Abstract:
:Melanoma patients with BRAFV600E -mutant tumors display striking responses to BRAF inhibitors (BRAFi); however, almost all invariably relapse with drug-resistant disease. Here, we report that microRNA-125a (miR-125a) expression is upregulated in human melanoma cells and patient tissues upon acquisition of BRAFi resistance. We show that miR-125a induction confers resistance to BRAFV600E melanoma cells to BRAFi by directly suppressing pro-apoptotic components of the intrinsic apoptosis pathway, including BAK1 and MLK3. Apoptotic suppression and prolonged survival favor reactivation of the MAPK and AKT pathways by drug-resistant melanoma cells. We demonstrate that miR-125a inhibition suppresses the emergence of resistance to BRAFi and, in a subset of resistant melanoma cell lines, leads to partial drug resensitization. Finally, we show that miR-125a upregulation is mediated by TGFβ signaling. In conclusion, the identification of this novel role for miR-125a in BRAFi resistance exposes clinically relevant mechanisms of melanoma cell survival that can be exploited therapeutically.
journal_name
Pigment Cell Melanoma Resjournal_title
Pigment cell & melanoma researchauthors
Koetz-Ploch L,Hanniford D,Dolgalev I,Sokolova E,Zhong J,Díaz-Martínez M,Bernstein E,Darvishian F,Flaherty KT,Chapman PB,Tawbi H,Hernando Edoi
10.1111/pcmr.12578subject
Has Abstractpub_date
2017-05-01 00:00:00pages
328-338issue
3eissn
1755-1471issn
1755-148Xjournal_volume
30pub_type
杂志文章abstract::Transcription factors initiate programs of gene expression and are catalysts in downstream molecular cascades that modulate a variety of cellular processes. Pax3 is a transcription factor that is important in the melanocyte and influences melanocytic proliferation, resistance to apoptosis, migration, lineage specifici...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章,评审
doi:10.1111/j.1755-148X.2008.00514.x
更新日期:2008-12-01 00:00:00
abstract::We have previously shown that Wnt5A-mediated signaling can promote melanoma metastasis. It has been shown that Wnt signaling is antagonized by the protein Klotho, which has been implicated in aging. We show here that in melanoma cells, expressions of Wnt5A and Klotho are inversely correlated. In the presence of recomb...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2010.00792.x
更新日期:2011-02-01 00:00:00
abstract::Metastatic melanoma is extremely refractory to existing chemotherapeutic drugs and bioimmune adjuvant therapies, and the life span of patients with metastatic melanoma is often measured in months. Understanding the mechanisms responsible for the development of tumor metastasis is critical for finding successful curati...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章,评审
doi:10.1111/j.1755-148X.2009.00570.x
更新日期:2009-06-01 00:00:00
abstract::Defining markers of different phenotypic states in melanoma is important for understanding disease progression, determining the response to therapy, and defining the molecular mechanisms underpinning phenotype-switching driven by the changing intratumor microenvironment. The ABCB5 transporter is implicated in drug-res...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12830
更新日期:2020-01-01 00:00:00
abstract::Binding of melanocortin peptide agonists to the melanocortin-1 receptor of melanocytes results in eumelanin production, whereas binding of the agouti signalling protein inverse agonist results in pheomelanin synthesis. Recently, a novel melanocortin-1 receptor ligand was reported. A β-defensin gene mutation was found ...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2012.00990.x
更新日期:2012-05-01 00:00:00
abstract::Melasma is a common hyperpigmentary disorder. The impact on the quality of life of affected individuals is well demonstrated, demanding new therapeutic strategies. However, the treatment of melasma remains highly challenging. Melasma is often considered as the main consequence of female hormone stimulation on a predis...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章,评审
doi:10.1111/pcmr.12684
更新日期:2018-07-01 00:00:00
abstract::From the onset of melanocyte specification from the neural crest, throughout their migration during embryogenesis and until they reside in their niche in the basal keratinocyte layer, melanocytes interact in dynamic ways with the extracellular environment of the growing embryo. To recognize and to adhere to their envi...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章,评审
