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Sa1691 MiR-181b-1 Controls Glycolysis As STAT3 Activator in Colon Cancer Cells
AGA Abstracts
Suite 6.0. The signaling pathways, metabolic pathways and network constituted by these proteins were identified by using Ingenuity Pathway Analysis (IPA). Results Of 27 metabolic proteins and 172 proteins of signaling pathway screened, 82 were detected in 37 paired colorectal adenoma samples and among which 19 were identified as significant proteins (Fig 1) by comparing between adenoma and normal tissues (Q-value ,0.05). Of 19 proteins, 18 were up-regulated in adenoma including MetRS, beta-catenin, p-cdc2 (Tyr15), p-PDK1 (Ser241), et al, while one phosphoprotein was down-regulated, i.e. p-ERK (Thr202/ Tyr204)(P44/42). Sixty four matched samples (37 adenoma and their matched normal mucosa) were used for hierarchical clustering analysis and these 19 proteins correctly grouped adenoma by PCA with 89% accuracy. The top signaling pathways (Fig 2 a) affected in colorectal adenoma were IL-3 pathway (-log(p-value)= 7.54), NF- κB pathway (-log(p-value)= 5.64), et al. The top metabolic pathways (Fig 2 b) affected in colorectal adenoma were Aldosterone pathway (-log(p-value)= 3.12), Docosahexaenoic Acid (DHA) pathway (-log(pvalue)= 2.94), et al. Conclusion Our current study demonstrated that many signaling pathways and metabolic pathways were affected in colorectal adenoma which may be involved in development of adenoma. Inflammatory pathways (IL-3, NF- κB and PI3K/AKT) and metabolic pathways (docosahexaenoic acid and leptin) are altered in colorectal adenoma, suggesting the critical role of these pathways.
of activated STAT3 (PIAS3) is the target of miR-181b-1, and further show that miR-181b1 promotes glycolysis by STAT3 activated in colon cancer cells, through down-regulating PIAS3. As STAT3 activation has been reported could promote the transcription and expression of miR-181b-1. Therefore, our results support a positive feedback loop as a mechanism for persistent STAT3 activation, in which miR-181b-1 represses PIAS3 to elevate STAT3 activity, which in turn promotes miR-181b-1 transcription. PIAS3 was found down-regulated and miR-181b-1 up-regulated in human colon tumors, and inverse correlation of miR-181b-1 and PIAS3 expression was also found in colon tumors. Moreover, miR-181b-1 inhibition or PIAS3 up-regulation in colon cancer cells led to reduce STAT3 activation, glycolysis and attenuated engraft tumour growth, indicating that miR-181b-1 overexpression contributes to STAT3 activation. Revealing this novel mechanism of STAT3 activation by a miRNA offers new avenues for therapeutic interventions against colon cancer.
The scatter of 19 proteins and phosphoproteins with Q-value ,0.05.
Sa1692 Characterization of the Helicobacter pylori-Induced STAT3 Activation and the Associated Signaling Network in Gastric Cancer Junhong Zhao, Wei Kang, Yu Juan Dong, Minnie Y. Go, Joanna H. Tong, Ka Fai To, Alfred S. Cheng, Joseph J. Y. Sung, Jun Yu Background and Aims: Helicobacter pylori (H. pylori) is the most important gastric carcinogen. In this study, we sought to evaluate the effect of H. pylori infection on STAT3 activation and dissect the signaling network of STAT3 in the H. pylori-infected gastric cancer. Methods and results: The expression of the active form of STAT3, phospho-STAT3 (pSTAT3), was significantly higher in H. pylori-positive gastritis (73.5%, 61/83) than in H. pylori-negative gastritis (50%, 35/70) (P = 0.003) as shown by immunohistochemistry. On the other hand, therapy-based eradication of H. pylori significantly decreased pSTAT3 expression in 44 H. pylori-positive patients (P , 0.001). The association between H. pylori infection and pSTAT3 expression was further evaluated in mouse model with or without H. pylori infection (SS1 strain). Importantly, pSTAT3 was only detected in the H. pylori-infected gastric tissues of mice, but not in those of the control mice without H. pylori-infection, providing direct evidence that H. pylori infection stimulated the activation of STAT3 in the stomach. pSTAT3 expression was further detected in 147 human gastric cancers. pSTAT3 was marginally associated with the intestinal type than the diffuse type of gastric cancer ( P = 0.07). To elucidate the signaling network of STAT3 in the H. pylori-infected gastric cancer, the gastric cancer cell line AGS was co-cultured with two CagA+ve H. pylori strains (SS1 and ATCC43504) and one CagA-ve H. pylori strain, respectively. pSTAT3 expression was markedly induced in the ATCC43504 H. pyloriy-infected AGS as shown by Western blot. The signaling network of STAT3 induced by H. pylori was dissected using gene expression microarray. By comparing the gene expression profiles of H. pylori-infected and non-infected AGS cells by expression microarray, we identified a total of 849 genes with expression changes. KEGG pathway analysis showed that the de-regulated genes were enriched in 11 different cancer pathways including MAPK signaling pathway. Gene ontology analysis revealed significant up-regulation of genes with prominent roles in multiple cellular processes including signal transduction. Conclusions: H. pylori infection triggers the activation of STAT3 to de-regulate a multitude of tumorigenic genes which may contribute to the initiation and transformation of gastric carcinogenesis at early stage. Acknowledgment: The project was supported by a research fund (RFCID, 10090942).
