Researchers at Vanderbilt University Medical Center completed one of the first studies to link lower levels of protein Rab25 with cancer. The findings, which will appear in the March 2010 issue of The Journal of Clinical Investigation, suggest that Rab25, an epithelial specific protein previously linked to regulation of intracellular membrane trafficking, may help suppress tumor formation in the intestinal mucosae.
James R. Goldenring, M.D., Ph.D., and his colleagues studied data from both mice and humans. They found that lower levels of Rab25 expression promoted the development of neoplasia in mice, and that these lower levels of Rab25 were also associated with colorectal cancer in humans.
Goldenring and his colleagues sought to determine the effects of a loss of Rab25 on the potential for colon cancer. To achieve this, they studied Rab25 expression in two cohorts of colorectal cancer patients from Vanderbilt Medical Center and the Moffitt Cancer Center.
They found that Rab25 expression was significantly lower in the group with adenocarcinoma compared with adenomas or normal colon tissue. The study revealed that Rab25 expression was significantly lower in human colon cancers, independent of stage of cancer, and that lower Rab25 expression correlated with markedly lower cancer survival rates.
The findings in humans were confirmed in a mouse model for deletion of Rab25. Breeding of Rab25 knockout mice with two different strains of mice that are prone to the development of intestinal and colonic tumors caused a significant increase in the formation of tumors. Further studies demonstrated that Rab25 deficient mice have decreases in the display of normal adhesion molecules on their cell surface, and this may predispose cells to loss of polarity and transformation.
The results from these studies represent the one of the first studies to demonstrate that alteration of a key trafficking molecule can increase susceptibility to transformation and neoplasia.
(Vanderbilt study team includes: James R. Goldenring, Ki Taek Nam, Hyuk-Joon Lee, J. Joshua Smith, Lynne LaPierre, Xi Chen, Daniel R. Beauchamp, Robert J. Coffey. Colleagues from other institutions include Vidya P. Kamath, Bruce J. Aronow, Timothy J. Yeatman, Sheela G. Bhartur, Benjamin C. Calhoun, Brian Condie, and Nancy R. Manley.)