Inappropriate induction of endothelial to mesenchymal transition (EMT) confers migratory and stem-like properties to epithelial cells and enables cancer cells to metastasize and invade other sites. Enhanced expression of placenta-specific 8 (PLAC8) has been implicated in colorectal cancer (CRC); however, it is not clear how PLAC8 promotes CRC cell growth. Using zebrafish models and human tissue, Cunxi Li, Haiting Ma, and colleagues at Vanderbilt University and Washington University, respectively, determined that endogenous PLAC8 localizes to the apical membrane of the intestinal epithelium in healthy tissue, and that PLAC8 is cytosolic in CRC. CRC cells with elevated PLAC8 exhibited enhanced invasiveness, motility, growth, and mesenchylmal gene expression. PLAC8-induced EMT was linked to ERK2 phosphorylation, which was the result of PLAC8 binding to and inhibiting the ERK2 phosphatase DUSP6. Furthermore, multiplex imaging of the leading edge of a human colorectal tumor revealed cytosolic PLAC8 and expression of EMT markers, supporting a role for PLAC8 dysfunction in CRC invasion. The accompanying immunofluorescence image reveals that endogenous PLAC8 (red) in normal human colon localizes to the apical domain of the differentiated colonic epithelium (green) at the top of crypts.
The epithelial-to-mesenchymal transition (EMT) transcriptional program is characterized by repression of E-cadherin (
Cunxi Li, Haiting Ma, Yang Wang, Zheng Cao, Ramona Graves-Deal, Anne E. Powell, Alina Starchenko, Gregory D. Ayers, Mary Kay Washington, Vidya Kamath, Keyur Desai, Michael J. Gerdes, Lila Solnica-Krezel, Robert J. Coffey