Enhanced peritoneal ovarian tumor dissemination by tissue transglutaminase.
Tissue transglutaminase (TG2) is involved in Ca(2+)-dependent aggregation and polymerization of proteins. We previously reported that TG2 mRNA is up-regulated in epithelial ovarian cancer (EOC) cells compared with normal ovarian epithelium. Here, we show overexpression of the TG2 protein in ovarian cancer cells and tumors and its secretion in ascites fluid and define its role in EOC. By stable knockdown and overexpression, we show that TG2 enhances EOC cell adhesion to fibronectin and directional cell migration. This phenotype is preserved in vivo, where the pattern of tumor dissemination in the peritoneal space is dependent on TG2 expression levels. TG2 knockdown diminishes dissemination of tumors on the peritoneal surface and mesentery in an i.p. ovarian xenograft model. This phenotype is associated with deficient beta(1) integrin-fibronectin interaction, leading to weaker anchorage of cancer cells to the peritoneal matrix. Highly expressed in ovarian tumors, TG2 facilitates i.p. tumor dissemination by enhancing cell adhesion to the extracellular matrix and modulating beta(1) integrin subunit expression.
Department of Medicine, Indiana University School of Medicine, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA. dmatei@iupui.edu
Minati
M
Satpathy
Liyun
L
Cao
Roxana
R
Pincheira
Robert
R
Emerson
Robert
R
Bigsby
Harikrishna
H
Nakshatri
Daniela
D
Matei
D000818:Animals; D001201:Ascites / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D002465:Cell Movement; D017077:Culture Media, Conditioned; D003600:Cytosol / Q000201:enzymology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins; D006801:Humans; D047468:Immunoprecipitation; D039641:Integrin beta Chains; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000201:enzymology / Q000556:secondary*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D011503:Transglutaminases / Q000502:physiology*
D017077:Culture Media, Conditioned; D005353:Fibronectins; D039641:Integrin beta Chains; D034741:RNA, Small Interfering; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins