Chemotherapy Supports Cancer Cell Dissemination in a Melanoma Preclinical Model

OBJECTIVE: The aim of the study was to determine how the chemotherapeutic alkylating agent dacarbazine, together with the application of the miR-204-5p mimic in vivo, affects the presence of disseminated melanoma cells in distant organs - the lungs and liver. METHODS: The study was carried out on B16 melanoma-bearing mice (n = 48). The animals were treated with dacarbazine (50 mg/kg) or dacarbazine combined with the microRNA miR-204-5p mimic (5 nM). Real-time PCR was used to evaluate the expression of miR-204-5p target genes following miR-204-5p mimic application. The presence of melanoma cells in distant organs was assessed by immunovisualization of the melanocyte marker PMEL using an immunohistochemical assay and by evaluating the expression of the melanocyte-specific protein tyrosinase via real-time PCR. RESULT: The level of PMEL expression increased twofold in the lungs of mice treated with dacarbazine (p = 0.014) and 4.2-fold in the group of animals treated with a combination of dacarbazine and the miR-204-5p mimic (p = 0.001), as compared to the control group. However, tyrosinase expression was detected in the lungs of B16 melanoma-bearing mice treated with dacarbazine and the negative control only, due to the sporadic presence of melanoma cells in distant organs. CONCLUSION: Taken together, dacarbazine and the miR-204-5p mimic favor the dissemination of B16 melanoma cells in the lungs, which may support further metastatic development. Although miR-204-5p has been described as a tumor-suppressive microRNA in melanoma, the application of a synthetic mimic to overexpress it in distant organs promoted tumor cell dissemination.