1. Loss of SR-BI Down-Regulates MITF and Suppresses Extracellular Vesicle Release in Human Melanoma.
- Author
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Kinslechner K, Schütz B, Pistek M, Rapolter P, Weitzenböck HP, Hundsberger H, Mikulits W, Grillari J, Röhrl C, Hengstschläger M, Stangl H, and Mikula M
- Subjects
- Cell Line, Tumor, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Melanoma genetics, Microphthalmia-Associated Transcription Factor metabolism, Proto-Oncogene Mas, Scavenger Receptors, Class B metabolism, Synaptosomal-Associated Protein 25 genetics, Synaptosomal-Associated Protein 25 metabolism, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, rab GTP-Binding Proteins genetics, rab GTP-Binding Proteins metabolism, Extracellular Vesicles metabolism, Melanoma metabolism, Microphthalmia-Associated Transcription Factor genetics, Scavenger Receptors, Class B genetics
- Abstract
Melanoma is a skin tumor with a high tendency for metastasis and thus is one of the deadliest cancers worldwide. Here, we investigated the expression of the scavenger receptor class B type 1 (SR-BI), a high-density lipoprotein (HDL) receptor, and tested for its role in melanoma pigmentation as well as extracellular vesicle release. We first analyzed the expression of SR-BI in patient samples and found a strong correlation with MITF expression as well as with the melanin synthesis pathway. Hence, we asked whether SR-BI could also play a role for the secretory pathway in metastatic melanoma cells. Interestingly, gain- and loss-of-function of SR-BI revealed regulation of the proto-oncogene MET. In line, SR-BI knockdown reduced expression of the small GTPase RABB22A, the ESCRT-II protein VPS25, and SNAP25, a member of the SNARE complex. Accordingly, reduced overall extracellular vesicle generation was detected upon loss of SR-BI. In summary, SR-BI expression in human melanoma enhances the formation and transport of extracellular vesicles, thereby contributing to the metastatic phenotype. Therapeutic targeting of SR-BI would not only interfere with cholesterol uptake, but also with the secretory pathway, therefore suppressing a key hallmark of the metastatic program.
- Published
- 2019
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