Abstract | BACKGROUND & AIMS: METHODS: We performed microarray analysis to compare changes in gene expression in the colonic mucosa of mice that express a human progastrin transgene, gastrin knockout mice, and C57BL/6 mice (controls); the effects of progastrin were also determined on in vitro colonic crypt cultures from cholecystokinin 2 receptor knockout and wild-type mice. Human colorectal and gastric cancer cells that expressed CCK2R were incubated with progastrin or Bmp2; levels of β- arrestin 1 and 2 were knocked down using small interfering RNAs. Cells were analyzed for progastrin binding, proliferation, changes in gene expression, and symmetric cell division. RESULTS: The BMP pathway was down-regulated in the colons of human progastrin mice compared with controls. Progastrin suppressed transcription of Bmp2 through a pathway that required CCK2R and was mediated by β- arrestin 1 and 2. In mouse colonic epithelial cells, down-regulation of Bmp2 led to decreased phosphorylation of Smads1/5/8 and suppression of inhibitor of DNA binding 4. In human gastric and colorectal cancer cell lines, CCK2R was necessary and sufficient for progastrin binding and induction of proliferation; these effects were blocked when cells were incubated with recombinant Bmp2. Incubation with progastrin increased the number of CD44(+), bromodeoxyuridine+, and NUMB(+) cells, indicating an increase in symmetric divisions of putative cancer stem cells. CONCLUSIONS:
Progastrin stimulates proliferation in colons of mice and cultured human cells via CCK2R- and β- arrestin 1 and 2-dependent suppression of Bmp2 signaling. This process promotes symmetric cell division.
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Authors | Guangchun Jin, C Benedikt Westphalen, Yoku Hayakawa, Daniel L Worthley, Samuel Asfaha, Xiangdong Yang, Xiaowei Chen, Yiling Si, Hongshan Wang, Yagnesh Tailor, Richard A Friedman, Timothy C Wang |
Journal | Gastroenterology
(Gastroenterology)
Vol. 145
Issue 4
Pg. 820-30.e10
(Oct 2013)
ISSN: 1528-0012 [Electronic] United States |
PMID | 23891976
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- ARRB1 protein, human
- Arrb1 protein, mouse
- Arrestins
- Bmp2 protein, mouse
- Bone Morphogenetic Protein 2
- Gastrins
- Protein Precursors
- Receptor, Cholecystokinin B
- beta-Arrestin 1
- beta-Arrestins
- big gastrin
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Topics |
- Animals
- Arrestins
(physiology)
- Bone Morphogenetic Protein 2
(antagonists & inhibitors, physiology)
- Cell Proliferation
(drug effects)
- Colon
(cytology, drug effects)
- Gastrins
(pharmacology)
- Mice
- Mice, Inbred C57BL
- Protein Precursors
(pharmacology)
- Receptor, Cholecystokinin B
(physiology)
- Signal Transduction
- Stem Cells
(drug effects)
- beta-Arrestin 1
- beta-Arrestins
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