Oncogenic B-RAFV600E Signaling Induces the T-Box3 Transcriptional Repressor to Repress E-Cadherin and Enhance Melanoma Cell Invasion
Open accessAbstract
Approximately 50% of melanomas require oncogenic B-RAF(V600E) signaling for proliferation, survival, and metastasis, and the use of highly selective B-RAF inhibitors has yielded remarkable, although short-term, clinical responses. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may therefore provide new strategies for managing melanoma. In this report, we applied whole-genome expression analyses to reveal that oncogenic B-RAF(V600E) regulates genes associated with epithelial-mesenchymal transition in normal cutaneous human melanocytes. Most prominent was the B-RAF-mediated transcriptional repression of E-cadherin, a keratinocyte-melanoma adhesion molecule whose loss is intimately associated with melanoma invasion and metastasis. Here we identify a link between oncogenic B-RAF, the transcriptional repressor Tbx3, and E-cadherin. We show that B-RAF(V600E) induces the expression of Tbx3, which potently represses E-cadherin expression in melanocytes and melanoma cells. Tbx3 expression is normally restricted to developmental embryonic tissues and promoting cell motility, but it is also aberrantly increased in various cancers and has been linked to tumor cell invasion and metastasis. We propose that this B-RAF/Tbx3/E-cadherin pathway has a critical role in promoting the metastasis of B-RAF-mutant melanomas.
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TBX3 is often up-regulated in tumorigenesis and promotes tumor cell proliferation and metastasis, especially during BRAF/MAPK induced tumorigenesis.
“Recently, the oncogenic function of TBX3 draws attention, where TBX3 is often up-regulated in tumorigenesis and promotes tumor cell proliferation and metastasis, especially during BRAF/MAPK induced tumorigenesis12–16.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [12]
The Results (‘B-RAFV600E upregulates the Tbx3 transcriptional repressor’) and Discussion report TBX3 upregulation by oncogenic B-RAF, and the invasion Results show that silencing TBX3 reduces melanoma-cell invasion. But the paper does not show that TBX3 promotes metastasis: its direct test is an invasion assay. The Discussion says TBX3 may favor proliferation when combined with loss of p16INK4a, while B-RAFV600E induces senescence in primary melanocytes despite TBX3 accumulation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMultiple oncogenic pathways regulate TBX3 expression in melanoma, lung, thyroid, breast and other cancers.
“Multiple oncogenic pathways have been found to regulate TBX3 expression in occurrence of melanoma, lung, thyroid, breast and other types of cancers12,15,16,20,21,53,54”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [12]
The Results and Discussion (page unavailable) show that oncogenic B-RAFV600E upregulates TBX3 in melanocytes and melanoma cells. The Discussion also notes TBX3 overexpression in several other cancers, but it does not establish that multiple oncogenic pathways regulate TBX3 across lung, thyroid, breast and other cancers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCritical morphogenic and oncogenic signaling pathways, including BMPs, Shh, TGF-β, FGFs, Wnt/β-catenin, and BRAF/MAPK, participate in TBX3 expression regulation, mostly at the transcriptional level.
“Thus, critical morphogenic and oncogenic signaling pathways, such as BMPs17, Shh18, TGF-β19, FGFs20, Wnt/β-catenin21, as well as BRAF/MAPK pathway, participate in TBX3 expression regulation, mostly at the transcriptional level12,15.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [12]
Upregulation of pioneer developmental organizers such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, and BCL6 is reported downstream of BRAF/MAPK-driven tumor.
