Abstract
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.
Highlights
Epithelial ovarian cancer (EOC) is the leading cause of death in gynecological malignancy and ranks fifth in mortality rates among all cancers in the United States.[1,2] Termed the ‘silent killer’, EOC is accompanied by vague and minor symptoms during onset and initial stages of the disease progression, which impedes patient diagnosis at an early stage
Because high-grade serous ovarian carcinomas (HGSOCs) originates from the fallopian tube,[16,17,18] normal fallopian tissue was stained for the presence of Sushi domain containing 2 (SUSD2)
Using an anti-SUSD2 antibody, IHC analysis was performed on HGSOC cell line monolayers and OVCAR3 spheroids
Summary
Epithelial ovarian cancer (EOC) is the leading cause of death in gynecological malignancy and ranks fifth in mortality rates among all cancers in the United States.[1,2] Termed the ‘silent killer’, EOC is accompanied by vague and minor symptoms during onset and initial stages of the disease progression (stages I and II), which impedes patient diagnosis at an early stage. The American Cancer Society estimates that ~ 67% of women diagnosed with ovarian cancer in 2015 will die from their disease, showing the need for early detection tools and novel approaches to treatment.[4]. The majority of EOC cases are diagnosed as high-grade serous ovarian carcinomas (HGSOCs), representing the most deadly of all EOC subtypes.[5] Unique in its dissemination process, EOC does not typically require hematogenous intravasation/
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