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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant melanoma is a malignant neoplasm originating from the melanocyte lineage. Microphthalmia-associated transcription factor (Mitf) is crucially involved in the melanin synthesis as well as proliferation and survival of melanocyte and melanoma. We previously showed that short interfering RNA (siRNA) that is specific for the Mitf gene (Mitf-siRNA) significantly inhibited growth of B16 melanoma after electro-transfected in vivo into preestablished tumor in mice. Here we assessed efficacy of electroporation-mediated co-transfection of Mitf-siRNA and IL-12 gene in the treatment of murine melanoma. As results, the tumor growth was more strongly inhibited by intratumor co-transfection with Mitf-siRNA and IL-12-encoding plasmid DNA than by transfection with either of the molecules alone. The co-transfection induced intratumor infiltration of CD4+ and CD8+ T cells, and hampered neoangiogenesis in the tumor. The findings suggest that the RNAi/cytokine gene combination therapy by means of electroporation may become a novel and efficacious therapeutic modality to treat neoplasms including melanoma.
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PMID:Mitf silencing cooperates with IL-12 gene transfer to inhibit melanoma in mice. 2007 74

The microphthalmia-associated transcription factor (MITF) is required for melanocyte development, maintenance of the melanocyte-specific transcription, and survival of melanoma cells. MITF positively regulates expression of more than 25 genes in pigment cells. Recently, it has been demonstrated that expression of several MITF downstream targets requires the SWI/SNF chromatin remodeling complex, which contains one of the two catalytic subunits, Brm or Brg1. Here we show that the expression of MITF itself critically requires active SWI/SNF. In several Brm/Brg1-expressing melanoma cell lines, knockdown of Brg1 severely compromised MITF expression with a concomitant downregulation of MITF targets and decreased cell proliferation. Although Brm was able to substitute for Brg1 in maintaining MITF expression and melanoma cell proliferation, sequential knockdown of both Brm and Brg1 in 501mel cells abolished proliferation. In Brg1-null SK-MEL-5 melanoma cells, depletion of Brm alone was sufficient to abrogate MITF expression and cell proliferation. Chromatin immunoprecipitation confirmed the binding of Brg1 or Brm to the promoter of MITF. Together these results demonstrate the essential role of SWI/SNF for expression of MITF and suggest that SWI/SNF may be a promissing target in melanoma therapy.
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PMID:SWI/SNF chromatin remodeling complex is critical for the expression of microphthalmia-associated transcription factor in melanoma cells. 2008 88

We report that melanoma cell lines expressing the interleukin-1 receptor exhibit 4- to 10-fold lower levels of mRNA of microphthalmia-associated transcription factor (MITF-M) when treated with interleukin-1beta. This effect is NF-kappaB and JNK-dependent. MITF-M regulates the expression of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigens recognized on melanoma cells by autologous cytolytic T lymphocytes. Accordingly, treating some melanoma cells with IL-1beta reduced by 40-100% their ability to activate such antimelanoma cytolytic T lymphocytes. Finally, we observed large amounts of biologically active IL-1alpha or IL-1beta secreted by two melanoma cell lines that did not express MITF-M, suggesting an autocrine MITF-M downregulation. We estimate that approximately 13% of melanoma cell lines are MITF-M-negative and secrete IL-1 cytokines. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.
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PMID:Interleukins 1alpha and 1beta secreted by some melanoma cell lines strongly reduce expression of MITF-M and melanocyte differentiation antigens. 2009 79

Copy gains involving chromosome 7p represent one of the most common genomic alterations found in melanomas, suggesting the presence of "driver" cancer genes. We identified several tumor samples that harbored focal amplifications situated at the peak of common chromosome 7p gains, in which the minimal common overlapping region spanned the ETV1 oncogene. Fluorescence in situ hybridization analysis revealed copy gains spanning the ETV1 locus in >40% of cases, with ETV1 amplification (>6 copies/cell) present in 13% of primary and 18% of metastatic melanomas. Melanoma cell lines, including those with ETV1 amplification, exhibited dependency on ETV1 expression for proliferation and anchorage-independent growth. Moreover, overexpression of ETV1 in combination with oncogenic NRAS(G12D) transformed primary melanocytes and promoted tumor formation in mice. ETV1 overexpression elevated microphthalmia-associated transcription factor expression in immortalized melanocytes, which was necessary for ETV1-dependent oncogenicity. These observations implicate deregulated ETV1 in melanoma genesis and suggest a pivotal lineage dependency mediated by oncogenic ETS transcription factors in this malignancy.
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PMID:An oncogenic role for ETV1 in melanoma. 2016 28

