Anders Krüger Olsen

Næstved Hospital, Нествед, Zealand, Denmark

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Publications (7)35.44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor necrosis factor-α (TNF-α) is highly up-regulated in inflammation and reduces the expression of the intestinal transcription factor, CDX2. Wnt/β-catenin signaling is critical for intestinal cell proliferation, but a decreased CDX2 expression has influence on the Wnt signaling-related genes and progression of colorectal cancer. Although several inflammatory signaling pathways, including TNF-α, have been reported to promote Wnt/β-catenin activity and development of cancer, the underlying molecular mechanisms remain unclear. The aim was to investigate the signaling pathways involved in the TNF-α-mediated down-regulation of CDX2, and its influence on Wnt/β-catenin signaling components in colon cancer cells. The expression of TNF-α and CDX2 at the invasive front were evaluated by immunohistochemical staining and showed reduced CDX2 positive-cells in tumor buddings in areas with TNF-α expression in the surrounding inflammatory cells. In vitro studies revealed that TNF-α treatment showed a dose-dependent decrease of CDX2 mRNA and protein expression in Caco-2 cells. Inhibition of NF-kB or p38 pathways showed that these are involved in the TNF-α-dependent down-regulation of CDX2. Furthermore, TNF-α-mediated down-regulation of CDX2 was found to significantly decrease the mRNA levels of APC, AXIN2, and GSK3β, whereas the mRNA levels of Wnt targets were significantly elevated in TNF-α-treated Caco-2 cells. These findings were associated with reduced binding of CDX2 to promoter or enhancer regions of APC, AXIN2, and GSK3β. In conclusion it was found that TNF-α induces the expression of Wnt signaling components through a down-regulation of the CDX2 expression that might have a tumor-promoting effect on colon cancer cells.
    Carcinogenesis 02/2014; · 5.64 Impact Factor
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    ABSTRACT: The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (À13910*T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (À13907*G, rs41525747; À13915*G, rs41380347; À14010*C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, À14009T>G (ss 820486563), is signifi-cantly associated with lactose-digester status, and in vitro functional tests confirm that the À14009*G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spread through several ethnic groups, and we report a greater genetic diversity in lactose digesters than in nondigesters. By examining flanking markers to control for the effects of mutation and demography, we further describe, from empirical evidence, the signature of a soft selective sweep. Lactase, the enzyme that digests the milk sugar lactose, persists into adult life in approximately 35% of the world's population. 1 This genetic trait of adult lactase persistence (LP [MIM 223100]) is a recent human adaptation permit-ting those who carry it to use animal milk more readily as a source of nutrition. This LP phenotype is in contrast to the ancestral mammalian phenotype shared by most of the human population where lactase is downregulated before adulthood. LP is attributable to nucleotide changes in a regulatory region that acts as an enhancer of the expression of the gene encoding lactase, LCT (MIM 603202). This LCT enhancer is located in intron 13 of the neighboring gene, MCM6 (MIM 601806), immediately upstream of LCT (for review see Ingram et al. 1). LP in Europe is generally attrib-utable to a single allele (À13910*T, rs4988235) that seems to have been under strong directional selection in the last 5,000–10,000 years. 2 The evidence for selection comes from the fact that the allele lies on an extended haplo-type 3,4 with low microsatellite diversity and is at a signifi-cantly higher frequency than expected for the age of the allele. 1,4–6 Tests of haplotype homozygosity and popula-tion differentiation in genome-wide studies that focus on European samples show that the region of chromosome 2 containing LCT has one of the highest ''signatures'' of selection. 7 In Africa and the Middle East, the situation is more complicated and three additional alleles (À13907*G, rs41525747; À13915*G, rs41380347; À14010*C, rs145946881) in the same LCT enhancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (-13910(∗)T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (-13907(∗)G, rs41525747; -13915(∗)G, rs41380347; -14010(∗)C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, -14009T>G (ss 820486563), is significantly associated with lactose-digester status, and in vitro functional tests confirm that the -14009(∗)G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spread through several ethnic groups, and we report a greater genetic diversity in lactose digesters than in nondigesters. By examining flanking markers to control for the effects of mutation and demography, we further describe, from empirical evidence, the signature of a soft selective sweep.
    The American Journal of Human Genetics 08/2013; · 11.20 Impact Factor