“Even upregulation of pioneer developmental organizers, such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, BCL6, et al., are reported downstream of BRAF/MAPK-driven tumor, the pathways causing lineage reprogramming are not clear12,15,30–36.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [12]
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References 44 · Cited by 53
Research works printed but not linked: 37
- Balch CM Soong SJ Gershenwald JE Thompson JF Reintgen DS Cascinelli N Prognostic factors analysis of 17,600 melanoma patients: validation of the american joint committee on cancer melanoma staging system J Clin Oncol 2001 19 3622 3634 11504744
- Bamshad M Lin RC Law DJ Watkins WC Krakowiak PA Moore ME Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome Nat Genet 1997 16 311 315 9207801
- Basolo F Torregrossa L Giannini R Miccoli M Lupi C Sensi E Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1060 cases J Clin Endocrinol Metab 2010 95 4197 4205 20631031
- Becker TM Philipsz S Scurr LL Fung C Haferkamp S Kefford RF Oncogenic B-RAF(V600E) promotes anchorage-independent survival of human melanocytes J Invest Dermatol 2010 130 2144 2147 20445557
- Bolos V Peinado H Perez-Moreno MA Fraga MF Esteller M Cano A The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors J Cell Sci 2003 116 499 511 12508111
- Broekaert SM Roy R Okamoto I van den Oord J Bauer J Garbe C Genetic and morphologic features for melanoma classification Pigment Cell Melanoma Res 2010 23 763 770 20874733 PMC3107973
- Brummer T Martin P Herzog S Misawa Y Daly RJ Reth M Functional analysis of the regulatory requirements of B-Raf and the B-Raf(V600E) oncoprotein Oncogene 2006 25 6262 6276 16702958
- Cano A Perez-Moreno MA Rodrigo I Locascio A Blanco MJ del Barrio MG The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression Nat Cell Biol 2000 2 76 83 10655586
- Conacci-Sorrell M Simcha I Ben-Yedidia T Blechman J Savagner P Ben-Ze’ev A Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK J Cell Biol 2003 163 847 857 14623871 PMC2173691
- Flaherty KT Puzanov I Kim KB Ribas A McArthur GA Sosman JA Inhibition of mutated, activated BRAF in metastatic melanoma N Engl J Med 2010 363 809 819 20818844 PMC3724529
- Haass NK Smalley KS Li L Herlyn M Adhesion, migration and communication in melanocytes and melanoma Pigment Cell Res 2005 18 150 159 15892711
- Haferkamp S Tran SL Becker TM Scurr LL Kefford RF Rizos H The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence Aging 2009 1 542 556 20157537 PMC2806033
- Hajra KM Chen DY Fearon ER The SLUG zinc-finger protein represses E-cadherin in breast cancer Cancer Res 2002 62 1613 1618 11912130
- Hoek K Rimm DL Williams KR Zhao H Ariyan S Lin A Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas Cancer Res 2004 64 5270 5282 15289333
- Hoogaars WM Barnett P Rodriguez M Clout DE Moorman AF Goding CR TBX3 and its splice variant TBX3 + exon 2a are functionally similar Pigment Cell Melanoma Res 2008 21 379 387 18444963
- Hsu MY Meier FE Nesbit M Hsu JY Van Belle P Elder DE E-cadherin expression in melanoma cells restores keratinocyte-mediated growth control and down-regulates expression of invasion-related adhesion receptors Am J Pathol 2000 156 1515 1525 10793063 PMC1876923
- Ikoma N Yamazaki H Abe Y Oida Y Ohnishi Y Suemizu H S100A4 expression with reduced E-cadherin expression predicts distant metastasis of human malignant melanoma cell lines in the NOD/SCID/gammaCnull (NOG) mouse model Oncol Rep 2005 14 633 637 16077966
- Johansson P Pavey S Hayward N Confirmation of a BRAF mutation-associated gene expression signature in melanoma Pigment Cell Res 2007 20 216 221 17516929
- Knauf JA Sartor MA Medvedovic M Lundsmith E Ryder M Salzano M Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFbeta signaling Oncogene 2011 30 3153 3162 21383698 PMC3136543
- Kreizenbeck GM Berger AJ Subtil A Rimm DL Gould Rothberg BE Prognostic significance of cadherin-based adhesion molecules in cutaneous malignant melanoma Cancer Epidemiol Biomarkers Prev 2008 17 949 958 18398036 PMC3312613
- Kuphal S Bosserhoff AK E-cadherin cell-cell communication in melanogenesis and during development of malignant melanoma Arch Biochem Biophys 2011 22085498
