Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients
High-grade serous ovarian carcinoma (HGSOC) usually spreads directly into the peritoneal cavity following a transcoelomic dissemination route, although distant hematogenous metastasis exist and have been reported. However, no tumor markers can currently predict the risk of distant metastases in HGSO...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.01287/full |
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| author | Chiara Romani Chiara Romani Valentina Zizioli Marco Silvestri Marco Silvestri Laura Ardighieri Mattia Bugatti Michela Corsini Paola Todeschini Sergio Marchini Maurizio D'Incalci Laura Zanotti Antonella Ravaggi Antonella Ravaggi Antonella Ravaggi Fabio Facchetti Angela Gambino Angela Gambino Franco Odicino Franco Odicino Enrico Sartori Enrico Sartori Alessandro Davide Santin Stefania Mitola Eliana Bignotti Eliana Bignotti Stefano Calza Stefano Calza |
| author_facet | Chiara Romani Chiara Romani Valentina Zizioli Marco Silvestri Marco Silvestri Laura Ardighieri Mattia Bugatti Michela Corsini Paola Todeschini Sergio Marchini Maurizio D'Incalci Laura Zanotti Antonella Ravaggi Antonella Ravaggi Antonella Ravaggi Fabio Facchetti Angela Gambino Angela Gambino Franco Odicino Franco Odicino Enrico Sartori Enrico Sartori Alessandro Davide Santin Stefania Mitola Eliana Bignotti Eliana Bignotti Stefano Calza Stefano Calza |
| author_sort | Chiara Romani |
| collection | DOAJ |
| description | High-grade serous ovarian carcinoma (HGSOC) usually spreads directly into the peritoneal cavity following a transcoelomic dissemination route, although distant hematogenous metastasis exist and have been reported. However, no tumor markers can currently predict the risk of distant metastases in HGSOC. Claudins, belonging to tight-junction proteins, are dysregulated in HGSOC and functionally related to cancer progression. Here we analyzed claudin-3, -4, and -7 expression as potential markers of distant metastases. Using quantitative RT-PCR and immunohistochemistry we assessed the expression of claudins in primary HGSOC tissues, normal ovarian, and normal fallopian tube epithelia and correlated it with clinicopathological features, including the site of metastasis and the route of dissemination. Gene set enrichment analysis was performed on microarray-generated gene expression data to investigate key pathways in patients with distant metastases. We found the overall expression level of claudin-3, -4, and -7 mRNA decreased in HGSOC compared to normal tubal epithelium, currently considered the potential site of origin of many HGSOC. The reduced expression of claudin-7 is significantly associated with the development of distant metastases (p = 0.016), mainly by hematogenous route (p = 0.025). In patients with diminished expression of claudin-7, immunohistochemical staining revealed a heterogeneous pattern of membranous staining with discontinuous expression of claudin-7 along the cell border, indicative of a dischoesive architecture. The estimated reduction in the probability of distant disease is of 39% per unit increase in the level of claudin-7 (p = 0.03). Genes involved in epithelial to mesenchymal transition, hypoxia, and angiogenesis processes resulted strongly associated to hematogenous recurrence. Our data suggest a potential role of claudin-7 in discriminating distant metastatic events in HGSOC patients. The quantification of its expression levels could be a useful tool to identify patient deserving a personalized follow-up in terms of clinical and radiological assessment. |
| first_indexed | 2024-12-21T04:50:47Z |
| format | Article |
| id | doaj.art-8a3b8f139a7a4efa94b6ab8f116c19a7 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T04:50:47Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-8a3b8f139a7a4efa94b6ab8f116c19a72022-12-21T19:15:26ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-08-011010.3389/fonc.2020.01287538185Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma PatientsChiara Romani0Chiara Romani1Valentina Zizioli2Marco Silvestri3Marco Silvestri4Laura Ardighieri5Mattia Bugatti6Michela Corsini7Paola Todeschini8Sergio Marchini9Maurizio D'Incalci10Laura Zanotti11Antonella Ravaggi12Antonella Ravaggi13Antonella Ravaggi14Fabio Facchetti15Angela Gambino16Angela Gambino17Franco Odicino18Franco Odicino19Enrico Sartori20Enrico Sartori21Alessandro Davide Santin22Stefania Mitola23Eliana Bignotti24Eliana Bignotti25Stefano Calza26Stefano Calza27Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ‘Angelo Nocivelli’ Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyBiomarkers Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, ItalyUnit of Biostatistics and Bioinformatics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Pathology, ASST Spedali Civili of Brescia, Brescia, ItalyDepartment of Pathology, ASST Spedali Civili of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyDepartment of Oncology, IRCCS, “Mario Negri” Institute for Pharmacological Research, Milan, ItalyDepartment of Oncology, IRCCS, “Mario Negri” Institute for Pharmacological Research, Milan, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ‘Angelo Nocivelli’ Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, Department of Clinical and Experimental Sciences University of Brescia, Brescia, ItalyDepartment of Pathology, ASST Spedali Civili of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, Department of Clinical and Experimental Sciences University of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, Department of Clinical and Experimental Sciences University of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, Department of Clinical and Experimental Sciences University of Brescia, Brescia, ItalyDepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ‘Angelo Nocivelli’ Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, ItalyDivision of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, ItalyUnit of Biostatistics and Bioinformatics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy0Big & Open Data Innovation Laboratory, University of Brescia, Brescia, ItalyHigh-grade serous ovarian carcinoma (HGSOC) usually spreads directly into the peritoneal cavity following a transcoelomic dissemination route, although distant hematogenous metastasis exist and have been reported. However, no tumor markers can currently predict the risk of distant metastases in HGSOC. Claudins, belonging to tight-junction proteins, are dysregulated in HGSOC and functionally related to cancer progression. Here we analyzed claudin-3, -4, and -7 expression as potential markers of distant metastases. Using quantitative RT-PCR and immunohistochemistry we assessed the expression of claudins in primary HGSOC tissues, normal ovarian, and normal fallopian tube epithelia and correlated it with clinicopathological features, including the site of metastasis and the route of dissemination. Gene set enrichment analysis was performed on microarray-generated gene expression data to investigate key pathways in patients with distant metastases. We found the overall expression level of claudin-3, -4, and -7 mRNA decreased in HGSOC compared to normal tubal epithelium, currently considered the potential site of origin of many HGSOC. The reduced expression of claudin-7 is significantly associated with the development of distant metastases (p = 0.016), mainly by hematogenous route (p = 0.025). In patients with diminished expression of claudin-7, immunohistochemical staining revealed a heterogeneous pattern of membranous staining with discontinuous expression of claudin-7 along the cell border, indicative of a dischoesive architecture. The estimated reduction in the probability of distant disease is of 39% per unit increase in the level of claudin-7 (p = 0.03). Genes involved in epithelial to mesenchymal transition, hypoxia, and angiogenesis processes resulted strongly associated to hematogenous recurrence. Our data suggest a potential role of claudin-7 in discriminating distant metastatic events in HGSOC patients. The quantification of its expression levels could be a useful tool to identify patient deserving a personalized follow-up in terms of clinical and radiological assessment.https://www.frontiersin.org/article/10.3389/fonc.2020.01287/fullhigh grade serous ovarian carcinomafallopian tube epitheliumclaudinsdistant metastaseshematogenous spread |
| spellingShingle | Chiara Romani Chiara Romani Valentina Zizioli Marco Silvestri Marco Silvestri Laura Ardighieri Mattia Bugatti Michela Corsini Paola Todeschini Sergio Marchini Maurizio D'Incalci Laura Zanotti Antonella Ravaggi Antonella Ravaggi Antonella Ravaggi Fabio Facchetti Angela Gambino Angela Gambino Franco Odicino Franco Odicino Enrico Sartori Enrico Sartori Alessandro Davide Santin Stefania Mitola Eliana Bignotti Eliana Bignotti Stefano Calza Stefano Calza Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients Frontiers in Oncology high grade serous ovarian carcinoma fallopian tube epithelium claudins distant metastases hematogenous spread |
| title | Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients |
| title_full | Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients |
| title_fullStr | Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients |
| title_full_unstemmed | Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients |
| title_short | Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients |
| title_sort | low expression of claudin 7 as potential predictor of distant metastases in high grade serous ovarian carcinoma patients |
| topic | high grade serous ovarian carcinoma fallopian tube epithelium claudins distant metastases hematogenous spread |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.01287/full |
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