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    ABSTRACT: Wnt signalling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signalling-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3β in migrating colon cancer cells at the invasive front. CDX2 bound promoter and enhancer regions from APC, AXIN2 and GSK3β were analysed for gene regulatory activity and the expression pattern of APC and GSK3β at the invasive front was evaluated by immunohistochemical procedures. Transfection of intestinal and non-intestinal cell lines demonstrated that CDX2 activated APC and AXIN2 promoter activity via intestinal cell-specific enhancer elements. Suppressed CDX2 expression was associated with endogenous down-regulation of APC and AXIN2 expression in Caco-2 cells but did not effect GSK3β expression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results suggest that a low CDX2 level has influence on the Wnt signalling in invasive colon cancer cells possibly promoting cellular migration.
    Carcinogenesis 02/2013; · 5.64 Impact Factor
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    ABSTRACT: High levels of pro-inflammatory cytokines are linked to inflammatory bowel disease (IBD). The transcription factor Caudal-related homeobox transcription factor 2 (CDX2) plays a crucial role in differentiation of intestinal epithelium and regulates IBD-susceptibility genes, including meprin 1A (MEP1A). The aim was to investigate the expression of CDX2 and MEP1A in colitis; to assess if they are regulated by tumor necrosis factor-α (TNF-α), and finally to reveal if CDX2 is involved in a TNF-α-induced down-regulation of MEP1A. Expression of CDX2 and MEP1A was investigated in colonic biopsies of ulcerative colitis (UC) patients and in dextran sodium sulfate (DSS)-induced colitis. CDX2 protein expression was investigated by immunoblotting and immunohistochemical procedures. CDX2 and MEP1A regulation was examined in TNF-α-treated Caco-2 cells by reverse transcription-polymerase chain reaction and with reporter gene assays, and the effect of anti-TNF-α treatment was assessed using infliximab. Finally, in vivo CDX2-DNA interactions were investigated by chromatin immunoprecipitation. The CDX2 and MEP1A mRNA expression was significantly decreased in active UC patients and in DSS-colitis. Colonic biopsy specimens from active UC showed markedly decreased CDX2 staining. TNF-α treatment diminished the CDX2 and MEP1A mRNA levels, a decrease which, was counteracted by infliximab treatment. Reporter gene assays showed significantly reduced CDX2 and MEP1A activity upon TNF-α stimulation. Finally, TNF-α impaired the ability of CDX2 to interact and activate its own, as well as the MEP1A expression. The present results indicate that a TNF-α-mediated down-regulation of CDX2 can be related to suppressed expression of MEP1A during intestinal inflammation.
    Biochimica et Biophysica Acta 02/2012; 1822(6):843-51. · 4.66 Impact Factor
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    ABSTRACT: Upon developmental or environmental cues, the composition of transcription factors in a transcriptional regulatory network is deeply implicated in controlling the signature of the gene expression and thereby specifies the cell or tissue type. Novel methods including ChIP-chip and ChIP-Seq have been applied to analyze known transcription factors and their interacting regulatory DNA elements in the intestine. The intestine is an example of a dynamic tissue where stem cells in the crypt proliferate and undergo a differentiation process toward the villus. During this differentiation process, specific regulatory networks of transcription factors are activated to target specific genes, which determine the intestinal cell fate. The expanding genomewide mapping of transcription factor binding sites and construction of transcriptional regulatory networks provide new insight into how intestinal differentiation occurs. This review summarizes the current overview of the transcriptional regulatory networks driving epithelial differentiation in adult intestine. The novel technologies that have been implied to study these networks are presented and their prospects for implications in future research are also addressed.
    AJP Gastrointestinal and Liver Physiology 11/2011; 302(3):G277-86. · 3.65 Impact Factor
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    ABSTRACT: The CDX2 transcription factor is known to play a crucial role in inhibiting proliferation, promoting differentiation and the expression of intestinal specific genes in intestinal cells. The overall effect of CDX2 in intestinal cells has previously been investigated in conditional knock-out mice, revealing a critical role of CDX2 in the formation of the normal intestinal identity. The identification of direct targets of transcription factors is a key problem in the study of gene regulatory networks. The ChIP-seq technique combines chromatin immunoprecipitation (ChIP) with next generation sequencing resulting in a high throughput experimental method of identifying direct targets of specific transcription factors. The method was applied to CDX2, leading to the identification of the direct binding of CDX2 to several known and novel target genes in the intestinal cell. Examination of the transcript levels of selected genes verified the regulatory role of CDX2 binding. The results place CDX2 as a key node in a transcription factor network controlling the proliferation and differentiation of intestinal cells.
    Journal of Biological Chemistry 08/2010; 285(33):25115-25. · 4.65 Impact Factor

Publication Stats

45 Citations
35.44 Total Impact Points

Institutions

  • 2013
    • Næstved Hospital
      Нествед, Zealand, Denmark
  • 2012
    • Herlev Hospital
      • Department of Pathology
      Herlev, Capital Region, Denmark
  • 2011–2012
    • University of Copenhagen
      • Department of Cellular and Molecular Medicine
      København, Capital Region, Denmark