- Lee HS Cho HH Kim HK Bae YC Baik HS Jung JS Tbx3, a transcriptional factor, involves in proliferation and osteogenic differentiation of human adipose stromal cells Mol Cell Biochem 2007 296 129 136 16955224
- Lin K Baritaki S Militello L Malaponte G Bevelacqua Y Bonavida B The Role of B-RAF Mutations in Melanoma and the Induction of EMT via Dysregulation of the NF-kappaB/Snail/RKIP/PTEN Circuit Genes Cancer 2010 1 409 420 20827424 PMC2933925
- Lu J Li XP Dong Q Kung HF He ML TBX2 and TBX3: the special value for anticancer drug targets Biochim Biophys Acta 2010 1806 268 274 20624445 PMC7127380
- Minoo P Moyer MP Jass JR Role of BRAF-V600E in the serrated pathway of colorectal tumourigenesis J Pathol 2007 212 124 133 17427169
- Mowla S Pinnock R Leaner VD Goding CR Prince S TPA-induced upregulation of TBX3 is mediated by AP-1 and contributes to breast cancer cell migration Biochem J 2010 20942798
- Nucera C Porrello A Antonello ZA Mekel M Nehs MA Giordano TJ B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression Proc Natl Acad Sci U S A 2010 107 10649 10654 20498063 PMC2890809
- Peres J Davis E Mowla S Bennett DC Li JA Wansleben S The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process Genes Cancer 2010 1 272 282 21779450 PMC3092191
- Platz A Egyhazi S Ringborg U Hansson J Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site Mol Oncol 2008 1 395 405 19383313 PMC5543839
- Poser I Dominguez D de Herreros AG Varnai A Buettner R Bosserhoff AK Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail J Biol Chem 2001 276 24661 24666 Epub 22001 Apr 24625 11323412
- Rodriguez M Aladowicz E Lanfrancone L Goding CR Tbx3 represses E-cadherin expression and enhances melanoma invasiveness Cancer Res 2008 68 7872 7881 18829543
- Rowley M Grothey E Couch FJ The role of Tbx2 and Tbx3 in mammary development and tumorigenesis J Mammary Gland Biol Neoplasia 2004 9 109 118 15300007
- Scurr LL Pupo GM Becker TM Lai K Schrama D Haferkamp S IGFBP7 is not required for B-RAF-induced melanocyte senescence Cell 2010 141 717 727 20478260
- Tsai CN Tsai CL Tse KP Chang HY Chang YS The Epstein-Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases Proc Natl Acad Sci U S A 2002 99 10084 10089 12110730 PMC126628
- Tsutsumida A Hamada J Tada M Aoyama T Furuuchi K Kawai Y Epigenetic silencing of E- and P-cadherin gene expression in human melanoma cell lines Int J Oncol 2004 25 1415 1421 15492833
- Tucci MG Lucarini G Brancorsini D Zizzi A Pugnaloni A Giacchetti A Involvement of E-cadherin, beta-catenin, Cdc42 and CXCR4 in the progression and prognosis of cutaneous melanoma Br J Dermatol 2007 157 1212 1216 17970806
- Viros A Fridlyand J Bauer J Lasithiotakis K Garbe C Pinkel D Improving melanoma classification by integrating genetic and morphologic features PLoS Med 2008 5 e120 18532874 PMC2408611
- Authors
- Boyd, S. C., Mijatov, B., Pupo, G. M., Tran, S. L., Gowrishankar, K., Shaw, H. M., Goding, C. R., Scolyer, R. A., Mann, G. J., Kefford, R. F., Rizos, H., & Becker, T. M.
- Affiliations
- The University of Sydney (AU)
- University of Oxford (GB)
- Melanoma Institute Australia (AU)
- Corresponding author
- Becker, Therese M.
- ORCID
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 133
- Issue
- 5
- Pages
- 1269-1277
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC3788590
- OpenAlex
- W2012078419
- Cited by
- 53
- References
- 44
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 6 · 2014: 8 · 2013: 2
- FWCI
- 2.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (078040)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- BrafV600E, TBX3, E-cadherin, melanoma, transcriptional repression, epithelial-mesenchymal transition, metastasis, BRAF inhibitors, acquired drug resistance, cell motility
- MeSH terms
- Cell Adhesion, Cell Movement, Cells, Cultured, Humans, Melanocytes, Melanoma, Neoplasm Invasiveness, Skin Neoplasms, Transcription, Genetic, Signal Transduction, Down-Regulation, Cadherins, T-Box Domain Proteins, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Epithelial-Mesenchymal Transition
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