SOX9 is a dose-dependent metastatic fate determinant in melanoma
Abstract Background In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma. Methods...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0998-6 |
| _version_ | 1819170323289866240 |
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| author | Xintao Yang Rui Liang Chunxi Liu Jessica Aijia Liu May Pui Lai Cheung Xuelai Liu On Ying Man Xin-Yuan Guan Hong Lok Lung Martin Cheung |
| author_facet | Xintao Yang Rui Liang Chunxi Liu Jessica Aijia Liu May Pui Lai Cheung Xuelai Liu On Ying Man Xin-Yuan Guan Hong Lok Lung Martin Cheung |
| author_sort | Xintao Yang |
| collection | DOAJ |
| description | Abstract Background In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma. Methods Immunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases. Results High SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling. Conclusions These results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma. |
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| id | doaj.art-8e3fb6e0950842bdb71f40a6a415d000 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-22T19:33:34Z |
| publishDate | 2019-01-01 |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-8e3fb6e0950842bdb71f40a6a415d0002022-12-21T18:15:03ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-01-0138111910.1186/s13046-018-0998-6SOX9 is a dose-dependent metastatic fate determinant in melanomaXintao Yang0Rui Liang1Chunxi Liu2Jessica Aijia Liu3May Pui Lai Cheung4Xuelai Liu5On Ying Man6Xin-Yuan Guan7Hong Lok Lung8Martin Cheung9School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Anesthesiology, Zhejiang Cancer HospitalSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Pediatric Surgery, Second Hospital of Hebei Medical UniversityDepartment of Biology, Faculty of Science, Hong Kong Baptist UniversityDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Biology, Faculty of Science, Hong Kong Baptist UniversitySchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongAbstract Background In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma. Methods Immunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases. Results High SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling. Conclusions These results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma.http://link.springer.com/article/10.1186/s13046-018-0998-6SOX9; SOX10NEDD9RHOARAC1MelanomaMetastatic |
| spellingShingle | Xintao Yang Rui Liang Chunxi Liu Jessica Aijia Liu May Pui Lai Cheung Xuelai Liu On Ying Man Xin-Yuan Guan Hong Lok Lung Martin Cheung SOX9 is a dose-dependent metastatic fate determinant in melanoma Journal of Experimental & Clinical Cancer Research SOX9; SOX10 NEDD9 RHOA RAC1 Melanoma Metastatic |
| title | SOX9 is a dose-dependent metastatic fate determinant in melanoma |
| title_full | SOX9 is a dose-dependent metastatic fate determinant in melanoma |
| title_fullStr | SOX9 is a dose-dependent metastatic fate determinant in melanoma |
| title_full_unstemmed | SOX9 is a dose-dependent metastatic fate determinant in melanoma |
| title_short | SOX9 is a dose-dependent metastatic fate determinant in melanoma |
| title_sort | sox9 is a dose dependent metastatic fate determinant in melanoma |
| topic | SOX9; SOX10 NEDD9 RHOA RAC1 Melanoma Metastatic |
| url | http://link.springer.com/article/10.1186/s13046-018-0998-6 |
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