The top signaling pathways (a) and metabolic pathways (b) altered in colorectal adenoma as determined by Ingenuity Pathway Analysis (IPA). Protein signaling network altered in colorectal adenoma (c). The network is displayed graphically as nodes (protein) and edges (the biological relationship between the nodes). The nodes are represented using various shapes that represent the functional class of the protein products. The up- and downregulated proteins in colorectal adenoma shaded in red and green, respectively. The nodes without color were not assessed in this study but identified by IPA as important nodes involved in the network. Sa1691 MiR-181b-1 Controls Glycolysis As STAT3 Activator in Colon Cancer Cells Xiaolin Pan, Jin Feng, Guoxin Zhang Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is an anomalous characteristic of glucose metabolism in cancer cells. Signal transducer and activator of transcription factor 3 (STAT3) is constitutively activated in human malignancies, and served a crucial in cell survival, angiogenesis, immune evasion, inflammation and aerobic glycolysis. In this work, we show that protein inhibitor
AGA Abstracts
S-284
Suite 6.0. The signaling pathways, metabolic pathways and network constituted by these proteins were identified by using Ingenuity Pathway Analysis (IPA). Results Of 27 metabolic proteins and 172 proteins of signaling pathway screened, 82 were detected in 37 paired colorectal adenoma samples and among which 19 were identified as significant proteins (Fig 1) by comparing between adenoma and normal tissues (Q-value ,0.05). Of 19 proteins, 18 were up-regulated in adenoma including MetRS, beta-catenin, p-cdc2 (Tyr15), p-PDK1 (Ser241), et al, while one phosphoprotein was down-regulated, i.e. p-ERK (Thr202/ Tyr204)(P44/42). Sixty four matched samples (37 adenoma and their matched normal mucosa) were used for hierarchical clustering analysis and these 19 proteins correctly grouped adenoma by PCA with 89% accuracy. The top signaling pathways (Fig 2 a) affected in colorectal adenoma were IL-3 pathway (-log(p-value)= 7.54), NF- κB pathway (-log(p-value)= 5.64), et al. The top metabolic pathways (Fig 2 b) affected in colorectal adenoma were Aldosterone pathway (-log(p-value)= 3.12), Docosahexaenoic Acid (DHA) pathway (-log(pvalue)= 2.94), et al. Conclusion Our current study demonstrated that many signaling pathways and metabolic pathways were affected in colorectal adenoma which may be involved in development of adenoma. Inflammatory pathways (IL-3, NF- κB and PI3K/AKT) and metabolic pathways (docosahexaenoic acid and leptin) are altered in colorectal adenoma, suggesting the critical role of these pathways.
of activated STAT3 (PIAS3) is the target of miR-181b-1, and further show that miR-181b1 promotes glycolysis by STAT3 activated in colon cancer cells, through down-regulating PIAS3. As STAT3 activation has been reported could promote the transcription and expression of miR-181b-1. Therefore, our results support a positive feedback loop as a mechanism for persistent STAT3 activation, in which miR-181b-1 represses PIAS3 to elevate STAT3 activity, which in turn promotes miR-181b-1 transcription. PIAS3 was found down-regulated and miR-181b-1 up-regulated in human colon tumors, and inverse correlation of miR-181b-1 and PIAS3 expression was also found in colon tumors. Moreover, miR-181b-1 inhibition or PIAS3 up-regulation in colon cancer cells led to reduce STAT3 activation, glycolysis and attenuated engraft tumour growth, indicating that miR-181b-1 overexpression contributes to STAT3 activation. Revealing this novel mechanism of STAT3 activation by a miRNA offers new avenues for therapeutic interventions against colon cancer.