doi:10.1111/j.1755-148X.2010.00806.x
更新日期:2011-04-01 00:00:00
abstract::A SNP within intron4 of the interferon regulatory factor4 (IRF4) gene, rs12203592*C/T, has been independently associated with pigmentation and age-specific effects on naevus count in European-derived populations. We have characterized the cis-regulatory activity of this intronic region and using human foreskin-derived...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12620
更新日期:2018-01-01 00:00:00
abstract::Bromodomain and extra-terminal inhibitors (BETi) delay tumor growth, in part, through tumor cell intrinsic alterations and initiation of anti-tumor CD8+ T-cell responses. By contrast, BETi effects on pro-tumoral immune responses remain unclear. Here, we show that the next-generation BETi, PLX51107, delayed tumor growt...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12845
更新日期:2020-03-01 00:00:00
abstract::The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk of mesothelioma and melanocytic tumors. Here, we show that Bap1 deletion in melanocytes cooperates with the constitutively active, oncogenic form of BRAF (BRAFV600E ) and UV to cause melanoma in mice, albeit at very low freque...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12735
更新日期:2019-03-01 00:00:00
abstract::Melanoma is a disease associated with a very high mutation burden and thus the possibility of a diverse range of oncogenic mechanisms that allow it to evade therapeutic interventions and the immune system. Here, we describe the characterization of a panel of 102 cell lines from metastatic melanomas (the NZM lines), in...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12908
更新日期:2021-01-01 00:00:00
abstract::From a therapeutic standpoint, vitiligo is still regarded by many physicians as a simple problem of regenerative medicine, with the main aim to repopulate the depigmented skin with functional melanocytes from the margins of the lesions or from intact progenitors in hair follicles. However, recent research in vitiligo ...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章,评审
doi:10.1111/j.1755-148X.2011.00939.x
更新日期:2012-01-01 00:00:00
abstract::The quantification of melanins is a complex task due to the chemical heterogeneity of the pigments and the difficulty of their isolation. The best accepted procedure currently consists in the chemical cleavage of melanins and the subsequent detection of degradation products by HPLC, which implies the destruction of sa...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12140
更新日期:2013-11-01 00:00:00
abstract::In response to the dynamic intra-tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia is driven by hypoxia-inducible transcription factors (HIFs) that reprogram metabolism an...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12802
更新日期:2019-11-01 00:00:00
abstract::Oncogenic mutations in BRAF are common in melanoma and drive constitutive activation of the MEK/ERK pathway. To elucidate the transcriptional events downstream of (V600E)BRAF/MEK signalling we performed gene expression profiling of A375 melanoma cells treated with potent and selective inhibitors of (V600E)BRAF and MEK...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2009.00618.x
更新日期:2009-12-01 00:00:00
abstract::While sunlight is important for life, ultraviolet radiation (UVR) can have harmful and mutagenic effects. This duality is particularly relevant to human skin, in which UVR both participates in evolutionarily important photochemical reactions yet may act as a potential carcinogen. UVR can upregulate production of melan...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章,评审
doi:10.1111/j.1755-148X.2010.00775.x
更新日期:2010-12-01 00:00:00
abstract::Retinoic acid (RA) is considered to control melanocytes; however, its precise mechanism remains unclear because of a bimodal effect, which promotes or inhibits melanin synthesis depending on the cell type, culture condition of melanocytes and skin conditions. In this study, we examined the effects of RA throughout eac...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2012.00988.x
更新日期:2012-05-01 00:00:00
abstract::Although L-tyrosine is well known for its melanogenic effect, the contribution of D-tyrosine to melanin synthesis was previously unexplored. Here, we reveal that, unlike L-tyrosine, D-tyrosine dose-dependently reduced the melanin contents of human MNT-1 melanoma cells and primary human melanocytes. In addition, 500 μM...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12668
