Plakophilin3 downregulation leads to a decrease in cell adhesion and promotes metastasis

Plakophilin3 is a desmosomal plaque protein whose levels are reduced in poorly differentiated tumors of the oropharyngeal cavity and in invasive colon carcinomas. To test the hypothesis that plakophilin3 loss stimulates neoplastic progression, plakophilin3 expression was inhibited by DNA vector driv...

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Bibliographic Details
Published in:International journal of cancer 2008-11, Vol.123 (10), p.2303-2314
Main Authors: Kundu, Samrat T., Gosavi, Prajakta, Khapare, Nileema, Patel, Rachana, Hosing, Amol S., Maru, Girish B., Ingle, Arvind, DeCaprio, James A., Dalal, Sorab N.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blotting, Western
Carcinogenesis, carcinogens and anticarcinogens
cell adhesion
Cell Adhesion - physiology
desmosome
Down-Regulation
General aspects
Humans
Medical sciences
metastasis
Mice
Mice, Nude
Neoplasm Metastasis
plakophilin3
Plakophilins - genetics
Plakophilins - physiology
Reverse Transcriptase Polymerase Chain Reaction
transformation
Tumors
Wound Healing
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Summary:Plakophilin3 is a desmosomal plaque protein whose levels are reduced in poorly differentiated tumors of the oropharyngeal cavity and in invasive colon carcinomas. To test the hypothesis that plakophilin3 loss stimulates neoplastic progression, plakophilin3 expression was inhibited by DNA vector driven RNA interference in 3 epithelial cell lines, HCT116, HaCaT and fetal buccal mucosa. The plakophilin3‐knockdown clones showed a decrease in cell–cell adhesion as assessed in a hanging drop assay, which was accompanied by an increase in cell migration. The HCT116 plakophilin3‐knockdown clones showed a decrease in desmosome size as revealed by electron microscopy. These altered desmosomal properties were accompanied by colony formation in soft agar and growth to high density in culture. The HCT116‐derived clones showed accelerated tumor formation in nude mice and increased metastasis to the lung, a phenotype consistent with the increased migration observed in vitro and is consistent with data from human tumors that suggests that plakophililn3 is lost in invasive and metastatic tumors. These data indicate that plakophilin3 loss leads to a decrease in cell–cell adhesion leading to the stimulation of neoplastic progression and metastasis. © 2008 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.23797