Skin hyperpigmentation disorders due to abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and cosmetic problem. UV irradiation stimulates melanin production in melanocytes by increasing intracellular cAMP. Expression of heat shock proteins (HSPs), especially HSP70, is induced by various stressors, including UV irradiation, to provide cellular resistance to such stressors. In this study we examined the effect of expression of HSP70 on melanin production both in vitro and in vivo. 3-Isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, stimulated melanin production in cultured mouse melanoma cells, and this stimulation was suppressed in cells overexpressing HSP70. IBMX-dependent transcriptional activation of the tyrosinase gene was also suppressed in HSP70-overexpressing cells. Expression of microphthalmia-associated transcription factor (MITF), which positively regulates transcription of the tyrosinase gene, was up-regulated by IBMX; however, this up-regulation was not suppressed in HSP70-overexpressing cells. On the other hand, immunoprecipitation and immunostaining analyses revealed a physical interaction between and co-localization of MITF and HSP70, respectively. Furthermore, the transcription of tyrosinase gene in nuclear extract was inhibited by HSP70. In vivo, UV irradiation of wild-type mice increased the amount of melanin in the basal layer of the epidermis, and this increase was suppressed in transgenic mice expressing HSP70. This study provides the first evidence of an inhibitory effect of HSP70 on melanin production both in vitro and in vivo. This effect seems to be mediated by modulation of MITF activity through a direct interaction between HSP70 and MITF.
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PMID:Suppression of melanin production by expression of HSP70. 2017 67

This study was conducted to determine whether saponified evening primrose oil (sap-EPO) has the potential for use as a whitening agent and to investigate its underlying mechanisms of action. In B16 melanoma cells, sap-EPO dose-dependently inhibited isobutylmethylxanthine-induced melanogenesis with no cytotoxicity. This decrease in melanin production was correlated with reduced enzyme activity and decreased mRNA and protein levels of tyrosinase. The mRNA levels of tyrosinase-related proteins 1 and 2 decreased in response to treatment with sap-EPO, indicating that it regulated tyrosinase at the transcriptional level. Expression of microphthalmia-associated transcription factor was also decreased by sap-EPO as evidenced by decreased mRNA and protein levels. Additionally, topical application of sap-EPO resulted in efficient whitening of UVB-induced hyperpigmentation of human skin. Taken together, these results suggest that sap-EPO has the potential for use as a cosmetic whitening agent.
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PMID:Saponified evening primrose oil reduces melanogenesis in B16 melanoma cells and reduces UV-induced skin pigmentation in humans. 2035 96

The aim of this study was to analyze microphthalmia-associated transcription factor (MITF) as a marker for the detection of circulating melanoma cells, determine its prognostic value in melanoma patients, and compare it with tyrosinase. Blood samples from 201 melanoma patients in all stages of the disease and 40 healthy volunteers were analyzed. RNA was isolated from mononuclear cell fraction of the blood and assayed by reverse transcription-PCR for the expression of MITF and tyrosinase. All samples from healthy volunteers were negative for both MITF and tyrosinase. Out of 201 blood samples from melanoma patients 32 were positive for MITF, 20 for tyrosinase, and four for both MITF and tyrosinase. Analysis of MITF as an additional marker to tyrosinase allowed for detection of circulating melanoma cells in a larger number of melanoma patients in comparison to tyrosinase analysis alone (48 vs. 20 positive). A positive value of MITF was associated with shorter progression-free (P=0.005) and overall survival (P=0.042). A positive value of tyrosinase was associated with shorter overall survival (P=0.012), whereas there was no significant association between the value of tyrosinase and progression-free survival. The value of MITF was selected with multivariate analysis as the independent prognostic factor for progression-free survival, whereas the only independent prognostic factor for overall survival was the stage of disease. This study has shown that MITF is a specific marker for detection of circulating melanoma cells that has a prognostic value in melanoma patients. Determination of MITF in addition to tyrosinase improved the detection of circulating melanoma cells in melanoma patients.
Melanoma Res 2010 Aug
PMID:Prognostic value of microphthalmia-associated transcription factor and tyrosinase as markers for circulating tumor cells detection in patients with melanoma. 2035 86

