Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4 in Pancreatic Cancer Cells

Abdelrahim, Maen; Baker, Cheryl H.; Abbruzzese, James L.; Sheikh-Hamad, David; Liu, Shengxi; Cho, Sung Dae; Yoon, Kyungsil; Safe, Stephen

doi:10.1158/0008-5472.can-06-3831

Cited by 100 publications

(164 citation statements)

References 46 publications

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“…adenocarcinoma and was associated with advanced stage and poor survival. Aberrant Sp1 overexpression was also found in cell lines derived from pancreatic cancers (22,23). Our study, for the first time, has described the expression of Sp1 in patients with pancreatic adenocarcinoma and showed the association of Sp1 with advanced stage and poor survival.…”

Section: Discussionsupporting

confidence: 63%

Sp1, a New Biomarker That Identifies a Subset of Aggressive Pancreatic Ductal Adenocarcinoma

Jiang

Woda²,

Banner³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

140

115

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Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths in the United States. Sp1 is a sequence-specific DNA binding protein that is important in the transcription of a number of regulatory genes involved in cancer cell growth, differentiation, and metastasis. In this study, we investigated Sp1 expression in pancreatic ductal adenocarcinoma and its association with clinical outcome. We studied 42 patients with primary pancreatic adenocarcinoma. The expression of Sp1 in pancreatic adenocarcinoma was evaluated by immunohistochemical staining. All 42 patients had clinical follow-up information and were evaluated for survival. Sp1 protein was aberrantly overexpressed in a subset of primary pancreatic adenocarcinoma. These tumors all developed metastasis, whereas none of the primary tumors without lymph node metastasis showed Sp1 overexpression. Statistically, Sp1 overexpression was associated with higher stage, higher grade, and lymph node metastasis (P < 0.001, P = 0.036, and P < 0.0001, respectively). Additionally, patients of this subset had a much shorter overall survival than patients without Sp1 overexpression, as evidenced by Kaplan-Meier plots and the log-rank test (P = 0.002). The 5-year overall survival rate was 19% in patients with Sp1 overexpression, compared with 55% in patients without Sp1 overexpression. The median survival was only 13 months for patients with Sp1 overexpression, compared with 65 months for patients without Sp1 overexpression. In conclusion, Sp1 is a new biomarker that identifies a subset of pancreatic ductal adenocarcinoma with aggressive clinical behavior. It can be used at initial diagnosis of pancreatic adenocarcinoma to identify patients with an increased probability of cancer metastasis and much shortened overall survival.

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Section: Discussionsupporting

confidence: 63%

Sp1, a New Biomarker That Identifies a Subset of Aggressive Pancreatic Ductal Adenocarcinoma

Jiang

Woda²,

Banner³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

140

115

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“…Moreover, knockdown of Sp1 in pancreatic cancer cells decreases growth and invasion and induces apoptosis, confirming the pro-oncogenic functions of this factor (49). These results suggest that drugs such as metformin and other agents (31)(32)(33)(34)(35)(36)39) that target Sp1, Sp3, and Sp4 represent a class of new mechanism-based drugs that can be used in combination therapies for treating this deadly disease.…”

Section: Discussionsupporting

confidence: 52%

“…This involved down-regulation of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and pro-oncogenic Sp-regulated genes such as bcl2, fatty acid synthase (FAS), survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1) (31). The anticancer activities of metformin are also similar to * This work was supported, in whole or in part, by National Institutes of Health that observed after knockdown of Sp1 or all three Sp proteins by RNA interference in cancer cells, and this includes growth inhibition, induction of apoptosis, reversal of epithelial to mesenchymal transition, and decreased migration/invasion (32)(33)(34)(35)(36). Metformin also inhibits NFB and decreases cyclin D1 and ErbB2 in cancer cell lines (13,20,27,28), and these gene products are also decreased after Sp1, Sp3, and Sp4 silencing by RNAi or by other drugs that down-regulate Sp proteins (32)(33)(34)(35)(36).…”

mentioning

confidence: 84%

“…Orthotopic Nude Mice Study and Immunohistochemical Staining-Male athymic nude mice (NCI-nu) (at least four per treatment group) were injected with suspensions of L3.6pL cells consisting of single cells with Ͼ90% viability directly into the pancreas as described previously (31,32). Mice were treated (orally) with vehicle (control) or 250 mg/kg of metformin daily and sacrificed 4 -5 weeks after injection, and body weights were recorded.…”