The scatter of 19 proteins and phosphoproteins with Q-value ,0.05.
Sa1692 Characterization of the Helicobacter pylori-Induced STAT3 Activation and the Associated Signaling Network in Gastric Cancer Junhong Zhao, Wei Kang, Yu Juan Dong, Minnie Y. Go, Joanna H. Tong, Ka Fai To, Alfred S. Cheng, Joseph J. Y. Sung, Jun Yu Background and Aims: Helicobacter pylori (H. pylori) is the most important gastric carcinogen. In this study, we sought to evaluate the effect of H. pylori infection on STAT3 activation and dissect the signaling network of STAT3 in the H. pylori-infected gastric cancer. Methods and results: The expression of the active form of STAT3, phospho-STAT3 (pSTAT3), was significantly higher in H. pylori-positive gastritis (73.5%, 61/83) than in H. pylori-negative gastritis (50%, 35/70) (P = 0.003) as shown by immunohistochemistry. On the other hand, therapy-based eradication of H. pylori significantly decreased pSTAT3 expression in 44 H. pylori-positive patients (P , 0.001). The association between H. pylori infection and pSTAT3 expression was further evaluated in mouse model with or without H. pylori infection (SS1 strain). Importantly, pSTAT3 was only detected in the H. pylori-infected gastric tissues of mice, but not in those of the control mice without H. pylori-infection, providing direct evidence that H. pylori infection stimulated the activation of STAT3 in the stomach. pSTAT3 expression was further detected in 147 human gastric cancers. pSTAT3 was marginally associated with the intestinal type than the diffuse type of gastric cancer ( P = 0.07). To elucidate the signaling network of STAT3 in the H. pylori-infected gastric cancer, the gastric cancer cell line AGS was co-cultured with two CagA+ve H. pylori strains (SS1 and ATCC43504) and one CagA-ve H. pylori strain, respectively. pSTAT3 expression was markedly induced in the ATCC43504 H. pyloriy-infected AGS as shown by Western blot. The signaling network of STAT3 induced by H. pylori was dissected using gene expression microarray. By comparing the gene expression profiles of H. pylori-infected and non-infected AGS cells by expression microarray, we identified a total of 849 genes with expression changes. KEGG pathway analysis showed that the de-regulated genes were enriched in 11 different cancer pathways including MAPK signaling pathway. Gene ontology analysis revealed significant up-regulation of genes with prominent roles in multiple cellular processes including signal transduction. Conclusions: H. pylori infection triggers the activation of STAT3 to de-regulate a multitude of tumorigenic genes which may contribute to the initiation and transformation of gastric carcinogenesis at early stage. Acknowledgment: The project was supported by a research fund (RFCID, 10090942).
The top signaling pathways (a) and metabolic pathways (b) altered in colorectal adenoma as determined by Ingenuity Pathway Analysis (IPA). Protein signaling network altered in colorectal adenoma (c). The network is displayed graphically as nodes (protein) and edges (the biological relationship between the nodes). The nodes are represented using various shapes that represent the functional class of the protein products. The up- and downregulated proteins in colorectal adenoma shaded in red and green, respectively. The nodes without color were not assessed in this study but identified by IPA as important nodes involved in the network. Sa1691 MiR-181b-1 Controls Glycolysis As STAT3 Activator in Colon Cancer Cells Xiaolin Pan, Jin Feng, Guoxin Zhang Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is an anomalous characteristic of glucose metabolism in cancer cells. Signal transducer and activator of transcription factor 3 (STAT3) is constitutively activated in human malignancies, and served a crucial in cell survival, angiogenesis, immune evasion, inflammation and aerobic glycolysis. In this work, we show that protein inhibitor
AGA Abstracts
S-284