Key elements of the BMP/SMAD pathway co‐localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines

Barros, Rita; Pereira, Bruno; Duluc, Isabelle; Azevedo, Mafalda; Mendes, Nuno; Camilo, Vânia; Jacobs, Rutger J.; Paulo, Paula; Santos-Silva, Filipe; Seuningen, Isabelle Van; Brink, Gijs R. van den; David, Leonor; Freund, Jean–Noël; Almeida, Raquel

doi:10.1002/path.2369

Cited by 62 publications

(58 citation statements)

References 42 publications

(48 reference statements)

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“…CDX2 regulates CDH17 expression in colorectal cancer cell lines and gastric adenocarcinoma [Hinoi et al, 2002;Ko et al, 2005;Barros et al, 2008;Ge et al, 2008]. In this study, three putative CDX2-binding sites were found in the 1-kb CDH17 promoter region (Fig.…”

Section: Discussionmentioning

confidence: 90%

“…Recently, caudal-related homeobox 2 (CDX2) was found to play important roles in up-regulation of CDH17 expression in colorectal cancer cell lines and gastric adenocarcinoma [Hinoi et al, 2002;Ko et al, 2005;Ge et al, 2008], which was in turn regulated by bone morphogenetic protein 2 (BMP2) and BMP4 in gastric cancer cells [Barros et al, 2008]. Hepatic nuclear factor 1 (HNF1) is one of the key transcriptional factors (TF) that regulate serum a-fetoprotein levels in hepatocellular carcinoma [Nakabayashi et al, 2004].…”

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confidence: 99%

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HNF1α and CDX2 transcriptional factors bind to cadherin‐17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma

Zhu

Wong

Lee

et al. 2010

J of Cellular Biochemistry

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Cadherin-17 (CDH17) belongs to the cell adhesion cadherin family with a prominent role in tumorigenesis. It is highly expressed in human hepatocellular carcinoma (HCC) and is proposed to be a biomarker and therapeutic molecule for liver malignancy. The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC. A 1-kb upstream sequence of CDH17 gene was cloned and the promoter activity was studied by luciferase reporter assay. By bioinformatics analysis, deletion and mutation assays, and chromatin immunoprecipitation studies, we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L). A consistent down-regulation of CDH17 and the two transcriptional activators (HNF1α and CDX2) expression was found in the liver of mouse during development, as well as in human liver cancer cells with less metastatic potential. Suppression of HNF1α and CDX2 expression by small interfering RNA (siRNA) significantly down-regulated expressions of CDH17 and its downstream target cyclin D1 and the viability of HCC cells in vitro. In summary, we identified the minimal promoter region of CDH17 that is regulated by HNF1α and CDX2 transcriptional factors. The present findings enhance our understanding on the regulatory mechanisms of CDH17 oncogene in HCC, and may shed new insights into targeting CDH17 expression as potential therapeutic intervention for cancer treatment.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

HNF1α and CDX2 transcriptional factors bind to cadherin‐17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma

Zhu

Wong

Lee

et al. 2010

J of Cellular Biochemistry

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“…24,25 As NKX6.3 did not affect BMP4 expression, we examined the effects of NKX6.3 on TWSG1, which is a novel inhibitor for the BMP signaling pathway 26,27 in AGS and MKN1 cells. Treatment with BMP4 induced p-SMAD1/5/8 and CDX2 expression and downregulated SOX2 expression in AGS and MKN1 cells (Figure 8a).…”

Section: Nkx63 Inhibits Bmp4 Signaling By Inducing Twsg1mentioning

confidence: 99%

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

et al. 2016

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Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS NKX6.3 and MKN1 NKX6.3 cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6. Gastric cancer is still one of the malignancies with high incidence and mortality rates worldwide. 1 The stages of the precancerous cascade for gastric adenocarcinoma are a series of histologically recognizable changes in the gastric mucosa that follow a specific sequence: non-atrophic gastritis, multifocal atrophic gastritis, intestinal metaplasia, and dysplasia. 2-4 Of these, intestinal metaplasia is the replacement of gastric epithelium by epithelium displaying an intestinal phenotype with the appearance of goblet, Paneth, and absorptive cells. It is well known that Helicobacter pylori infection, high salt intake, smoking, and alcohol consumption are risk factors for gastric intestinal metaplasia. [5][6][7][8] Interestingly, altered expression of Muc5ac with the aberrant expression of Muc2 and caudal-related homologue 2 (CDX2) was detected in intestinal metaplasia of the stomach, which is characterized by the appearance of goblet cells and is considered to be a preneoplastic stage of gastric carcinogenesis. [9][10][11][12] Patients with gastric intestinal metaplasia showed a six-fold increased risk of gastric cancer than did those without gastric intestinal metaplasia. 13 Although much is known about the morphology and physiology of gastric intestinal metaplasia, the regulatory mechanisms that govern their intestinal differentiation still remain unclear.It was recently reported that NKX6.3, a third member of the NKX6 subfamily of NKX genes, is a novel transcription factor required for gastric epithelial differentiation. 14 In mouse embryos, NKX6.3 expression is restricted to endoderm-derived cells in the gastric antrum, pylorus, and proximal duodenum. 15 As a stratified squamous epithelium extends from the esophagus to the fundus of the m...

