Immunohistochemical analyses of HNF-4α and their controlled proteins in human ulcerative colitis and colorectal cancer tissues
Main Article Content
http://orcid.org/0000-0002-9705-3162
Abstract
The gene coding the transcription factor HNF-4α is located on chromosome 20q and is expressed in the liver, pancreas, kidneys, stomach and in the small and large intestine, where it controls important aspects related to morphogenesis and epithelial function.
Mucin type MUC4 and MUC2, and β-catenin are representative genes controlled by HNF-4α and expressed in colonic tissue. We used in the present study immunohistochemical analyses to detect different levels of expression of the above mentioned proteins in colonic tissues of colorectal cancer and ulcerative colitis patients.
We demonstrate high expression levels of HNF-4α in normal colon tissue, however, in adenoma, HNF-4α levels of expression decreased and in carcinoma of the large intestine; the levels were very low or invisible. Similarly, in ulcerative colitis patients the expression HNF-4α levels of the protein were significantly lower than the control group. Expression levels of MUC2 and MUC4 levels were significantly lower in the adenocarcinoma and ulcerative colitis groups than in the control group. In contrast, the expression level of β-catenin increased and changed from a membrane to a nuclear localization in the adenocarcinoma group only.
We surmise that HNF-4α plays an important role in prevention of ulcerative colitis and colorectal cancer in humans. As a result, altered expression of the proteins MUC2 and MUC4 controlled by HNF-4α indicate that the defensive role attributed to them is not properly performed. In contrast, the Wnt / β-catenin pathway controlled by HNF-4α becomes active in samples from the stage of the adenoma and reached its peak in the carcinoma samples.Article Details
How to Cite
SCHWARTZ, Betty; A, Harari; M, Huszar.
Immunohistochemical analyses of HNF-4α and their controlled proteins in human ulcerative colitis and colorectal cancer tissues.
Medical Research Archives, [S.l.], v. 5, n. Issue 9, sep. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1483>. Date accessed: 09 nov. 2024.
Keywords
HNF-4α, MUC2, MUC4, β-catenin, Wnt / β-catenin pathway, immunohistochemical, analyses.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
References
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[2] Sladek FM, Darnell JE. Mechanisms of liver-specific gene expression. Current opinion in genetics & development. 1992; 2(2):256-9.
[3] Cattin AL, Le Beyec J, Barreau F, et al. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Molecular and cellular biology. 2009; 29(23):6294-308.
[4] Jiang S, Tanaka T, Iwanari H, et al. Expression and localization of P1 promoter-driven hepatocyte nuclear factor-4alpha (HNF4alpha) isoforms in human and rats. Nuclear receptor. 2003; 1(1):5.
[5] Garrison WD, Battle MA, Yang C, et al. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology. 2006; 130(4):1207-20.
[6] Algamas-Dimantov A, Yehuda-Shnaidman E, Peri I, et al. Epigenetic control of HNF-4alpha in colon carcinoma cells affects MUC4 expression and malignancy. Cellular oncology. 2013; 36(2):155-67.
[7] van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002; 111(2):241-50.
[8] Colony PC. Structural characterization of colonic cell types and correlation with specific functions. Digestive diseases and sciences. 1996; 41(1):88-104.
[9] Vanuytsel T, Senger S, Fasano A, et al. Major signaling pathways in intestinal stem cells. Biochimica et biophysica acta. 2013; 1830(2):2410-26.
[10] Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nature reviews Immunology. 2014; 14(10):667-85.
[11] Pelaseyed T, Bergstrom JH, Gustafsson JK, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunological reviews. 2014; 260(1):8-20.
[12] Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Current gastroenterology reports. 2010; 12(5):319-30.
[13] Andrianifahanana M, Moniaux N, Batra SK. Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochimica et biophysica acta. 2006; 1765(2):189-222.
[14] Darsigny M, Babeu JP, Dupuis AA, et al. Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PloS one. 2009; 4(10):e7609.
[15] Algamas-Dimantov A, Davidovsky D, Ben-Ari J, et al. Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice. Journal of lipid research. 2012; 53(6):1056-70.
[16] Jonckheere N, Vincent A, Perrais M, et al. The human mucin MUC4 is transcriptionally regulated by caudal-related homeobox, hepatocyte nuclear factors, forkhead box A, and GATA endodermal transcription factors in epithelial cancer cells. The Journal of biological chemistry. 2007; 282(31):22638-50.
[17] Chaturvedi P, Singh AP, Batra SK. Structure, evolution, and biology of the MUC4 mucin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2008; 22(4):966-81.
[18] Shanmugam C, Jhala NC, Katkoori VR, et al. Prognostic value of mucin 4 expression in colorectal adenocarcinomas. Cancer. 2010; 116(15):3577-86.
