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 1

Rab25 gene expression and human colon cancer.

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Rab25 gene expression and human colon cancer. (A) Rab25 expression ...
(A) Rab25 expression in a cohort of colon cancer patients and controls with extensive gene microarray expression profiling. Gene expression was assessed for Rab25 using the Affymetrix 218186 probe set (numbers in bars indicate patient numbers). Expression of Rab25 was significantly decreased in colon adenocarcinomas compared with normal colon (NL) (*P < 0.03) independent of Duke’s stage. Rab25 expression was also reduced in LN metastases as well as in liver (LiM) and lung (LuM) metastases. All values are shown as mean ± SEM. (B) Comparison of overall survival in colon cancer patient data for gene Rab25. Kaplan-Meier analysis was performed comparing patients with Rab25 expression above the median (high Rab25 expression) or with Rab25 expression below the median (low Rab25 expression). Lower expression of Rab25 correlated with significantly lower survival (P < 0.035). (C) Normalized expression for Rab25 in 6 colon adenoma and 55 colon adenocarcinoma samples from Vanderbilt analyzed by microarray. Rab25 expression was significantly decreased in the adenocarcinoma group compared with the adenomas (*P = 0.02). All values are shown as mean ± SEM. (D) Normalized expression data for Rab25 across adenomas and individual AJCC stages (I–IV). Rab25 transcript expression was significantly lower in stage I and stage IV tumor specimens (*P < 0.001 and **P = 0.02, respectively) compared with specimens from patients with adenomas. All values are shown as mean ± SEM.