The Expression and Clinical Significance of pSTAT3, VEGF and VEGF-C in Pancreatic Adenocarcinoma

Huang, Chen; Huang, R. Stephanie; Chang, Wen Hsin; Jiang, Tian; Huang, Kejie; Cao, J; Sun, Xiuxuan; Qiu, Zheng

doi:10.4149/neo_2012_007

Cited by 48 publications

(45 citation statements)

References 17 publications

(19 reference statements)

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“…Angiogenesis, as quantitated via microvessel density, plays significant clinical and pathological roles in cancer, 21,22 and may be an independent, highly significant and accurate prognostic indicator. 20 Gastric cancer is a leading cause of death in Asia.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase B Phosphorylation Correlates with Vascular Endothelial Growth Factor A and Microvessel Density in Gastric Adenocarcinoma

et al. 2012

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Objective: The signalling molecule protein kinase B (Akt) modulates many cellular processes. Phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathways play important roles in tumour angiogenesis. The aim of this study was to determine the role of phosphorylated Akt (pAkt) in angiogenesis and its correlation with vascular endothelial growth factor (VEGF)-A in gastric adenocarcinoma. Methods: Tumour tissue and matched healthy gastric mucosa were obtained from patients undergoing surgical resection of gastric adenocarcinoma. Akt and pAkt were detected via Western blotting. VEGF-A, pAkt and CD34 were examined by immunohistochemistry. Results: Akt and pAkt protein levels were significantly higher in gastric cancer tissue than in normal tissue (n = 48 patients). Positive VEGF-A immuno -staining was significantly associated with pAkt immunostaining. Microvessel density was correlated with both VEGF-A and pAkt positivity. Conclusions: Phosphorylated Akt and VEGF-A are involved in angiogenesis of gastric adenocarcinoma, and Akt activation may contribute to angiogenesis via VEGF-A upregulation. The PI3K/Akt/VEGF signalling pathway may be involved in gastric adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase B Phosphorylation Correlates with Vascular Endothelial Growth Factor A and Microvessel Density in Gastric Adenocarcinoma

et al. 2012

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“…Activated STAT3 (phospho-STAT3 (p-STAT3)) in particular is constitutively overexpressed in several tumor types and is a negative prognostic factor for multiple cancers (34 -40). In pancreatic cancer, high expression of STAT3 is correlated with increased tumor size and stage and lymphatic metastasis (34), and the prognostic significance of microRNA-130b, which targets STAT3, was inversely correlated with STAT3 (35). The critical functional importance of STAT3 in cancer is aptly summarized in Ref.…”

Section: Stat2 Stat3 Stat4 Stat5a Stat5b and Stat6 (43)mentioning

confidence: 99%

Benzyl Isothiocyanate (BITC) Induces Reactive Oxygen Species-dependent Repression of STAT3 Protein by Down-regulation of Specificity Proteins in Pancreatic Cancer

