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Claudin 4 Is Differentially Expressed between Ovarian Cancer Subtypes and Plays a Role in Spheroid Formation
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
Cheryl Brown Ovarian Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver, Canada
* Author to whom correspondence should be addressed.
Received: 17 January 2011; in revised form: 12 February 2011 / Accepted: 12 February 2011 / Published: 22 February 2011
Abstract: Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved in tumor progression. We examined claudin 4 expression in ovarian cancer tissues and cell lines, as well as by immunohistochemical staining of tissue microarrays (TMAs; n = 500), spheroids present in patients’ ascites, and spheroids formed in vitro. Claudin 4 was expressed in nearly 70% of the ovarian cancer tissues examined and was differentially expressed across ovarian cancer subtypes, with the lowest expression in clear cell subtype. No association was found between claudin 4 expression and disease-specific survival in any subtype. Claudin 4 expression was also observed in multicellular spheroids obtained from patients’ ascites. Using an in vitro spheroid formation assay, we found that NIH:OVCAR5 cells treated with shRNA against claudin 4 required a longer time to form compact spheroids compared to control NIH:OVCAR5 cells that expressed high levels of claudin 4. The inability of the NIH:OVCAR5 cells treated with claudin 4 shRNA to form compact spheroids was verified by FITC-dextran exclusion. These results demonstrate a role for claudin 4 and tight junctions in spheroid formation and integrity.
Keywords: ovarian cancer; claudin 4; biomarker; spheroid; ascites
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Boylan, K.L.M.; Misemer, B.; DeRycke, M.S.; Andersen, J.D.; Harrington, K.M.; Kalloger, S.E.; Gilks, C.B.; Pambuccian, S.E.; Skubitz, A.P.N. Claudin 4 Is Differentially Expressed between Ovarian Cancer Subtypes and Plays a Role in Spheroid Formation. Int. J. Mol. Sci. 2011, 12, 1334-1358.
Boylan KLM, Misemer B, DeRycke MS, Andersen JD, Harrington KM, Kalloger SE, Gilks CB, Pambuccian SE, Skubitz APN. Claudin 4 Is Differentially Expressed between Ovarian Cancer Subtypes and Plays a Role in Spheroid Formation. International Journal of Molecular Sciences. 2011; 12(2):1334-1358.
Boylan, Kristin L. M.; Misemer, Benjamin; DeRycke, Melissa S.; Andersen, John D.; Harrington, Katherine M.; Kalloger, Steve E.; Gilks, C. Blake; Pambuccian, Stefan E.; Skubitz, Amy P.N. 2011. "Claudin 4 Is Differentially Expressed between Ovarian Cancer Subtypes and Plays a Role in Spheroid Formation." Int. J. Mol. Sci. 12, no. 2: 1334-1358.