Melanoma cell–derived exosomes promote epithelial–mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

•Melanoma cell–derived exosomes promote phenotype switching in primary melanocytes.•MAPK pathway and let-7i were involved in exosome-mediated EMT.•EMT-related miRNAs (miR-191and let-7a) in exosomes may be used for melanoma diagnosis.•Targeting exosome-mediated EMT may be an approach to prevent tumor...

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Vydáno v:	Cancer letters Ročník 376; číslo 2; s. 318 - 327
Hlavní autoři:	Xiao, Deyi, Barry, Samantha, Kmetz, Daniel, Egger, Michael, Pan, Jianmin, Rai, Shesh N., Qu, Jifu, McMasters, Kelly M., Hao, Hongying
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Ireland Elsevier Ireland Ltd 01.07.2016 Elsevier Limited
Témata:	Adult Aged Autocrine Communication Case-Control Studies Cell culture Cell Line, Tumor Colleges & universities Conflicts of interest Epithelial-Mesenchymal Transition Epithelial-to-mesenchymal transition Exosomes Exosomes - metabolism Female Hematology, Oncology and Palliative Medicine Humans Kinases Male Melanocytes - metabolism Melanocytes - pathology Melanoma Melanoma - genetics Melanoma - metabolism Melanoma - secondary Metastasis Microenvironment MicroRNAs - genetics MicroRNAs - metabolism Middle Aged Mitogen-Activated Protein Kinases - metabolism Paracrine Communication Paracrine/autocrine Signal Transduction Skin cancer Skin Neoplasms - genetics Skin Neoplasms - metabolism Skin Neoplasms - pathology Transfection Tumor Microenvironment Tumor progression PBS Melanoma ROC HEMa-LP NHEM-c Microenvironment Exosomes MAPK MKK EMT AUC PI3K/AKT Epithelial-to-mesenchymal transition Paracrine/autocrine RT-PCR Tumor progression MKKK MAP PCR mitogen-activated protein kinase mitogen-activated protein phosphoinositide 3-kinase/protein kinase B receiver operating characteristic polymerase chain reaction human epidermal melanocytes adult-lightly pigmented normal human epidermal melanocytes mitogen-activated protein kinase kinase kinase area under ROC (receiver operating characteristic) curve phosphate buffered saline reverse transcription polymerase chain reaction mitogen-activated protein kinase kinase
ISSN:	0304-3835, 1872-7980, 1872-7980
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Shrnutí:	•Melanoma cell–derived exosomes promote phenotype switching in primary melanocytes.•MAPK pathway and let-7i were involved in exosome-mediated EMT.•EMT-related miRNAs (miR-191and let-7a) in exosomes may be used for melanoma diagnosis.•Targeting exosome-mediated EMT may be an approach to prevent tumor progression. The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell–derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell–derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell–derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0304-3835 1872-7980 1872-7980
DOI:	10.1016/j.canlet.2016.03.050