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

Research output: Contribution to journalArticle

92 Citations (Scopus)

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 Apc Min/+ 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.

Original languageEnglish
Pages (from-to)840-849
Number of pages10
JournalJournal of Clinical Investigation
Volume120
Issue number3
DOIs
Publication statusPublished - 2010 Mar 1

Fingerprint

Adenocarcinoma
Neoplasms
Cell Membrane
Intestinal Polyps
Epithelial Cells
Cell Polarity
Protein Transport
Integrins
Blood Proteins
Membrane Proteins
Pathology
Staining and Labeling
Survival
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Nam, Ki Taek ; Lee, Hyuk Joon ; Smith, J. Joshua ; Lapierre, Lynne A. ; Kamath, Vidya P. ; Chen, Xi ; Aronow, Bruce J. ; Yeatman, Timothy J. ; Bhartur, Sheela G. ; Calhoun, Benjamin C. ; Condie, Brian ; Manley, Nancy R. ; Beauchamp, R. Daniel ; Coffey, Robert J. ; Goldenring, James R. / Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 3. pp. 840-849.
@article{2a1dd375aa7e44b78af1a191b5646bd4,
title = "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 Apc Min/+ 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.",
author = "Nam, {Ki Taek} and Lee, {Hyuk Joon} and Smith, {J. Joshua} and Lapierre, {Lynne A.} and Kamath, {Vidya P.} and Xi Chen and Aronow, {Bruce J.} and Yeatman, {Timothy J.} and Bhartur, {Sheela G.} and Calhoun, {Benjamin C.} and Brian Condie and Manley, {Nancy R.} and Beauchamp, {R. Daniel} and Coffey, {Robert J.} and Goldenring, {James R.}",
year = "2010",
month = "3",
day = "1",
doi = "10.1172/JCI40728",
language = "English",
volume = "120",
pages = "840--849",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "3",

}

Nam, KT, Lee, HJ, Smith, JJ, Lapierre, LA, Kamath, VP, Chen, X, Aronow, BJ, Yeatman, TJ, Bhartur, SG, Calhoun, BC, Condie, B, Manley, NR, Beauchamp, RD, Coffey, RJ & Goldenring, JR 2010, 'Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas', Journal of Clinical Investigation, vol. 120, no. 3, pp. 840-849. https://doi.org/10.1172/JCI40728

Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas. / Nam, Ki Taek; Lee, Hyuk Joon; Smith, J. Joshua; Lapierre, Lynne A.; Kamath, Vidya P.; Chen, Xi; Aronow, Bruce J.; Yeatman, Timothy J.; Bhartur, Sheela G.; Calhoun, Benjamin C.; Condie, Brian; Manley, Nancy R.; Beauchamp, R. Daniel; Coffey, Robert J.; Goldenring, James R.

In: Journal of Clinical Investigation, Vol. 120, No. 3, 01.03.2010, p. 840-849.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas

AU - Nam, Ki Taek

AU - Lee, Hyuk Joon

AU - Smith, J. Joshua

AU - Lapierre, Lynne A.

AU - Kamath, Vidya P.

AU - Chen, Xi

AU - Aronow, Bruce J.

AU - Yeatman, Timothy J.

AU - Bhartur, Sheela G.

AU - Calhoun, Benjamin C.

AU - Condie, Brian

AU - Manley, Nancy R.

AU - Beauchamp, R. Daniel

AU - Coffey, Robert J.

AU - Goldenring, James R.

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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 Apc Min/+ 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.

AB - 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 Apc Min/+ 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.

UR - http://www.scopus.com/inward/record.url?scp=77949756773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949756773&partnerID=8YFLogxK

U2 - 10.1172/JCI40728

DO - 10.1172/JCI40728

M3 - Article

C2 - 20197623

AN - SCOPUS:77949756773

VL - 120

SP - 840

EP - 849

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 3

ER -