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Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer
Cunxi Li, … , Lila Solnica-Krezel, Robert J. Coffey
Cunxi Li, … , Lila Solnica-Krezel, Robert J. Coffey
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):2172-2187. https://doi.org/10.1172/JCI71103.
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Research Article Oncology Article has an altmetric score of 30

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

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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.

Authors

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

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Figure 2

Increased PLAC8 protein is linked to tumor progression.

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Increased PLAC8 protein is linked to tumor progression.
(A) Immunoblotti...
(A) Immunoblotting of CRC cell lines shows PLAC8 levels are higher in cells derived from metastatic tumors (SW620 and KM12SM) compared with cells derived from primary tumors (SW480 and KM12C), as well as in more invasive SC cells compared with CC or parental HCA-7 cells. (B) Left: DIC micrographs of 2 distinct types of HCA-7 colonies in 3D collagen culture: cystic clones (CC) that form smooth-edged spheres and spiky clones (SC) that grow as a solid mass with ill-defined borders and multiple protrusions (left panel) and phalloidin staining (right panel). Right: H&E staining of subcutaneous xenograft tumors of CC and SC cells (left panels); PLAC8 immunofluorescence of CC and SC subcutaneous xenograft tumors (right panels). (C) In 3D collagen culture, by immunoblotting, PLAC8 was undetectable in CC cells, but highly expressed in SC cells, and could be efficiently knocked down by 2 shRNAs in SC cells (left panel). PLAC8 knockdown in SC cells significantly decreased colony number in 3D collagen culture, and reduced tumor volume in xenografts (right panel; **P < 0.01). (D) Knockdown of endogenous PLAC8 in the KM12SM CRC cell line significantly reduced tumor volume of xenografts (left graph, *P < 0.05, n = 7). Right panels are representative H&E-stained tissue sections of xenografts. Data in all graphs are presented as mean ± SEM. Scale bars: 100 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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