Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancer
Abstract Background Cancer mortality is mainly caused by organ failure and thrombotic events. It has been demonstrated that NETosis, a chromatin release mechanism implemented by neutrophils, may contribute to these lethal systemic effects. Our aim was to investigate NETosis biomarkers in endometrial...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-04-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02359-5 |
| _version_ | 1827781032527527936 |
|---|---|
| author | Livia Ronchetti Irene Terrenato Margherita Ferretti Giacomo Corrado Frauke Goeman Sara Donzelli Chiara Mandoj Roberta Merola Ashanti Zampa Mariantonia Carosi Giovanni Blandino Laura Conti Anna Maria Lobascio Marcello Iacobelli Enrico Vizza Giulia Piaggio Aymone Gurtner |
| author_facet | Livia Ronchetti Irene Terrenato Margherita Ferretti Giacomo Corrado Frauke Goeman Sara Donzelli Chiara Mandoj Roberta Merola Ashanti Zampa Mariantonia Carosi Giovanni Blandino Laura Conti Anna Maria Lobascio Marcello Iacobelli Enrico Vizza Giulia Piaggio Aymone Gurtner |
| author_sort | Livia Ronchetti |
| collection | DOAJ |
| description | Abstract Background Cancer mortality is mainly caused by organ failure and thrombotic events. It has been demonstrated that NETosis, a chromatin release mechanism implemented by neutrophils, may contribute to these lethal systemic effects. Our aim was to investigate NETosis biomarkers in endometrial cancer (EC). Methods The experiments were conducted on 21 healthy subjects (HS) with no gynecological conditions, and on 63 EC patients. To assess the presence of NETosis features, IHC and IF was performed using antibodies against citrullinated histone H3 (citH3), neutrophil elastase (NE) and histone 2B. Serum levels of cell free DNA (cfDNA), cell free mitochondrial DNA (cfmtDNA) and citH3 were measured by qPCR using one microliter of deactivated serum, and by ELISA assay respectively. Fragmentation pattern of serum cfDNA was analyzed using the Agilent 2100 Bioanalyzer and High Sensitivity DNA Chips. Receiver operating characteristic (ROC) analysis was used to identify a cut off for cfDNA and cfmtDNA values able to discriminate between ECs and HSs. Correlation analysis and multiple correspondence analysis (MCA) between cfDNA, mtcfDNA, citH3 and blood parameters were used to identify the potential association among serum parameters in EC grades. Results We demonstrated the presence of NETosis features in tissues from all EC grades. Serum cfDNA and cfmtDNA levels discriminate ECs from HSs and a direct correlation between citH3 and cfDNA content and an inverse correlation between cfmtDNA and citH3 in EC sera was observed, not detectable in HSs. MCA indicates cfDNA, cfmtDNA and citH3 as features associated to G1 and G2 grades. A correlation between increased levels of cfDNA, citH3 and inflammation features was found. Finally, serum nucleosomal cfDNA fragmentation pattern varies in EC sera and correlates with increased levels of cfDNA, citH3, lymphocytes and fibrinogen. Conclusion Our data highlight the occurrence of NETosis in EC and indicate serum cfDNA and citH3 as noninvasive biomarkers of tumor-induced systemic effects in endometrial cancer. |
| first_indexed | 2024-03-11T15:13:09Z |
| format | Article |
| id | doaj.art-d0d2c136d7ed49c5a822421ef635520c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-11T15:13:09Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-d0d2c136d7ed49c5a822421ef635520c2023-10-29T12:40:22ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-04-0141111410.1186/s13046-022-02359-5Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancerLivia Ronchetti0Irene Terrenato1Margherita Ferretti2Giacomo Corrado3Frauke Goeman4Sara Donzelli5Chiara Mandoj6Roberta Merola7Ashanti Zampa8Mariantonia Carosi9Giovanni Blandino10Laura Conti11Anna Maria Lobascio12Marcello Iacobelli13Enrico Vizza14Giulia Piaggio15Aymone Gurtner16SAFU Unit, IRCCS - Regina Elena National Cancer InstituteClinical Trial Center - Biostatistics & Bioinformatics, IRCCS - Regina Elena National Cancer InstituteSAFU Unit, IRCCS - Regina Elena National Cancer InstituteDepartment of Women and Children Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS - Università Cattolica del Sacro CuoreSAFU Unit, IRCCS - Regina Elena National Cancer InstituteOncogenomics and Epigenetics Unit, IRCCS - Regina Elena National Cancer InstituteClinical Pathology Unit, IRCCS - Regina Elena National Cancer InstituteClinical Pathology Unit, IRCCS - Regina Elena National Cancer InstituteGynecologic Oncology Unit, IRCCS - Regina Elena National Cancer InstituteAnatomy Pathology Unit, IRCCS - Regina Elena National Cancer InstituteOncogenomics and Epigenetics Unit, IRCCS - Regina Elena National Cancer InstituteClinical Pathology Unit, IRCCS - Regina Elena National Cancer InstituteGynecologic Oncology Unit, IRCCS - Regina Elena National Cancer InstituteGynecologic Oncology Unit, IRCCS - Regina Elena