Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas
Ki Taek Nam, … , Robert J. Coffey, James R. Goldenring
Ki Taek Nam, … , Robert J. Coffey, James R. Goldenring
Published February 8, 2010
Citation Information: J Clin Invest. 2010;120(3):840-849. https://doi.org/10.1172/JCI40728.
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Research Article Oncology

Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas

Abstract

Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, ApcMin/+ mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental ApcMin/+ mice. Rab25-deficient mice had decreased β1 integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the ApcMin/+ background. Additionally, Smad3+/– mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface.

Authors

Ki Taek Nam, Hyuk-Joon Lee, J. Joshua Smith, Lynne A. Lapierre, Vidya P. Kamath, Xi Chen, Bruce J. Aronow, Timothy J. Yeatman, Sheela G. Bhartur, Benjamin C. Calhoun, Brian Condie, Nancy R. Manley, R. Daniel Beauchamp, Robert J. Coffey, James R. Goldenring

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Figure 4

Rab25 deficiency promotes intestinal adenoma formation in ApcMin/+ mice.

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Rab25 deficiency promotes intestinal adenoma formation in ApcMin/+ mice....
(A) Gross appearance of small intestine from ApcMin/+;Rab25+/+ (+/+) and ApcMin/+;Rab25–/– (–/–) mice. Rab25-deficient mice showed an increase in tumor numbers and size throughout the intestine. (B) Anatomical distribution of polyps in small intestine (SI) of ApcMin/+;Rab25+/+ (+/+) and ApcMin/+;Rab25–/– (–/–) mice. Polyp number was determined in the proximal, middle, and distal intestine as well as in the total intestines of ApcMin/+;Rab25+/+ (+/+) (n = 7), ApcMin/+;Rab25+/– (+/–) (n = 16), and ApcMin/+;Rab25–/– (–/–) (n = 12) mice. The distal intestine showed a greater increase in the number of polyps than the proximal intestine. ApcMin/+;Rab25+/– mice also showed a significant increase in tumor numbers that was intermediate between wild-type and Rab25-deficient mice. Data represent mean ± SEM. (C) Representative Swiss rolls of proximal and distal intestine from ApcMin/+;Rab25+/+ (+/+) and ApcMin/+;Rab25–/– (–/–) mice. Both proximal and distal intestine from ApcMin/+;Rab25–/– (–/–) mice showed an increase in tumor number. Scale bars: 1 mm.