[19] Froicu M, Weaver V, Wynn TA, et al. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Molecular endocrinology. 2003; 17(12):2386-92.
[20] Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011; 474(7351):307-17.
[21] Delaunoit T, Limburg PJ, Goldberg RM, et al. Colorectal cancer prognosis among patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2006; 4(3):335-42.
[22] Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. American journal of physiology Gastrointestinal and liver physiology. 2004; 287(1):G7-17.
[23] Bolotin E, Liao H, Ta TC, et al. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays. Hepatology. 2010; 51(2):642-53.
[24] Chellappa K, Robertson GR, Sladek FM. HNF4alpha: a new biomarker in colon cancer? Biomarkers in medicine. 2012; 6(3):297-300.
[25] Boyd M, Bressendorff S, Moller J, et al. Mapping of HNF4alpha target genes in intestinal epithelial cells. BMC gastroenterology. 2009; 9:68.
[26] Battle MA, Konopka G, Parviz F, et al. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103(22):8419-24.
[27] Schwartz B, Algamas-Dimantov A, Hertz R, et al. Inhibition of colorectal cancer by targeting hepatocyte nuclear factor-4alpha. International journal of cancer. 2009; 124(5):1081-9.
[28] Zhang B, Wang J, Wang X, et al. Proteogenomic characterization of human colon and rectal cancer. Nature. 2014; 513(7518):382-7.
[29] Lazarevich NL, Shavochkina DA, Fleishman DI, et al. Deregulation of hepatocyte nuclear factor 4 (HNF4)as a marker of epithelial tumors progression. Experimental oncology. 2010; 32(3):167-71.
[30] Tanaka T, Jiang S, Hotta H, et al. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. The Journal of pathology. 2006; 208(5):662-72.
[31] Sehgal M, Gupta R, Moussa A, et al. An Integrative Approach for Mapping Differentially Expressed Genes and Network Components Using Novel Parameters to Elucidate Key Regulatory Genes in Colorectal Cancer. PloS one. 2015; 10(7):e0133901.
[32] Blank M, Klussmann E, Kruger-Krasagakes S, et al. Expression of MUC2-mucin in colorectal adenomas and carcinomas of different histological types. International journal of cancer. 1994; 59(3):301-6.
[33] Byrd JC, Bresalier RS. Mucins and mucin binding proteins in colorectal cancer. Cancer metastasis reviews. 2004; 23(1-2):77-99.
[34] Hanski C, Riede E, Gratchev A, et al. MUC2 gene suppression in human colorectal carcinomas and their metastases: in vitro evidence of the modulatory role of DNA methylation. Laboratory investigation; a journal of technical methods and pathology. 1997; 77(6):685-95.
[35] Ahn SH, Shah YM, Inoue J, et al. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflammatory bowel diseases. 2008; 14(7):908-20.
[36] Van Klinken BJ, Van der Wal JW, Einerhand AW, et al. Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut. 1999; 44(3):387-93.
[37] Van der Sluis M, De Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006; 131(1):117-29.
[38] Johansson ME, Phillipson M, Petersson J, et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105(39):15064-9.
[39] Dorofeyev AE, Vasilenko IV, Rassokhina OA, et al. Mucosal barrier in ulcerative colitis and Crohn's disease. Gastroenterology research and practice. 2013; 2013:431231.
[1] Sladek FM, Zhong WM, Lai E, et al. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes & development. 1990; 4(12B):2353-65.
[2] Sladek FM, Darnell JE. Mechanisms of liver-specific gene expression. Current opinion in genetics & development. 1992; 2(2):256-9.
[3] Cattin AL, Le Beyec J, Barreau F, et al. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Molecular and cellular biology. 2009; 29(23):6294-308.
[4] Jiang S, Tanaka T, Iwanari H, et al. Expression and localization of P1 promoter-driven hepatocyte nuclear factor-4alpha (HNF4alpha) isoforms in human and rats. Nuclear receptor. 2003; 1(1):5.
[5] Garrison WD, Battle MA, Yang C, et al. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology. 2006; 130(4):1207-20.
[6] Algamas-Dimantov A, Yehuda-Shnaidman E, Peri I, et al. Epigenetic control of HNF-4alpha in colon carcinoma cells affects MUC4 expression and malignancy. Cellular oncology. 2013; 36(2):155-67.
[7] van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002; 111(2):241-50.
[8] Colony PC. Structural characterization of colonic cell types and correlation with specific functions. Digestive diseases and sciences. 1996; 41(1):88-104.
[9] Vanuytsel T, Senger S, Fasano A, et al. Major signaling pathways in intestinal stem cells. Biochimica et biophysica acta. 2013; 1830(2):2410-26.
