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( Mi Ryung Roh ),( Jung Min Kim ),( Sang Hee Lee ),( Hong Sun Jang ),( Kyu Hyun Park ),( Kee Yang Chung ),( Sun Young Rha ) 대한피부과학회 2014 대한피부과학회 학술발표대회집 Vol.66 No.2
Background: Cutaneous squamous cell carcinomas and keratoacanthomas commonly occur in patients treated with BRAF inhibitors. Objectives: We investigated the effect of BRAF inhibitor vemurafenib on normal immortalized human HaCaT keratinocytes to explore the mechanism of hyperproliferative cutaneous neoplasia associated with the use of BRAF inhibitors. Methods: Human Melanoma cell lines SK-MEL-24(BRAF V600E mutation), G361(BRAF V600E mutation), SK-MEL-2(NRAS Q61R mutation) and HaCaT were cultured. Cell viability assay, immunoblotting, proliferation assay, Matrigel transwell assay, and gelatin zymography was performed to evaluate the effect of vemurafenib on the cell lines. Results: Vemurafenib induced an increase in viable cell number in BRAF wild-type cell lines but not in BRAF mutant cell lines. In HaCaT keratinocytes, a low concentration(2μM) of vemurafenib increased cell proliferation and activated MEK/ERK in a CRAF-dependent manner. Invasiveness of HaCaT cells in a Matrigel assay significantly increased upon cultivation of cells with 2μM vemurafenib for 24h. Gelatin zymography revealed that 2μM vemurafenib increased activated MMP-2 expression in both cytosol and conditioned media while MMP-9 expression increased in cytosol. Conclusion: These results offer additional insight into the complex mechanism of paradoxical MAPK signaling involved in hyperproliferative cutaneous neoplasia that arise after BRAF inhibition and suggest a possible role for MMPs in tumor progression and invasion.