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“…Eighteen hours posttransfection, cells were incubated in serum-free, Ca 2ϩ -free DMEM containing 4 mM L-glutamine, 0.2% BSA, penicillin 100 U/ml, and 0.5 mM CaCl 2 for 8 h. This medium was removed and substituted with the same medium supplemented with 0. 5 . The PCR reaction was prepared in a volume of 50 l containing the following reagents: 0.2 mM dNTP mixture; 1.5 mM MgCl2; 1 l template cDNA; 1.0 U platinum Taq DNA polymerase (Invitrogen, Carlsbad, CA).…”

Section: Transient Transfections and Luciferase Reporter Assays Ht-2mentioning

confidence: 99%

“…CDX2 stimulates differentiation and expression of sucrase-isomaltase (SI), lactase-phlorizin hydrolase, LI-cadherin, and Muc2 in intestinal epithelial cells (12,31,71,79). BMP will increase CDX2 transcripts and protein in gastric cell lines (5). CDX2 expression is retained in the intestinal epithelium throughout adulthood but becomes reduced in colon cancer (21,27,52,71).…”

mentioning

confidence: 99%

CaSR stimulates secretion of Wnt5a from colonic myofibroblasts to stimulate CDX2 and sucrase-isomaltase using Ror2 on intestinal epithelia

Pacheco

Macleod²

2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Pacheco II, MacLeod RJ. CaSR stimulates secretion of Wnt5a from colonic myofibroblasts to stimulate CDX2 and sucraseisomaltase using Ror2 on intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 295: G748 -G759, 2008. First published August 14, 2008 doi:10.1152/ajpgi.00560.2007.-To understand whether extracellular calcium-sensing receptor (CaSR) expression on colonic myofibroblast cells (18Co) contributed to epithelial homeostasis, we activated the CaSR with 5 mM Ca 2ϩ , screened by RT-PCR Wnt family members, and measured their secretion. Transcripts for Wnt 1, 2, 2b, 3a, 4, and 7a were either absent or unchanged whereas Wnt3 decreased and Wnt5a increased. We assessed Wnt5a secretion by Western blot. High Ca 2ϩ (5 mM) substantially increased Wnt5a secretion; small interfering RNA (siRNA) against the CaSR reduced this to constitutive amounts. Expression of Wnt5a plasmid but not Wnt1 or Wnt3a increased caudal homeodomain factor CDX2 transcripts and protein in HT-29 adenocarcinoma cells. Wnt5a increased activity of a sucrase-isomaltase (SI) promoter in Caco-2BBE cells. Wnt5a protein stimulation of CDX2 transcripts and protein and SI reporter were increased by overexpression of wild-type Ror2, a Wnt5a receptor, and reduced with siRNA against Ror2. CaSR activation of HT-29 cells increased Ror2 protein expression. Ror2 protein was expressed in mouse jejunum from crypt base to villus tip and in the colon on surface epithelia. Our results show that activation of a G protein-coupled receptor, the CaSR, stimulates secretion of Wnt5a from myofibroblasts. Stimulation of epithelia by the CaSR increased the expression of a receptor for Wnt5a, the tyrosine kinase Ror2, suggesting existence of a unique paracrine relationship for CDX2 homoeostasis in the intestine and revealing new contributions of CaSRactivated myofibroblasts to intestinal stem cell niche microenvironments.

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Key elements of the BMP/SMAD pathway co‐localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines

Cited by 62 publications

References 42 publications

HNF1α and CDX2 transcriptional factors bind to cadherin‐17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma

HNF1α and CDX2 transcriptional factors bind to cadherin‐17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

CaSR stimulates secretion of Wnt5a from colonic myofibroblasts to stimulate CDX2 and sucrase-isomaltase using Ror2 on intestinal epithelia

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