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Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b
- Source :
- Oncotarget
- Publication Year :
- 2015
-
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 :
- 0301 basic medicine
Male
Indoles
medicine.medical_treatment
Drug resistance
Tumor Cells, Cultured
Medicine
Vemurafenib
Chemokine CCL2
Sulfonamides
Reverse Transcriptase Polymerase Chain Reaction
Melanoma
Middle Aged
Prognosis
Gene Expression Regulation, Neoplastic
Survival Rate
Cytokine
Oncology
miRNAs
Female
MiRNA
CCL2
medicine.drug
Research Paper
Adult
BRAF inhibitor
Blotting, Western
Real-Time Polymerase Chain Reaction
03 medical and health sciences
microRNA
melanoma
Humans
RNA, Messenger
Aged
Neoplasm Staging
drug resistance
business.industry
Cell growth
Gene Expression Profiling
medicine.disease
MicroRNAs
030104 developmental biology
Apoptosis
Tumor progression
Drug Resistance, Neoplasm
Case-Control Studies
Immunology
Cancer research
business
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 7
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....811599effb4e7e0a40f954bb47c56772