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Deleted in Malignant Brain Tumors 1 is a versatile mucin-like molecule likely to play a differential role in digestive tract cancer

Deleted in Malignant Brain Tumors 1 is a versatile mucin-like molecule likely to play a differential role in digestive tract cancer
Deleted in Malignant Brain Tumors 1 is a versatile mucin-like molecule likely to play a differential role in digestive tract cancer
Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor gene for brain, lung, and digestive tract cancer. In particular, alterations of the gene and/or a loss of expression have been observed in gastric, colorectal, and esophageal carcinomas. Initial evidence has accumulated that DMBT1 may represent a multifunctional protein. Because the consequences of a loss of DMBT1 function may be different depending on its original function in a particular tissue, we wondered if it is appropriate to assume a uniform role for DMBT1 in digestive tract carcinomas. We hypothesized that a systematic characterization of DMBT1 in the human alimentary tract would be useful to improve the understanding of this molecule and its role in digestive tract carcinomas. Our data indicate that the expression pattern and subcellular distribution of DMBT1 in the human alimentary tract is reminiscent of epithelial mucins. Bovine gallbladder mucin is identified as the DMBT1 homologue in cattle. An elaborate alternative splicing may generate a great variety of DMBT1 isoforms. Monolayered epithelia display transcripts of 6 kb and larger, and generally show a lumenal secretion of DMBT1 indicating a role in mucosal protection. The esophagus is the only tissue displaying an additional smaller transcript of approximately 5 kb. The stratified squamous epithelium of the esophagus is the only epithelium showing a constitutive targeting of DMBT1 to the extracellular matrix (ECM) suggestive of a role in epithelial differentiation. Squamous cell carcinomas of the esophagus show an early loss of DMBT1 expression. In contrast, adenocarcinomas of the esophagus commonly maintain higher DMBT1 expression levels. However, presumably subsequent to a transition from the lumenal secretion to a targeting to the ECM, a loss of DMBT1 expression also takes place in adenocarcinomas. Regarding DMBT1 as a mucin-like molecule is a new perspective that is instructive for its functions and its role in cancer. We conclude that DMBT1 is likely to play a differential role in the genesis of digestive tract carcinomas. However, although DMBT1 originally has divergent functions in monolayered and multilayered epithelia, carcinogenesis possibly converges in a common pathway that requires an inactivation of its functions in the ECM.

0008-5472
8880-8886
Mollenhauer, Jan
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Herbertz, Stephan
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Helmke, Burkhard
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Kollender, Gaby
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Krebs, Inge
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Madsen, Jens
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Holmskov, Uffe
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Sorger, Karin
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Schmitt, Liane
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Wiemann, Stefan
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Otto, Herwart F.
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Gröne, Hermann-Josef
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Poustka, Annemarie
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Mollenhauer, Jan
7280cbd1-7e49-4f84-badf-ab560b782750
Herbertz, Stephan
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Helmke, Burkhard
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Kollender, Gaby
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Krebs, Inge
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Madsen, Jens
b5d8ae35-00ac-4d19-930e-d8ddec497359
Holmskov, Uffe
8a55aecd-694c-4d61-849b-9cf32da8ba39
Sorger, Karin
2b07cdf8-d223-4c6a-bee6-a885018baaa2
Schmitt, Liane
b2e52663-9885-4ce8-848e-f31473ab5d96
Wiemann, Stefan
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Otto, Herwart F.
dfd066b2-531e-4161-a18a-686ee7b2318b
Gröne, Hermann-Josef
c817a780-cf3d-49e3-a454-ad0515ec65f0
Poustka, Annemarie
45b487f7-7339-4680-b251-5774d4a2dfd0

Mollenhauer, Jan, Herbertz, Stephan, Helmke, Burkhard, Kollender, Gaby, Krebs, Inge, Madsen, Jens, Holmskov, Uffe, Sorger, Karin, Schmitt, Liane, Wiemann, Stefan, Otto, Herwart F., Gröne, Hermann-Josef and Poustka, Annemarie (2001) Deleted in Malignant Brain Tumors 1 is a versatile mucin-like molecule likely to play a differential role in digestive tract cancer. Cancer Research, 61 (24), 8880-8886. (PMID:11751412)

Record type: Article

Abstract

Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor gene for brain, lung, and digestive tract cancer. In particular, alterations of the gene and/or a loss of expression have been observed in gastric, colorectal, and esophageal carcinomas. Initial evidence has accumulated that DMBT1 may represent a multifunctional protein. Because the consequences of a loss of DMBT1 function may be different depending on its original function in a particular tissue, we wondered if it is appropriate to assume a uniform role for DMBT1 in digestive tract carcinomas. We hypothesized that a systematic characterization of DMBT1 in the human alimentary tract would be useful to improve the understanding of this molecule and its role in digestive tract carcinomas. Our data indicate that the expression pattern and subcellular distribution of DMBT1 in the human alimentary tract is reminiscent of epithelial mucins. Bovine gallbladder mucin is identified as the DMBT1 homologue in cattle. An elaborate alternative splicing may generate a great variety of DMBT1 isoforms. Monolayered epithelia display transcripts of 6 kb and larger, and generally show a lumenal secretion of DMBT1 indicating a role in mucosal protection. The esophagus is the only tissue displaying an additional smaller transcript of approximately 5 kb. The stratified squamous epithelium of the esophagus is the only epithelium showing a constitutive targeting of DMBT1 to the extracellular matrix (ECM) suggestive of a role in epithelial differentiation. Squamous cell carcinomas of the esophagus show an early loss of DMBT1 expression. In contrast, adenocarcinomas of the esophagus commonly maintain higher DMBT1 expression levels. However, presumably subsequent to a transition from the lumenal secretion to a targeting to the ECM, a loss of DMBT1 expression also takes place in adenocarcinomas. Regarding DMBT1 as a mucin-like molecule is a new perspective that is instructive for its functions and its role in cancer. We conclude that DMBT1 is likely to play a differential role in the genesis of digestive tract carcinomas. However, although DMBT1 originally has divergent functions in monolayered and multilayered epithelia, carcinogenesis possibly converges in a common pathway that requires an inactivation of its functions in the ECM.

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Published date: 15 December 2001

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Local EPrints ID: 47972
URI: http://eprints.soton.ac.uk/id/eprint/47972
ISSN: 0008-5472
PURE UUID: f1594aa4-ad59-49af-9214-7feb7553a2c1
ORCID for Jens Madsen: ORCID iD orcid.org/0000-0003-1664-7645

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Date deposited: 16 Aug 2007
Last modified: 16 Mar 2024 03:56

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Contributors

Author: Jan Mollenhauer
Author: Stephan Herbertz
Author: Burkhard Helmke
Author: Gaby Kollender
Author: Inge Krebs
Author: Jens Madsen ORCID iD
Author: Uffe Holmskov
Author: Karin Sorger
Author: Liane Schmitt
Author: Stefan Wiemann
Author: Herwart F. Otto
Author: Hermann-Josef Gröne
Author: Annemarie Poustka

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