A pSMAD/CDX2 Complex Is Essential for the Intestinalization of Epithelial Metaplasia

Mari, Luigi; Milano, Francesca; Parikh, Kaushal; Straub, Daniëlle; Everts, Vincent; Hoeben, Kees K.; Fockens, Paul; Buttar, Navtej; Krishnadath, Kausilia K.

doi:10.1016/j.celrep.2014.03.074

Cited by 61 publications

(63 citation statements)

References 58 publications

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“…Notably, we did not detect expression of the columnar differentiation markers KRT8 or CDX2 (Supplemental Figure 2, G-I), suggesting that BMP activation does not promote columnar differentiation of basal progenitor cells. These findings contrast with previous reports that BMP activation is associated with intestinal differentiation of the squamous epithelium (12,33), one of the hypothetical models for the development of BE.…”

Section: Bmp Activation In the Differentiated Suprabasal Cells Of Thecontrasting

confidence: 99%

BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

Jiang¹,

Ku²,

Zhou³

et al. 2015

J. Clin. Invest.

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sion of the manuscript. We also thank Marc E. Study approval. All mouse experiments were conducted in accordance with procedures approved by the IACUC of the University of Rochester. In the case of human samples, adult participants from a cohort of control subjects or subjects with EoE at the Center for Esophageal Diseases and Swallowing of the University of North Carolina at Chapel Hill had esophageal biopsies prospectively collected and stored. These samples were provided and analyzed under IRB approval. Adult participants from a cohort of control subjects or subjects with EoE being treated at the Division of Gastroenterology of the University of Pennsylvania were also assessed and were provided under IRB approval. All participants in this study or their parents or legal guardians provided written informed consent.

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Section: Bmp Activation In the Differentiated Suprabasal Cells Of Thecontrasting

confidence: 99%

BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

Jiang¹,

Ku²,

Zhou³

et al. 2015

J. Clin. Invest.

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“…In BMP-responsive EPC2-hTERT cells (29), a normal human squamous esophageal cell line with no detectable basal levels of phosphorylated SMAD1/5/8, all VHHs were able to inhibit BMP4-mediated SMAD1/5/8 phosphorylation (Fig. 1A).…”

Section: Specificity and Functional Activity Of The Anti-bmp4 Vhhsmentioning

confidence: 98%

“…28) and was cultured as previously described (29). To detect phosphorylation of SMAD1/5/8 in vitro, EPC2-hTERTs were cultured in 24-well plates and activated with 100 ng/mL of BMP2, BMP4, BMP5, BMP6, or BMP7 (R&D Systems) for 4 hours with or without VHHs or Noggin at the indicated concentrations.…”

Section: Cell Culturementioning

confidence: 99%

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Calpe

Wagner

Khattabi³

et al. 2015

Molecular Cancer Therapeutics

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Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4 þ malignancies.

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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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A pSMAD/CDX2 Complex Is Essential for the Intestinalization of Epithelial Metaplasia

Cited by 61 publications

References 58 publications

BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

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

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