PUBLICATION

Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer

Authors
Li, C., Ma, H., Wang, Y., Cao, Z., Graves-Deal, R., Powell, A.E., Starchenko, A., Ayers, G.D., Washington, M.K., Kamath, V., Desai, K., Gerdes, M.J., Solnica-Krezel, L., Coffey, R.J.
ID
ZDB-PUB-140513-227
Date
2014
Source
J. Clin. Invest.   124(5): 2172-87 (Journal)
Registered Authors
Ma, Haiting, Solnica-Krezel, Lilianna, Wang, Yang
Keywords
none
MeSH Terms
  • Epithelial-Mesenchymal Transition*
  • Vimentin/biosynthesis
  • Vimentin/genetics
  • Humans
  • Cadherins/biosynthesis
  • Cadherins/genetics
  • Mitogen-Activated Protein Kinase 1/genetics
  • Mitogen-Activated Protein Kinase 1/metabolism*
  • Neoplasm Invasiveness
  • Mice
  • HEK293 Cells
  • Neoplasm Proteins/genetics
  • Neoplasm Proteins/metabolism*
  • Animals
  • Intestinal Mucosa/metabolism*
  • Intestinal Mucosa/pathology
  • Dual Specificity Phosphatase 6
  • Proteins/genetics
  • Proteins/metabolism*
  • Cell Line, Tumor
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Colonic Neoplasms/genetics
  • Colonic Neoplasms/metabolism*
  • Colonic Neoplasms/pathology
(all 27)
PubMed
24691442 Full text @ J. Clin. Invest.
Abstract
The epithelial-to-mesenchymal transition (EMT) transcriptional program is characterized by repression of E-cadherin (CDH1) and induction of N-cadherin (CDH2), and mesenchymal genes like vimentin (VIM). Placenta-specific 8 (PLAC8) has been implicated in colon cancer; however, how PLAC8 contributes to disease is unknown, and endogenous PLAC8 protein has not been studied. We analyzed zebrafish and human tissues and found that endogenous PLAC8 localizes to the apical domain of differentiated intestinal epithelium. Colon cancer cells with elevated PLAC8 levels exhibited EMT features, including increased expression of VIM and zinc finger E-box binding homeobox 1 (ZEB1), aberrant cell motility, and increased invasiveness. In contrast to classical EMT, PLAC8 overexpression reduced cell surface CDH1 and upregulated P-cadherin (CDH3) without affecting CDH2 expression. PLAC8-induced EMT was linked to increased phosphorylated ERK2 (p-ERK2), and ERK2 knockdown restored cell surface CDH1 and suppressed CDH3, VIM, and ZEB1 upregulation. In vitro, PLAC8 directly bound and inactivated the ERK2 phosphatase DUSP6, thereby increasing p-ERK2. In a murine xenograft model, knockdown of endogenous PLAC8 in colon cancer cells resulted in smaller tumors, reduced local invasion, and decreased p-ERK2. Using MultiOmyx, a multiplex immunofluorescence-based methodology, we observed coexpression of cytosolic PLAC8, CDH3, and VIM at the leading edge of a human colorectal tumor, supporting a role for PLAC8 in cancer invasion in vivo.
Genes / Markers
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
vu44
    		Point Mutation
    1 - 1 of 1
    Show
    Human Disease / Model
    Sequence Targeting Reagents
    Fish
    Antibodies
    Orthology
    Engineered Foreign Genes
    No data available
    Mapping
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    Citation
    Li, C., Ma, H., Wang, Y., Cao, Z., Graves-Deal, R., Powell, A.E., Starchenko, A., Ayers, G.D., Washington, M.K., Kamath, V., Desai, K., Gerdes, M.J., Solnica-Krezel, L., Coffey, R.J. (2014) Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer. J. Clin. Invest.. 124(5):2172-87.