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Article: SOX9 is a dose-dependent metastatic fate determinant in melanoma

TitleSOX9 is a dose-dependent metastatic fate determinant in melanoma
Authors
KeywordsSOX9; SOX10
NEDD9
RHOA
RAC1
Melanoma
Metastatic
p21
Issue Date2019
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.jeccr.com/home
Citation
Journal of Experimental and Clinical Cancer Research, 2019, v. 38 n. 1, article no. 17, p. 1-19 How to Cite?
AbstractBackground: 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.
Persistent Identifierhttp://hdl.handle.net/10722/266384
ISSN
2017 Impact Factor: 6.217
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYang, X-
dc.contributor.authorLiang, R-
dc.contributor.authorLiu, C-
dc.contributor.authorLiu, AJ-
dc.contributor.authorCheung, MPL-
dc.contributor.authorLiu, X-
dc.contributor.authorMan, OY-
dc.contributor.authorGuan, X-
dc.contributor.authorLung, HL-
dc.contributor.authorCheung, MCH-
dc.date.accessioned2019-01-18T08:18:31Z-
dc.date.available2019-01-18T08:18:31Z-
dc.date.issued2019-
dc.identifier.citationJournal of Experimental and Clinical Cancer Research, 2019, v. 38 n. 1, article no. 17, p. 1-19-
dc.identifier.issn1756-9966-
dc.identifier.urihttp://hdl.handle.net/10722/266384-
dc.description.abstractBackground: 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.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.jeccr.com/home-
dc.relation.ispartofJournal of Experimental and Clinical Cancer Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectSOX9; SOX10-
dc.subjectNEDD9-
dc.subjectRHOA-
dc.subjectRAC1-
dc.subjectMelanoma-
dc.subjectMetastatic-
dc.subjectp21-
dc.titleSOX9 is a dose-dependent metastatic fate determinant in melanoma-
dc.typeArticle-
dc.identifier.emailLiu, AJ: jessie11@hku.hk-
dc.identifier.emailCheung, MPL: mplcheun@hku.hk-
dc.identifier.emailGuan, X: xyguan@hku.hk-
dc.identifier.emailCheung, MCH: mcheung9@hku.hk-
dc.identifier.authorityGuan, X=rp00454-
dc.identifier.authorityCheung, MCH=rp00245-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s13046-018-0998-6-
dc.identifier.pmid30642390-
dc.identifier.pmcidPMC6330758-
dc.identifier.scopuseid_2-s2.0-85059957990-
dc.identifier.hkuros296710-
dc.identifier.volume38-
dc.identifier.issue1-
dc.identifier.spagearticle no. 17, p. 1-
dc.identifier.epagearticle no. 17, p. 19-
dc.identifier.isiWOS:000455639600001-
dc.publisher.placeUnited Kingdom-

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