzed the various TNFa-regulated genes that appeared to be upregulated in nasopharyngeal carcinoma tumor cells vs adjacent normal tissues, and found differential expression of various TNFa target genes MMP9, 12 MMP12, 13 MMP14, 14 BIRC5, 15 CXCL13, 16 IL12B, 17 c-FLIP, 18 and thymidine phosphorylase. [19][20][21] We further showed that the upregulation of thymidine phosphorylase in nasopharyngeal carcinoma tumor cells resulted at least in part from cytoplasmic heterogeneous nuclear ribonucleoprotein K (hnRNP K)-mediated stabilization of the thymidine phosphorylase mRNA. 22 High levels of thymidine phosphorylase and cytoplasmic hnRNP K were significantly correlated with overall survival and distant metastasis.…”

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confidence: 98%

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A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

Chen

et al. 2011

Modern Pathology

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Tumor necrosis factor alpha (TNFa) is an inflammatory cytokine that is present in the microenvironment of many tumors and is known to promote tumor progression. To examine how TNFa modulates the progression and metastasis of nasopharyngeal carcinoma, we used Affymetrix chips to identify TNFa-inducible genes that are dysregulated in this tumor. Elevated expression of TNFAIP2, which encodes TNFa-inducible protein 2 and not previously known to be associated with cancer, was found and confirmed by quantitative RT-PCR of TNFAIP2 expression in nasopharyngeal carcinoma and adjacent normal tissues. Immunohistochemical analysis showed that the TNFAIP2 protein was highly expressed in tumor cells. Analysis of 95 nasopharyngeal carcinoma biopsy specimens revealed that high TNFAIP2 expression was significantly correlated with highlevel intratumoral microvessel density (P ¼ 0.005) and low distant metastasis-free survival (P ¼ 0.001). A multivariate analysis further confirmed that TNFAIP2 was an independent prognostic factor for nasopharyngeal carcinoma (P ¼ 0.002). In vitro, TNFa treatment of nasopharyngeal carcinoma HK1 cells was found to induce TNFAIP2 expression, and siRNA-based knockdown of TNFAIP2 dramatically reduced the migration and invasion of nasopharyngeal carcinoma HK1 cells. These results collectively suggest for the first time that TNFAIP2 is a cell migration-promoting protein and its expression predicts distant metastasis. Our data suggest that TNFAIP2 may serve as an independent prognostic indicator for nasopharyngeal carcinoma.

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

Chen

et al. 2011

Modern Pathology

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“…Thus, our results strongly support a novel function of cytoplasmic hnRNP K in the stabilization of TP mRNA through the binding of hnRNP K to the CURE element at the 3 0 end of the TP mRNA. Although TP gene expression has been shown to be regulated by the Sp1 and STAT transcription factors (Zhu et al, 2002;Yao et al, 2005), the mechanisms of TP mRNA stabilization induced by interferon-a, -b and -g have yet not been fully elucidated (Schwartz et al, 1998;Yao et al, 2005). We herein show that TP is a new target for cytoplasmic hnRNP K, providing insight into the mystery of TP mRNA stabilization and perhaps explaining the regulation of TP mRNA stability in response to interferon-a, -b and -g.…”

Section: Discussionmentioning

confidence: 99%

“…TP expression is transcriptionally controlled by the transcription factors, Sp1 and STAT (Goto et al, 2001;Zhu et al, 2002;Yao et al, 2005), and posttranscriptional regulation of TP mRNA stability has been proposed in response to interferons (Schwartz et al, 1998;Yao et al, 2005). However the molecular mechanisms underlying the posttranscriptional regulation have not yet been established.…”

