title: Low-concentration vemurafenib induces the proliferation and invasion of human HaCaT keratinocytes through mitogen-activated protein kinase pathway activation.
abstract: Cutaneous squamous cell carcinomas and keratoacanthomas commonly occur in patients treated with BRAF inhibitors. We investigated the effect of the BRAF inhibitor vemurafenib on normal immortalized human HaCaT keratinocytes to explore the mechanism of hyperproliferative cutaneous neoplasia associated with the use of BRAF inhibitors. Vemurafenib induced an increase in viable cell number in BRAF wild-type cell lines (SK-MEL-2 and HaCaT) but not in BRAF mutant cell lines (SK-MEL-24 and G361). In HaCaT keratinocytes, a low concentration (2 μmol/L) of vemurafenib increased cell proliferation and activated mitogen-activated protein kinase kinase/extracellular signal-regulated kinase in a CRAF-dependent manner. Invasiveness of HaCaT cells in a Matrigel assay significantly increased upon cultivation of cells with 2 μmol/L vemurafenib for 24 h. Gelatin zymography, reverse transcription polymerase chain reaction and western blot results revealed that 2 μmol/L vemurafenib treatment increased matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities in HaCaT cells. These results offer additional insight into the complex mechanism of paradoxical mitogen-activated protein kinase signaling involved in hyperproliferative cutaneous neoplasias that arise after BRAF inhibition and suggest a possible role for MMP in tumor progression and invasion.
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.|Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mi Ryung
authors.initials: MR
authors.lastname: Roh
authors.affiliation: Songdam Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sang Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hong Sun
authors.initials: HS
authors.lastname: Jang
authors.affiliation: Songdam Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyu Hyun
authors.initials: KH
authors.lastname: Park
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kee Yang
authors.initials: KY
authors.lastname: Chung
authors.affiliation: Songdam Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.|Department of International Medicine, Yonsei University College of Medicine, Seoul, Korea.|Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy; D013449:Sulfonamides / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: human HaCaT keratinocyte; matrix metalloproteinase; mitogen-activated protein kinase pathway; squamous cell carcinoma; vemurafenib