Limits...
The role of KCNQ1 in mouse and human gastrointestinal cancers.

Than BL, Goos JA, Sarver AL, O'Sullivan MG, Rod A, Starr TK, Fijneman RJ, Meijer GA, Zhao L, Zhang Y, Largaespada DA, Scott PM, Cormier RT - Oncogene (2013)

Bottom Line: We also found genes implicated in inflammation and in cellular detoxification.Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis.Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA [2] Toxicology Graduate Program, University of Minnesota, Duluth, MN, USA.

ABSTRACT
Kcnq1, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer, we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wild-type littermate controls, suggesting a role for Kcnq1 in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.

Show MeSH

Related in: MedlinePlus

GSEAResults of GSEA showing enrichment scores (ES) of Cftr and Muc2 genesets with respect to the ranked Kcnq1 expression dataset. Shown are enrichment plots for genesets consisting of (A) genes upregulated in the small intestine of CFTR KO mice27; (B) genes downregulated in the small intestine of CFTR KO mice27;(C) genes downregulated in the small intestine of Muc2 KO mice37. (D) Normalized enrichment score (NES) and nominal P value (nom. P value) are shown for each comparison.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3935979&req=5

Figure 4: GSEAResults of GSEA showing enrichment scores (ES) of Cftr and Muc2 genesets with respect to the ranked Kcnq1 expression dataset. Shown are enrichment plots for genesets consisting of (A) genes upregulated in the small intestine of CFTR KO mice27; (B) genes downregulated in the small intestine of CFTR KO mice27;(C) genes downregulated in the small intestine of Muc2 KO mice37. (D) Normalized enrichment score (NES) and nominal P value (nom. P value) are shown for each comparison.

Mentions: To identify common pathways and genes disrupted by Kcnq1 and Cftr deficiencies we used Gene Set Enrichment Analysis (GSEA)24. The entire ranked expression data set from the Kcnq1 KO proximal small intestine array was compared to genesets compiled from a microarray analysis of gene expression in the small intestine of Cftr KO mice25. Cftr genesets consisted of all genes up or down regulated by 2-fold in the Cftr KO mouse. GSEA revealed significant correlation, with overlap of gene identity and direction of regulation. (Fig. 4 and Supp. Table 5, normalized enrichment score (NES) for Cftr KO upregulated genes 1.97, p < 0.001; NES for Cftr KO downregulated genes −1.92, p < 0.001.)


The role of KCNQ1 in mouse and human gastrointestinal cancers.

Than BL, Goos JA, Sarver AL, O'Sullivan MG, Rod A, Starr TK, Fijneman RJ, Meijer GA, Zhao L, Zhang Y, Largaespada DA, Scott PM, Cormier RT - Oncogene (2013)

GSEAResults of GSEA showing enrichment scores (ES) of Cftr and Muc2 genesets with respect to the ranked Kcnq1 expression dataset. Shown are enrichment plots for genesets consisting of (A) genes upregulated in the small intestine of CFTR KO mice27; (B) genes downregulated in the small intestine of CFTR KO mice27;(C) genes downregulated in the small intestine of Muc2 KO mice37. (D) Normalized enrichment score (NES) and nominal P value (nom. P value) are shown for each comparison.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3935979&req=5

Figure 4: GSEAResults of GSEA showing enrichment scores (ES) of Cftr and Muc2 genesets with respect to the ranked Kcnq1 expression dataset. Shown are enrichment plots for genesets consisting of (A) genes upregulated in the small intestine of CFTR KO mice27; (B) genes downregulated in the small intestine of CFTR KO mice27;(C) genes downregulated in the small intestine of Muc2 KO mice37. (D) Normalized enrichment score (NES) and nominal P value (nom. P value) are shown for each comparison.
Mentions: To identify common pathways and genes disrupted by Kcnq1 and Cftr deficiencies we used Gene Set Enrichment Analysis (GSEA)24. The entire ranked expression data set from the Kcnq1 KO proximal small intestine array was compared to genesets compiled from a microarray analysis of gene expression in the small intestine of Cftr KO mice25. Cftr genesets consisted of all genes up or down regulated by 2-fold in the Cftr KO mouse. GSEA revealed significant correlation, with overlap of gene identity and direction of regulation. (Fig. 4 and Supp. Table 5, normalized enrichment score (NES) for Cftr KO upregulated genes 1.97, p < 0.001; NES for Cftr KO downregulated genes −1.92, p < 0.001.)

Bottom Line: We also found genes implicated in inflammation and in cellular detoxification.Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis.Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA [2] Toxicology Graduate Program, University of Minnesota, Duluth, MN, USA.

ABSTRACT
Kcnq1, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer, we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wild-type littermate controls, suggesting a role for Kcnq1 in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.

Show MeSH
Related in: MedlinePlus