Section: Introductionmentioning

confidence: 99%

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Liu

et al. 2009

Oncogene

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The cytoplasmic level of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is significantly correlated with the elevated expression of thymidine phosphorylase (TP), and high levels of both proteins are predictive of a poor prognosis in nasopharyngeal carcinoma (NPC). We herein show that TP is highly induced by serum deprivation in NPC cells, and that this is due to an increase in the halflife of the TP mRNA, as shown by nuclear run-on and actinomycin D assays. We further show that the CU-rich element of the TP mRNA directly interacts with hnRNP K, as demonstrated by immunoprecipitation RT-PCR assays, and the nucleus-to-cytoplasm translocation of hnRNP K. Blockade of hnRNP K expression reduces TP expression, suggesting that hnRNP K acts in the upregulation of TP. Mechanistically, both MEK inhibitor and the hnRNP K ERK-phosphoacceptor-site mutant decrease cytoplasmic accumulation of hnRNP K, suggesting that ERK-dependent phosphorylation is critical for TP induction. Furthermore, we found that hnRNP Kmediated TP induction allows NPC cells to resist hypoxia-induced apoptosis. Our results collectively establish the regulation and role of ERK-mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP, suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer.

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“…In fact, a number of genes that can mediate angiogenesis have been shown to be modulated by Sp1, including VEGF (34), thymidine phosphorylase (48), and metalloprotease 2 (49).…”

Section: Bcl-2 In Upar Expression and Sp1 Transcriptional Activitymentioning

confidence: 99%

bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation

Trisciuoglio¹,

Iervolino²,

Candiloro³

et al. 2004

Journal of Biological Chemistry

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We have previously demonstrated that Bcl-2 overexpression in human breast carcinoma and melanoma cells synergizes with hypoxia to increase angiogenesis through up-regulation of vascular endothelial growth factor. In this work we demonstrated, for the first time, that Bcl-2 overexpression in cancer cells exposed to hypoxia modulates urokinase plasminogen activator receptor (uPAR) expression through Sp1 transcription factor and that the extracellular signal-regulated kinase (ERK) pathway plays a role in Sp1 transcriptional activity. In particular, an increase in uPAR protein and mRNA expression was found in melanoma bcl-2 transfectants grown under hypoxia when compared with control cells, and a decrease of uPAR protein expression was induced by treatment of cells with specific bcl-2 antisense oligonucleotides. Up-regulation of uPAR expression was accompanied by increased Sp1 protein expression, stability, serine phosphorylation, and DNA binding activity. Treatment of cells with mitramycin A, an inhibitor of Sp1 activity, confirmed the role of Sp1 transcriptional activity in uPAR induction by Bcl-2. The contribution of the ERK pathway in Sp1-increased transcriptional activity was demonstrated by the use of chemical inhibition. In fact, ERK kinase activation was induced in Bcl-2-overexpressing cells exposed to hypoxia, and the ERK kinase inhibitor UO126 was able to down-regulate Sp1 phosphorylation and DNA binding activity. Using a human breast carcinoma line, we obtained data supporting our findings with melanoma cells and identified a link between the induction of Sp1 and uPAR expression as a common bcl-2-controlled phenomenon in human tumors. In conclusion, our results strongly indicate that up-regulation of uPAR expression by Bcl-2 in hypoxia is modulated by Sp1 DNA binding activity through the ERK signaling pathway.Angiogenesis is a fundamental process required for tumor growth, invasion, and metastasis and is strongly induced by hypoxia. In fact, several cell types including tumor cells, macrophages, and endothelial cells respond to hypoxia by producing angiogenic factors, fibrinolytic factors, and adhesion molecules involved in pathologic angiogenesis (1-5). Four sequential steps can be distinguished during angiogenesis: the degradation of the basement membrane and interstitial matrix, endothelial cell migration, endothelial cell proliferation, and the formation of tubular structures with a lumen and a new basement membrane (6). Three of these steps critically depend on proteolytic activity generated by the matrix metalloproteinases and the plasminogen activator/plasmin system. In particular, the role of urokinase plasminogen activator receptor (uPAR) 1 in tumor cell invasion and migration and in the formation of new microvascular structures has been largely demonstrated (7-9).Angiogenesis is also controlled by alterations in oncogene and tumor suppressor gene expression (10 -14). In this context, we previously demonstrated that the bcl-2 oncogene increases in vitro and in vivo angiogenesis in two different t...

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The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells

Cited by 64 publications

References 51 publications

A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation

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