[10] Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nature reviews Immunology. 2014; 14(10):667-85.
[11] Pelaseyed T, Bergstrom JH, Gustafsson JK, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunological reviews. 2014; 260(1):8-20.
[12] Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Current gastroenterology reports. 2010; 12(5):319-30.
[13] Andrianifahanana M, Moniaux N, Batra SK. Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochimica et biophysica acta. 2006; 1765(2):189-222.
[14] Darsigny M, Babeu JP, Dupuis AA, et al. Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PloS one. 2009; 4(10):e7609.
[15] Algamas-Dimantov A, Davidovsky D, Ben-Ari J, et al. Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice. Journal of lipid research. 2012; 53(6):1056-70.
[16] Jonckheere N, Vincent A, Perrais M, et al. The human mucin MUC4 is transcriptionally regulated by caudal-related homeobox, hepatocyte nuclear factors, forkhead box A, and GATA endodermal transcription factors in epithelial cancer cells. The Journal of biological chemistry. 2007; 282(31):22638-50.
[17] Chaturvedi P, Singh AP, Batra SK. Structure, evolution, and biology of the MUC4 mucin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2008; 22(4):966-81.
[18] Shanmugam C, Jhala NC, Katkoori VR, et al. Prognostic value of mucin 4 expression in colorectal adenocarcinomas. Cancer. 2010; 116(15):3577-86.
[19] Froicu M, Weaver V, Wynn TA, et al. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Molecular endocrinology. 2003; 17(12):2386-92.
[20] Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011; 474(7351):307-17.
[21] Delaunoit T, Limburg PJ, Goldberg RM, et al. Colorectal cancer prognosis among patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2006; 4(3):335-42.
[22] Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. American journal of physiology Gastrointestinal and liver physiology. 2004; 287(1):G7-17.
[23] Bolotin E, Liao H, Ta TC, et al. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays. Hepatology. 2010; 51(2):642-53.
[24] Chellappa K, Robertson GR, Sladek FM. HNF4alpha: a new biomarker in colon cancer? Biomarkers in medicine. 2012; 6(3):297-300.
[25] Boyd M, Bressendorff S, Moller J, et al. Mapping of HNF4alpha target genes in intestinal epithelial cells. BMC gastroenterology. 2009; 9:68.
[26] Battle MA, Konopka G, Parviz F, et al. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103(22):8419-24.
[27] Schwartz B, Algamas-Dimantov A, Hertz R, et al. Inhibition of colorectal cancer by targeting hepatocyte nuclear factor-4alpha. International journal of cancer. 2009; 124(5):1081-9.
[28] Zhang B, Wang J, Wang X, et al. Proteogenomic characterization of human colon and rectal cancer. Nature. 2014; 513(7518):382-7.
[29] Lazarevich NL, Shavochkina DA, Fleishman DI, et al. Deregulation of hepatocyte nuclear factor 4 (HNF4)as a marker of epithelial tumors progression. Experimental oncology. 2010; 32(3):167-71.
[30] Tanaka T, Jiang S, Hotta H, et al. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. The Journal of pathology. 2006; 208(5):662-72.
[31] Sehgal M, Gupta R, Moussa A, et al. An Integrative Approach for Mapping Differentially Expressed Genes and Network Components Using Novel Parameters to Elucidate Key Regulatory Genes in Colorectal Cancer. PloS one. 2015; 10(7):e0133901.
[32] Blank M, Klussmann E, Kruger-Krasagakes S, et al. Expression of MUC2-mucin in colorectal adenomas and carcinomas of different histological types. International journal of cancer. 1994; 59(3):301-6.
[33] Byrd JC, Bresalier RS. Mucins and mucin binding proteins in colorectal cancer. Cancer metastasis reviews. 2004; 23(1-2):77-99.
[34] Hanski C, Riede E, Gratchev A, et al. MUC2 gene suppression in human colorectal carcinomas and their metastases: in vitro evidence of the modulatory role of DNA methylation. Laboratory investigation; a journal of technical methods and pathology. 1997; 77(6):685-95.
[35] Ahn SH, Shah YM, Inoue J, et al. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflammatory bowel diseases. 2008; 14(7):908-20.
[36] Van Klinken BJ, Van der Wal JW, Einerhand AW, et al. Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut. 1999; 44(3):387-93.
[37] Van der Sluis M, De Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006; 131(1):117-29.
[38] Johansson ME, Phillipson M, Petersson J, et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105(39):15064-9.
[39] Dorofeyev AE, Vasilenko IV, Rassokhina OA, et al. Mucosal barrier in ulcerative colitis and Crohn's disease. Gastroenterology research and practice. 2013; 2013:431231.