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Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b.
- Source :
-
Oncotarget [Oncotarget] 2016 Jan 26; Vol. 7 (4), pp. 4428-41. - Publication Year :
- 2016
-
Abstract
- In melanoma, the adaptative cell response to BRAF inhibitors includes altered patterns of cytokine production contributing to tumor progression and drug resistance. Among the factors produced by PLX4032-resistant melanoma cell lines, CCL2 was higher compared to the sensitive parental cell lines and increased upon drug treatment. CCL2 acted as an autocrine growth factor for melanoma cells, stimulating the proliferation and resistance to apoptosis. In patients, CCL2 is detected in melanoma cells in tumors and in plasma at levels that correlate with tumor burden and lactate dehydrogenase. Vemurafenib treatment increased the CCL2 levels in plasma, whereas the long-term clinical response was associated with low CCL2 levels.Increased CCL2 production was associated with miRNA deregulation in the resistant cells. miR-34a, miR-100 and miR-125b showed high expression in both resistant cells and in tumor biopsies that were obtained from treated patients, and they were involved in the control of cell proliferation and apoptosis. Inhibition of CCL2 and of the selected miRNAs restored both the cell apoptosis and the drug efficacy in resistant melanoma cells. Therefore, CCL2 and miRNAs are potential prognostic factors and attractive targets for counteracting treatment resistance in metastatic melanoma.
- Subjects :
- Adult
Aged
Blotting, Western
Case-Control Studies
Chemokine CCL2 genetics
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Male
Melanoma drug therapy
Melanoma metabolism
Melanoma pathology
Middle Aged
Neoplasm Staging
Prognosis
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
Tumor Cells, Cultured
Vemurafenib
Chemokine CCL2 metabolism
Drug Resistance, Neoplasm genetics
Indoles pharmacology
Melanoma genetics
MicroRNAs genetics
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26684239
- Full Text :
- https://doi.org/10.18632/oncotarget.6599