Section: Methodsmentioning

confidence: 99%

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Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

Nair

Sreevalsan

Basha

et al. 2014

Journal of Biological Chemistry

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119

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Background: Metformin inhibits pancreatic cancer cell and tumor growth and down-regulated Sp transcription factors. Results: Inhibition of mTOR and Ras signaling by metformin is due to decreased expression of Sp-regulated insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), respectively. Conclusion: Metformin-induced down-regulation of Sp proteins affects multiple pro-oncogenic pathways. Significance: These results identify important metformin-induced anticancer activities.

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“…Although Sp1 is widely expressed in tumors, there is increasing evidence that Sp3 and Sp4 are also expressed in cancer cells and contribute to Sp-dependent procarcinogenic responses (20)(21)(22)(23)(24)(25). Using RNA interference, it was shown that Sp1 knockdown using a small inhibitory RNA for Sp1 (iSp1) inhibited G 0 -G 1 to S phase progression in MCF-7 breast cancer cells (25).…”

Section: Introductionmentioning

confidence: 99%

The Oncogenic microRNA-27a Targets Genes That Regulate Specificity Protein Transcription Factors and the G2-M Checkpoint in MDA-MB-231 Breast Cancer Cells

et al. 2007

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There is evidence that specificity proteins (Sp), such as Sp1, Sp3, and Sp4, are overexpressed in tumors and contribute to the proliferative and angiogenic phenotype associated with cancer cells. Sp1, Sp3, and Sp4 are expressed in a panel of estrogen receptor (ER)-positive and ER-negative breast cancer cell lines, and we hypothesized that regulation of their expression may be due to microRNA-27a (miR-27a), which is also expressed in these cell lines and has been reported to regulate the zinc finger ZBTB10 gene, a putative Sp repressor. Transfection of ER-negative MDA-MB-231 breast cancer cells with antisense miR-27a (as-miR-27a) resulted in increased expression of ZBTB10 mRNA and decreased expression of Sp1, Sp3, and Sp4 at the mRNA and protein levels and also decreased activity in cells transfected with constructs containing Sp1 and Sp3 promoter inserts. In addition, these responses were accompanied by decreased expression of Spdependent survival and angiogenic genes, including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Moreover, similar results were observed in MDA-MB-231 cells transfected with ZBTB10 expression plasmid. Both as-miR-27a and ZBTB10 overexpression decreased the percentage of MDA-MB-231 cells in S phase of the cell cycle; however, ZBTB10 increased the percentage of cells in G 0 -G 1 , whereas as-miR-27a increased the percentage in G 2 -M. This latter response was associated with induction of Myt-1 (another miR-27a target gene), which inhibits G 2 -M through enhanced phosphorylation and inactivation of cdc2. Thus, the oncogenic activity of miR-27a in MDA-MB-231 cells is due, in part, to suppression of ZBTB10 and Myt-1. [Cancer Res 2007;67(22):11001-11]

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Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4 in Pancreatic Cancer Cells

Cited by 100 publications

References 46 publications

Sp1, a New Biomarker That Identifies a Subset of Aggressive Pancreatic Ductal Adenocarcinoma

Sp1, a New Biomarker That Identifies a Subset of Aggressive Pancreatic Ductal Adenocarcinoma

Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

The Oncogenic microRNA-27a Targets Genes That Regulate Specificity Protein Transcription Factors and the G2-M Checkpoint in MDA-MB-231 Breast Cancer Cells

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