The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells
Abstract Background Testicular germ cell cancer (TGCC) develops from pre-malignant germ neoplasia in situ (GCNIS) cells. GCNIS originates from fetal gonocytes (POU5F1+/MAGE-A4−), which fail to differentiate to pre-spermatogonia (POU5F1−/MAGE-A4+) and undergo malignant transformation. Gankyrin is an...
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BMC
2019-11-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-019-6340-7 |
| _version_ | 1818560357721964544 |
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| author | Maria E. Camacho-Moll Joni Macdonald L. H. J. Looijenga Michael P. Rimmer Roland Donat John A. Marwick C. J. Shukla Neil Carragher Anne Jørgensen Rod T. Mitchell |
| author_facet | Maria E. Camacho-Moll Joni Macdonald L. H. J. Looijenga Michael P. Rimmer Roland Donat John A. Marwick C. J. Shukla Neil Carragher Anne Jørgensen Rod T. Mitchell |
| author_sort | Maria E. Camacho-Moll |
| collection | DOAJ |
| description | Abstract Background Testicular germ cell cancer (TGCC) develops from pre-malignant germ neoplasia in situ (GCNIS) cells. GCNIS originates from fetal gonocytes (POU5F1+/MAGE-A4−), which fail to differentiate to pre-spermatogonia (POU5F1−/MAGE-A4+) and undergo malignant transformation. Gankyrin is an oncogene which has been shown to prevent POU5F1 degradation and specifically interact with MAGE-A4 in hepatocellular carcinoma (HCC) cells. We aimed to investigate the role of Gankyrin in progression from gonocyte to pre-invasive GCNIS and subsequent invasive TGCC. Methods We determined Gankyrin expression in human fetal testicular tissue (gestational weeks 9–20; n = 38), human adult testicular tissue with active spermatogenesis (n = 9), human testicular tissue with germ cell maturation delay (n = 4), testicular tissue from patients with pre-invasive GCNIS (n = 6), and invasive TGCC including seminoma (n = 6) and teratoma (n = 7). Functional analysis was performed in-vitro by siRNA knock-down of Gankyrin in the NTera2 cells (derived from embryonal carcinoma). Results Germ cell expression of Gankyrin was restricted to a sub-population of prespermatogonia in human fetal testes. Nuclear Gankyrin was also expressed in GCNIS cells of childhood and adult pre-invasive TGCC patients, and in GCNIS from seminoma and non-seminoma patients. Cytoplasmic expression was observed in seminoma tumour cells and NTera2 cells. Gankyrin knock-down in NTera2 cells resulted in an increase in apoptosis mediated via the TP53 pathway, whilst POU5F1 expression was unaffected. Furthermore, Gankyrin knock-down in NTera2 cells increased cisplatin sensitivity with an increase in cell death (13%, p < 0.05) following Gankyrin knock-down, when compared to cisplatin treatment alone, likely via BAX and FAS. Our results demonstrate that Gankyrin expression changes in germ cells during normal transition from gonocyte to prespermatogonia. In addition, changes in Gankyrin localisation are associated with progression of pre-invasive GCNIS to invasive TGCC. Furthermore, we found that Gankyrin is involved in the regulation of NTera2 cell survival and that a reduction in Gankyrin expression can modulate cisplatin sensitivity. Conclusions These results suggest that manipulation of Gankyrin expression may reduce the cisplatin dose required for the treatment of TGCC, with benefits in reducing dose-dependent side effects of chemotherapy. Further studies are required in order to assess the effects of modulating Gankyrin on GCNIS/TGCC using in vivo models. |
| first_indexed | 2024-12-14T00:37:28Z |
| format | Article |
| id | doaj.art-5116c25b5ec14df3b8877884ca464cfb |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-14T00:37:28Z |
| publishDate | 2019-11-01 |
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| series | BMC Cancer |