Apoptosis and senescence are cellular failsafe programs that counteract excessive mitogenic signaling observed in cancer cells. Melanoma is known for its notorious resistance to apoptotic processes; therefore, senescence, which remains poorly understood in melanomas, can be viewed as a therapeutic alternative. Microphthalmia-associated transcription factor (MITF), in which its M transcript is specifically expressed in melanocyte cells, plays a critical role in melanoma proliferation, and its specific inhibition is associated with G(0)-G(1) growth arrest. Interestingly, decreased MITF expression has been described in senescent melanocytes, and we have observed an inhibition of MITF expression in melanoma cells exposed to chemotherapeutic drugs that induce their senescence. All these observations thereby question the role of MITF in controlling senescence in melanoma cells. Here, we report that long-term depletion of MITF in melanoma cells triggers a senescence program characterized by typical morphologic and biochemical changes associated with a sustained growth arrest. Further, we show that MITF-silenced cells engage a DNA damage response (DDR) signaling pathway, leading to p53 upregulation, which is critically required for senescence entry. This study uncovers the existence of a lineage-restricted DDR/p53 signaling pathway that is inhibited by MITF to prevent senescence and favor melanoma cell proliferation.
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PMID:Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas. 2038 97

Baicalein is one of the major flavonoids in Scutellaria baicalensis. However, the effects of baicalein on melanogenesis are unknown. The objective of this study was to evaluate the depigmenting capacity of baicalein and to elucidate its mechanism of action. B16F10 mouse melanoma cells were used to examine the effect of baicalein on melanogenesis by measurement of melanin content and tyrosinase activity after treatment. To ascertain the baicalein activity, the effect on two protein kinases, ERK and Akt and downstream microphthalmia-associated transcription factor (MITF) were examined by Western blotting and RT-PCR. Baicalein significantly inhibited melanin synthesis in a concentration-dependent manner without cytotoxicity. Tyrosinase activity was also reduced. Baicalein decreased MITF and tyrosinase levels but did not decrease MITF mRNA. Western blotting showed that baicalein induced ERK activation. Using the specific ERK phosphorylation inhibitor, PD98059, we blocked the hypopigmentation effect, and also abrogated the baicalein-mediated activation of ERK. However, baicalein did not induce Akt activation. These results suggest that the ERK pathway is involved in the melanogenic signaling cascade, and that ERK activation by baicalein reduces melanin synthesis via MITF downregulation and is subsequent to the inhibition of tyrosinase synthesis.
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PMID:Baicalein inhibits melanogenesis through activation of the ERK signaling pathway. 2042 97

Alternative cleavage and polyadenylation generate multiple transcript variants of mRNA isoforms with different length of 3'-untranslated region (UTR). Alternative cleavage and polyadenylation enable differential post-transcriptional regulation of transcripts via the availability of different cis-acting elements in 3'-UTRs. Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte development and melanogenesis. It has also been implicated in melanoma development. Here we show that melanoma cells favor the expression of MITF mRNA with shorter 3'-UTR. This isoform of mRNA is regulated by microRNA, miR-340. miR-340 interacts with two of its target sites on the 3'-UTR of MITF mRNA, causing mRNA degradation and decreased expression and activity of MITF. On the other hand, the RNA-binding protein coding region determinant-binding protein, shown to be highly expressed in melanoma, directly binds to the 3'-UTR of MITF mRNA and prevents the binding of miR-340 to its target sites, resulting in stabilization of the MITF transcript and elevated expression and transcriptional activity of MITF. This interplay between RNA-binding protein and miRNA describes the important mechanism of regulation of MITF in melanocytes and malignant melanomas.
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PMID:MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor mRNA is inhibited by the coding region determinant-binding protein. 2477 39


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