National Cancer InstituteGynecologic Oncology Unit, IRCCS - Regina Elena National Cancer InstituteSAFU Unit, IRCCS - Regina Elena National Cancer InstituteSAFU Unit, IRCCS - Regina Elena National Cancer InstituteAbstract Background Cancer mortality is mainly caused by organ failure and thrombotic events. It has been demonstrated that NETosis, a chromatin release mechanism implemented by neutrophils, may contribute to these lethal systemic effects. Our aim was to investigate NETosis biomarkers in endometrial cancer (EC). Methods The experiments were conducted on 21 healthy subjects (HS) with no gynecological conditions, and on 63 EC patients. To assess the presence of NETosis features, IHC and IF was performed using antibodies against citrullinated histone H3 (citH3), neutrophil elastase (NE) and histone 2B. Serum levels of cell free DNA (cfDNA), cell free mitochondrial DNA (cfmtDNA) and citH3 were measured by qPCR using one microliter of deactivated serum, and by ELISA assay respectively. Fragmentation pattern of serum cfDNA was analyzed using the Agilent 2100 Bioanalyzer and High Sensitivity DNA Chips. Receiver operating characteristic (ROC) analysis was used to identify a cut off for cfDNA and cfmtDNA values able to discriminate between ECs and HSs. Correlation analysis and multiple correspondence analysis (MCA) between cfDNA, mtcfDNA, citH3 and blood parameters were used to identify the potential association among serum parameters in EC grades. Results We demonstrated the presence of NETosis features in tissues from all EC grades. Serum cfDNA and cfmtDNA levels discriminate ECs from HSs and a direct correlation between citH3 and cfDNA content and an inverse correlation between cfmtDNA and citH3 in EC sera was observed, not detectable in HSs. MCA indicates cfDNA, cfmtDNA and citH3 as features associated to G1 and G2 grades. A correlation between increased levels of cfDNA, citH3 and inflammation features was found. Finally, serum nucleosomal cfDNA fragmentation pattern varies in EC sera and correlates with increased levels of cfDNA, citH3, lymphocytes and fibrinogen. Conclusion Our data highlight the occurrence of NETosis in EC and indicate serum cfDNA and citH3 as noninvasive biomarkers of tumor-induced systemic effects in endometrial cancer.https://doi.org/10.1186/s13046-022-02359-5NETsNETosisCirculating cell-free DNACitrullinated Histone H3Neutrophil ElastaseTumor induced systemic effects |
| spellingShingle | Livia Ronchetti Irene Terrenato Margherita Ferretti Giacomo Corrado Frauke Goeman Sara Donzelli Chiara Mandoj Roberta Merola Ashanti Zampa Mariantonia Carosi Giovanni Blandino Laura Conti Anna Maria Lobascio Marcello Iacobelli Enrico Vizza Giulia Piaggio Aymone Gurtner Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancer Journal of Experimental & Clinical Cancer Research NETs NETosis Circulating cell-free DNA Citrullinated Histone H3 Neutrophil Elastase Tumor induced systemic effects |
| title | Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancer |
| title_full | Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancer |
| title_fullStr | Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancer |
| title_full_unstemmed | Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancer |
| title_short | Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of NETosis in endometrial cancer |
| title_sort | circulating cell free dna and citrullinated histone h3 as useful biomarkers of netosis in endometrial cancer |
| topic | NETs NETosis Circulating cell-free DNA Citrullinated Histone H3 Neutrophil Elastase Tumor induced systemic effects |
| url | https://doi.org/10.1186/s13046-022-02359-5 |
| work_keys_str_mv | AT liviaronchetti circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT ireneterrenato circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT margheritaferretti circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT giacomocorrado circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT fraukegoeman circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT saradonzelli circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT chiaramandoj circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT robertamerola circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT ashantizampa circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT mariantoniacarosi circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT giovanniblandino circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT lauraconti circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT annamarialobascio circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT marcelloiacobelli circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT enricovizza circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT giuliapiaggio circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer AT aymonegurtner circulatingcellfreednaandcitrullinatedhistoneh3asusefulbiomarkersofnetosisinendometrialcancer |