| spelling | doaj.art-5116c25b5ec14df3b8877884ca464cfb2022-12-21T23:24:33ZengBMCBMC Cancer1471-24072019-11-0119111410.1186/s12885-019-6340-7The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cellsMaria E. Camacho-Moll0Joni Macdonald1L. H. J. Looijenga2Michael P. Rimmer3Roland Donat4John A. Marwick5C. J. Shukla6Neil Carragher7Anne Jørgensen8Rod T. Mitchell9Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Delegación Nuevo León, Instituto Mexicano del Seguro SocialMRC Centre for Reproductive Health, The University of Edinburgh, Queen’s Medical Research InstituteDepartment of Pathology, Erasmus University, Medical Center, Cancer Center, Josephine Nefkens InstituteMRC Centre for Reproductive Health, The University of Edinburgh, Queen’s Medical Research InstituteDepartment of Urology, Western General Hospital, Crewe RoadThe MRC Centre for Inflammation Research, Queen’s Medical Research InstituteDepartment of Urology, Western General Hospital, Crewe RoadCancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular MedicineDepartment of Growth and Reproduction, University Hospital of CopenhagenMRC Centre for Reproductive Health, The University of Edinburgh, Queen’s Medical Research InstituteAbstract Background Testicular germ cell cancer (TGCC) develops from pre-malignant germ neoplasia in situ (GCNIS) cells. GCNIS originates from fetal gonocytes (POU5F1+/MAGE-A4−), which fail to differentiate to pre-spermatogonia (POU5F1−/MAGE-A4+) and undergo malignant transformation. Gankyrin is an oncogene which has been shown to prevent POU5F1 degradation and specifically interact with MAGE-A4 in hepatocellular carcinoma (HCC) cells. We aimed to investigate the role of Gankyrin in progression from gonocyte to pre-invasive GCNIS and subsequent invasive TGCC. Methods We determined Gankyrin expression in human fetal testicular tissue (gestational weeks 9–20; n = 38), human adult testicular tissue with active spermatogenesis (n = 9), human testicular tissue with germ cell maturation delay (n = 4), testicular tissue from patients with pre-invasive GCNIS (n = 6), and invasive TGCC including seminoma (n = 6) and teratoma (n = 7). Functional analysis was performed in-vitro by siRNA knock-down of Gankyrin in the NTera2 cells (derived from embryonal carcinoma). Results Germ cell expression of Gankyrin was restricted to a sub-population of prespermatogonia in human fetal testes. Nuclear Gankyrin was also expressed in GCNIS cells of childhood and adult pre-invasive TGCC patients, and in GCNIS from seminoma and non-seminoma patients. Cytoplasmic expression was observed in seminoma tumour cells and NTera2 cells. Gankyrin knock-down in NTera2 cells resulted in an increase in apoptosis mediated via the TP53 pathway, whilst POU5F1 expression was unaffected. Furthermore, Gankyrin knock-down in NTera2 cells increased cisplatin sensitivity with an increase in cell death (13%, p < 0.05) following Gankyrin knock-down, when compared to cisplatin treatment alone, likely via BAX and FAS. Our results demonstrate that Gankyrin expression changes in germ cells during normal transition from gonocyte to prespermatogonia. In addition, changes in Gankyrin localisation are associated with progression of pre-invasive GCNIS to invasive TGCC. Furthermore, we found that Gankyrin is involved in the regulation of NTera2 cell survival and that a reduction in Gankyrin expression can modulate cisplatin sensitivity. Conclusions These results suggest that manipulation of Gankyrin expression may reduce the cisplatin dose required for the treatment of TGCC, with benefits in reducing dose-dependent side effects of chemotherapy. Further studies are required in order to assess the effects of modulating Gankyrin on GCNIS/TGCC using in vivo models.http://link.springer.com/article/10.1186/s12885-019-6340-7GankyrinTesticular germ cell cancerGCNISApoptosisCisplatin sensitivity |
| spellingShingle | Maria E. Camacho-Moll Joni Macdonald L. H. J. Looijenga Michael P. Rimmer Roland Donat John A. Marwick C. J. Shukla Neil Carragher Anne Jørgensen Rod T. Mitchell The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells BMC Cancer Gankyrin Testicular germ cell cancer GCNIS Apoptosis Cisplatin sensitivity |
| title | The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells |
| title_full | The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells |
| title_fullStr | The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells |
| title_full_unstemmed | The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells |
| title_short | The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells |
| title_sort | oncogene gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells |
| topic | Gankyrin Testicular germ cell cancer GCNIS Apoptosis Cisplatin sensitivity |
| url | http://link.springer.com/article/10.1186/s12885-019-6340-7 |
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