更新日期:2018-05-01 00:00:00
abstract::The Wnt/beta-catenin signaling pathway is involved in the melanocyte differentiation and melanoma development. However, the effect of beta-catenin for dendrite formation has not been clearly elucidated yet in normal human epidermal melanocytes (NHEM). To investigate the effect of beta-catenin, we transduced NHEM with ...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2010.00695.x
更新日期:2010-06-01 00:00:00
abstract::Albinism is a rare genetic condition globally characterized by a number of specific deficits in the visual system, resulting in poor vision, in association with a variable hypopigmentation phenotype. This lack or reduction in pigment might affect the eyes, skin, and hair (oculocutaneous albinism, OCA), or only the eye...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章,评审
doi:10.1111/pcmr.12167
更新日期:2014-01-01 00:00:00
abstract::Oncogenic BRAF mutations are more frequent in cutaneous melanoma occurring at sites with little or moderate sun-induced damage than at sites with severe cumulative solar ultraviolet (UV) damage. We studied cutaneous melanomas from geographic regions with different levels of ambient UV radiation to delineate the relati...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2011.00837.x
更新日期:2011-04-01 00:00:00
abstract::The novel mutation named ru2(d) /Hps5(ru2-d) , characterized by light-colored coats and ruby-eyes, prohibits differentiation of melanocytes by inhibiting tyrosinase (Tyr) activity, expression of Tyr, Tyr-related protein 1 (Tyrp1), Tyrp2, and Kit. However, it is not known whether the ru2(d) allele affects pheomelanin s...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12118
更新日期:2013-09-01 00:00:00
abstract::The advent of immune checkpoint blockers and targeted therapies has changed the outcome of melanoma. However, many patients experience relapses, emphasizing the need for predictive and prognostic biomarkers. We developed a strategy based on plasmacytoid dendritic cells (pDCs) loaded with melanoma tumor antigens that a...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12618
更新日期:2018-01-01 00:00:00
abstract::Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an antitumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and exp...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12591
更新日期:2017-07-01 00:00:00
abstract::The complex genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, including transcripts regulated by either transforming growth factor, beta 1 (TGF...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12255
更新日期:2014-09-01 00:00:00
abstract::The Dark brown (DB) mutation in chickens reduces expression of black eumelanin and enhances expression of red pheomelanin, but only in certain parts of the plumage. Here, we present genetic evidence that an 8.3-kb deletion upstream of the SOX10 transcription start site is the causal mutation underlying the DB phenotyp...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2011.00825.x
更新日期:2011-04-01 00:00:00
abstract::Two biological processes regulate light-induced skin colour change. A fast 'physiological pigmentation change' (i.e. circadian variations or camouflage) involves alterations in the distribution of pigment containing granules in the cytoplasm of chromatophores, while a slower 'morphological pigmentation change' (i.e. s...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12531
更新日期:2016-11-01 00:00:00
abstract::The protease-activated receptor-2 (PAR-2) is a seven transmembrane G-protein-coupled receptor that could be activated by serine protease cleavage or by synthetic peptide agonists. We showed earlier that activation of PAR-2 with Ser-Leu-Ile-Gly-Arg-Leu-NH(2) (SLIGRL), a known PAR-2 activating peptide, induces keratinoc...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/j.1755-148X.2008.00441.x
更新日期:2008-04-01 00:00:00
abstract::Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human t...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12546
更新日期:2017-01-01 00:00:00
abstract::Mice lacking the E3 ubiquitin ligase mahogunin ring finger-1 (MGRN1) have a pleiotropic phenotype that includes spongiform neurodegeneration, embryonic patterning defects, and dark fur due to a defect in pigment-type switching. The only MGRN1 ubiquitination target identified to date is tumor susceptibility gene 101 (T...
journal_title:Pigment cell & melanoma research
pub_type: 杂志文章
doi:10.1111/pcmr.12059
更新日期:2013-03-01 00:00:00