Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas
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
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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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 7

β1 integrin expression in the intestinal mucosa of wild-type, Rab25–/–, ApcMin/+;Rab25+/+ (+/+), and ApcMin/+;Rab25–/– (–/–) mice.

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β1 integrin expression in the intestinal mucosa of wild-type, Rab25–/–, ...
Arrows in A–D indicate the positions of regions shown at higher magnification. (A) Wild-type mice showed prominent lateral membrane localization of β1 integrin in villus cells (arrowhead). Scale bars: 25 μm. (B) Villus cells in Rab25-deficient mice had diminished lateral staining with more prominent intracellular staining for β1 integrin (arrow). Scale bars: 25 μm. (C) In ApcMin/+ mice, we noted reduced β1 integrin staining in the lateral membranes of villus cells (arrow). Scale bars: 25 μm. (D) In ApcMin/+;Rab25–/– mice, we observed essentially complete loss of lateral β1 integrin staining, with staining only detected intracellularly (arrow). Scale bars: 25 μm. (E) All adenomatous polyps in ApcMin/+;Rab25+/– and ApcMin/+;Rab25–/– mice showed a similar marked loss of β1 integrin staining. Scale bar: 50 μm. (F) Higher magnification view of E. Scale bar: 50 μm.