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1.
J Transl Med ; 22(1): 758, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39138582

RESUMEN

BACKGROUND: While melanomas commonly harbor losses of 9p21, on which CDKN2A resides, the presence of additional tumor suppressor elements at this locus is incompletely characterized. Here we assess the expression levels and functional role of microRNA-876-3p (miR-876), whose gene also maps to 9p21. METHODS: Expression of miR-876 was assessed in human tissues and cell lines using quantitative miRNA reverse transcriptase polymerase chain reaction (qRT-PCR). MIR876 copy number was determined in The Cancer Genome Atlas (TCGA) melanoma cohort. The consequences of regulation of miR-876 expression were assessed on melanoma cell colony formation, migration, invasion, apoptosis, cell cycle progression, and drug sensitivity in culture, and on in vivo tumor growth in a xenograft model. Genome-wide transcriptomic changes induced by miR-876 overexpression were determined using RNA sequencing (RNA-Seq). RESULTS: miR-876 expression was significantly decreased in primary melanoma samples when compared with nevi, and in human melanoma cell lines when compared with human melanocytes. Analysis of the TCGA cohort revealed deletions in MIR876 in > 50% of melanomas. miR-876 overexpression resulted in decreased melanoma cell colony formation, migration, and invasion, which was accompanied by cell cycle arrest and increased apoptosis. Intra-tumoral injections of miR-876 significantly suppressed melanoma growth in vivo. RNA-Seq analysis of miR-876-treated tumors revealed downregulation of several growth-promoting genes, along with upregulation of tumor suppressor genes, which was confirmed by qRT-PCR analysis. Computational analyses identified MAPK1 (or ERK2) as a possible target of miR-876 action. Overexpression of miR-876 significantly suppressed luciferase expression driven by the MAPK1/ERK2 3' UTR, and resulted in decreased ERK protein expression in melanoma cells. MAPK1/ERK2 cDNA overexpression rescued the effects of miR-876 on melanoma colony formation. miR-876 overexpression sensitized melanoma cells to treatment with the BRAF inhibitor vemurafenib. CONCLUSIONS: These studies identify miR-876 as a distinct tumor suppressor on 9p21 that is inactivated in melanoma and suggest miR-876 loss as an additional mechanism to activate ERK and the mitogen activated protein kinase (MAPK) pathway in melanoma. In addition, they suggest the therapeutic potential of combining miR-876 overexpression with BRAF inhibition as a rational therapeutic strategy for melanoma.


Asunto(s)
Cromosomas Humanos Par 9 , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Melanoma , MicroARNs , Humanos , Melanoma/genética , Melanoma/patología , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Animales , Cromosomas Humanos Par 9/genética , Movimiento Celular/genética , Apoptosis/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proliferación Celular/genética , Secuencia de Bases , Invasividad Neoplásica
2.
Cancers (Basel) ; 16(15)2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39123494

RESUMEN

According to the American Joint Commission on Cancer (AJCC) 8th edition guidelines, SLN biopsy is recommended for primary melanomas with a Breslow thickness of at least 1 mm. Additionally, the National Comprehensive Cancer Network (NCCN) recommends that a SLN biopsy may be considered for melanoma patients with T1b lesions, which are 0.8-1 mm thick or less than 0.8 mm thick with ulceration. It can also be considered for T1a lesions that are less than 0.8 mm thick but have other adverse features, such as a high mitotic rate, lymphovascular invasion, or a positive deep margin. To reduce the false negative rate of melanoma SLN biopsy, we have introduced the intraoperative use of Sentinella, a gamma camera, to enhance the identification rate of SLNs beyond that of the traditional gamma hand-held probe. At the Center for Melanoma Research and Treatment at the California Pacific Medical Center, a multidisciplinary approach has been established to treat melanoma patients when the diagnosis of primary melanoma is made with a referral to our melanoma center. This comprehensive approach at the melanoma tumor board, including the efforts of pathologists, radiologists, dermatologists, surgical, medical and radiation oncologists, results in a consensus to deliver personalized and high-quality care for our melanoma patients. This multidisciplinary program for the management of melanoma can be duplicated for other types of cancer. This article consists of current knowledge to document the published methods of identification of sentinel lymph nodes. In addition, we have included new data as developed in our melanoma center as newly published materials in this article to demonstrate the utility of these methods in melanoma sentinel lymph node surgery. Informed consent has been waived by our IRB regarding the acquisition of clinical data as presented in this study.

3.
J Invest Dermatol ; 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38582370

RESUMEN

The evolution of primary melanoma to lymph node and distant metastasis is incompletely understood. We examined the genomic diversity in melanoma progression in matched primary melanomas and lymph node and distant metastases from 17 patients. FISH analysis revealed cancer cell fractions with monotonic copy number alterations, including PHIP gain and PTEN loss, in the metastatic cascade. By contrast, the cancer cell fraction with copy number alterations for BPTF and MITF was reduced in lymph node metastases but increased in distant metastases. Separately, the cancer cell fraction with NCOA3 copy number alteration was comparable between primary tumors and lymph node metastases yet increased in distant metastases. These results suggest enrichment of the phosphoinositide 3-kinase and MITF pathways in the transition through the metastatic cascade. By contrast, next-generation sequencing analysis did not identify a consistent pattern of changes in variant allele frequency while revealing several intriguing findings, including decreased variant allele frequency in distant metastases and distinct drivers in lymph node versus distant metastases. These results provide evidence that distant melanoma metastasis does not always emanate from lymph node metastasis. These results enhance our understanding of clonal patterns of melanoma metastasis, with possible implications for targeted therapy and metastasis competency.

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