Kasiappan

Jutooru²,

Karki

et al. 2016

Journal of Biological Chemistry

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Edited by Eric R. FearonThe antineoplastic agent benzyl isothiocyanate (BITC) acts by targeting multiple pro-oncogenic pathways/genes, including signal transducer and activator of transcription 3 (STAT3); however, the mechanism of action is not well known. As reported previously, BITC induced reactive oxygen species (ROS) in Panc1, MiaPaCa2, and L3.6pL pancreatic cancer cells. This was accompanied by induction of apoptosis and inhibition of cell growth and migration, and these responses were attenuated in cells cotreated with BITC plus glutathione (GSH). BITC also decreased expression of specificity proteins (Sp) Sp1, Sp3, and Sp4 transcription factors (TFs) and several pro-oncogenic Sp-regulated genes, including STAT3 and phospho-STAT3 (pSTAT3), and GSH attenuated these responses. Knockdown of Sp TFs by RNA interference also decreased STAT3/pSTAT3 expression. BITC-induced ROS activated a cascade of events that included down-regulation of c-Myc, and it was also demonstrated that c-Myc knockdown decreased expression of Sp TFs and STAT3. These results demonstrate that in pancreatic cancer cells, STAT3 is an Sp-regulated gene that can be targeted by BITC and other ROS inducers, thereby identifying a novel therapeutic approach for targeting STAT3. Isothiocyanates (ITCs)3 are a family of structurally related natural products that are found in cruciferous vegetables such as glucosinolates, which are hydrolyzed by the enzyme myrosinase to give the unconjugated ITCs. Cruciferous vegetables in the diet have been associated with decreased risks for human cancers and exhibit both chemoprevention and chemotherapeutic activities in animal models, and this has primarily been associated with ITCs (1-5). Sulforaphane, allyl isothiocyanate, phenethyl isothiocyanate (PEITC), and benzyl isothiocyanate (BITC) have been extensively investigated as anticancer agents, and a recent review summarizes the multiple genes and associated pathways activated by ITCs (4). Treatment of cancer cells or animal models that develop tumors with ITCs decreases cell growth, induces apoptosis, and inhibits epithelial-to-mesenchymal transition, angiogenesis, and cell cycle progression (6 -16). ITCs, including BITC, exhibit a broad spectrum of activities that include induction of ROS and ROS-regulated genes, direct inhibition of genes, and formation of peptide and protein adducts (4,5,(15)(16)(17). ITCs form adducts with both thiol and amino groups, and the formation of amino adducts forms the basis of the Edman procedure used in protein sequencing (15, 18 -20). Many of these ITC-induced effects contribute to their anticancer activities; however, a recent study suggests that the alkylation of peptides by ITCs may also be responsible for allergic skin reactions to these compounds (20).Studies in this laboratory have focused on specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 as non-oncogene addiction genes in cancer cells, and knockdown of Sp1, Sp3, and Sp4 individually and combined inhibits cell growth, induces apoptosis, and inhibi...

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“…However, angiogenesis plays a significant role in tumor metastasis and vascular endothelial growth factor (VEGF) is one of the most effective factors that promotes tumor neovessel angiogenesis. The high expression level of VEGF has been shown to be correlated with the metastasis of several cancers, including esophageal and pancreatic cancer (4,5). However, few studies have examined the correlation between the activation of PI3K/Akt signaling and VEGF expression in colon cancer tissue samples.…”

Section: Introductionmentioning

confidence: 99%

The expression and clinical significance of PI3K, pAkt and VEGF in colon cancer

et al. 2012

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Abstract. Background PI3K/Akt signaling has been shown to be activated in a variety of cancers. However, the correlation between Akt activation and VEGF expression is unclear in colon cancer tissues. This study aimed to investigate the expression and predictive value of phosphorylated Akt (pAkt) and VEGF in colon cancer tissues. The expression of PI3K, pAkt and VEGF was detected by immunohistochemical staining in 60 samples of colon cancer tissues and their corresponding adjacent normal colon tissues. In addition, the correlations between the expression levels of the 3 proteins and the clinicopathological parameters of the colon cancer cases were analyzed. The positive rates of PI3K, pAkt and VEGF expression were 71.7% (43/60), 68.3% (41/60) and 61.7% (37/60) in colon cancer, respectively, which were significantly higher than in adjacent normal colon tissues (P<0.001). Correlation analyses showed that PI3K expression was not significantly associated with the gender or age of the patients, tumor size or differentiation (P>0.05), but was closely associated with serous coat infiltration and lymphatic metastasis of colon cancer (P<0.05). Neither pAkt nor VEGF expression were significantly associated with the gender or age of the patients, or tumor differentiation (P>0.05), but were closely associated with tumor size, serous coat infiltration and lymphatic metastasis of colon cancer (P<0.05). In addition, the expression levels of Pl3K and pAkt were positively correlated with that of VEGF in colon cancer tissues (P<0.05). Our data show a positive correlation between PI3K/Akt activation and VEGF expression in colon cancer tissues and indicate that pAkt is an independent prognostic marker for colon cancer patients.

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The Expression and Clinical Significance of pSTAT3, VEGF and VEGF-C in Pancreatic Adenocarcinoma

Cited by 48 publications

References 17 publications

Protein Kinase B Phosphorylation Correlates with Vascular Endothelial Growth Factor A and Microvessel Density in Gastric Adenocarcinoma

Protein Kinase B Phosphorylation Correlates with Vascular Endothelial Growth Factor A and Microvessel Density in Gastric Adenocarcinoma

Benzyl Isothiocyanate (BITC) Induces Reactive Oxygen Species-dependent Repression of STAT3 Protein by Down-regulation of Specificity Proteins in Pancreatic Cancer

The expression and clinical significance of PI3K, pAkt and VEGF in colon cancer

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