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SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance

The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasi...

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Autores principales: Sheets, J N, Iwanicki, M, Liu, J F, Howitt, B E, Hirsch, M S, Gubbels, J A A, Drapkin, R, Egland, K A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117850/
https://www.ncbi.nlm.nih.gov/pubmed/27775699
http://dx.doi.org/10.1038/oncsis.2016.64
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author Sheets, J N
Iwanicki, M
Liu, J F
Howitt, B E
Hirsch, M S
Gubbels, J A A
Drapkin, R
Egland, K A
author_facet Sheets, J N
Iwanicki, M
Liu, J F
Howitt, B E
Hirsch, M S
Gubbels, J A A
Drapkin, R
Egland, K A
author_sort Sheets, J N
collection PubMed
description The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasis and implantation, including clearance of the mesothelium. Sushi domain containing 2 (SUSD2) encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Immunohistochemical analysis determined the presence of SUSD2 in several subtypes of EOC, with the strongest staining observed in high-grade serous ovarian carcinomas (HGSOCs). A high-density, clinically annotated HGSOC tissue microarray was stained with an anti-SUSD2 antibody. Patients with tumors that had a low percentage of SUSD2 staining cells had a shorter median survival (31.7 months) compared with patients who had tumors with extensive SUSD2 staining (49.1 months; P-value=0.0083). To investigate the role of SUSD2 in HGSOCs, stable OVCAR3, OVSAHO and KURAMOCHI cell lines were established with knockdown (KD) or non-targeting (NT) of SUSD2. Boyden chamber and wound-healing assays demonstrated that OVCAR3, OVSAHO and KURAMOCHI SUSD2-KD cells migrated at significantly higher rates compared with their SUSD2 NT counterpart cell lines. Quantitative reverse transcription–PCR and western immunoblot analysis indicated an inverse relationship between SUSD2 and well-characterized mesenchymal proteins, including Twist-1, Zeb-1, N-cadherin, STEAP1, AHNAK, Snail-1, COL5A2 and Snail-3 in OVCAR3, OVSAHO and KURAMOCHI cell line models. In addition, OVCAR3 and KURAMOCHI SUSD2-KD spheroids displayed increased mesothelial clearance ability compared with cells that express endogenous levels of SUSD2. These data suggest that SUSD2 has a role in the inhibition of mesothelial clearance, which is required for metastasis. Altogether, our findings indicate that SUSD2 impedes migration, epithelial-to-mesenchymal transitional and mesothelial clearance of HGSOC cells, consistent with prolonged survival of patients with SUSD2-expressing tumors.
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spelling pubmed-51178502016-12-09 SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance Sheets, J N Iwanicki, M Liu, J F Howitt, B E Hirsch, M S Gubbels, J A A Drapkin, R Egland, K A Oncogenesis Original Article The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasis and implantation, including clearance of the mesothelium. Sushi domain containing 2 (SUSD2) encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Immunohistochemical analysis determined the presence of SUSD2 in several subtypes of EOC, with the strongest staining observed in high-grade serous ovarian carcinomas (HGSOCs). A high-density, clinically annotated HGSOC tissue microarray was stained with an anti-SUSD2 antibody. Patients with tumors that had a low percentage of SUSD2 staining cells had a shorter median survival (31.7 months) compared with patients who had tumors with extensive SUSD2 staining (49.1 months; P-value=0.0083). To investigate the role of SUSD2 in HGSOCs, stable OVCAR3, OVSAHO and KURAMOCHI cell lines were established with knockdown (KD) or non-targeting (NT) of SUSD2. Boyden chamber and wound-healing assays demonstrated that OVCAR3, OVSAHO and KURAMOCHI SUSD2-KD cells migrated at significantly higher rates compared with their SUSD2 NT counterpart cell lines. Quantitative reverse transcription–PCR and western immunoblot analysis indicated an inverse relationship between SUSD2 and well-characterized mesenchymal proteins, including Twist-1, Zeb-1, N-cadherin, STEAP1, AHNAK, Snail-1, COL5A2 and Snail-3 in OVCAR3, OVSAHO and KURAMOCHI cell line models. In addition, OVCAR3 and KURAMOCHI SUSD2-KD spheroids displayed increased mesothelial clearance ability compared with cells that express endogenous levels of SUSD2. These data suggest that SUSD2 has a role in the inhibition of mesothelial clearance, which is required for metastasis. Altogether, our findings indicate that SUSD2 impedes migration, epithelial-to-mesenchymal transitional and mesothelial clearance of HGSOC cells, consistent with prolonged survival of patients with SUSD2-expressing tumors. Nature Publishing Group 2016-10 2016-10-24 /pmc/articles/PMC5117850/ /pubmed/27775699 http://dx.doi.org/10.1038/oncsis.2016.64 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Sheets, J N
Iwanicki, M
Liu, J F
Howitt, B E
Hirsch, M S
Gubbels, J A A
Drapkin, R
Egland, K A
SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance
title SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance
title_full SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance
title_fullStr SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance
title_full_unstemmed SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance
title_short SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance
title_sort susd2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117850/
https://www.ncbi.nlm.nih.gov/pubmed/27775699
http://dx.doi.org/10.1038/oncsis.2016.64
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