Loss of SR-BI down-regulates MITF and suppresses extracellular vesicle release in human melanoma

Katharina Kinslechner, Birgit Schütz, Martina Pistek, Philipp Rapolter, Hans P. Weitzenböck, Harald Hundsberger, Wolfgang Mikulits, Johannes Grillari, Clemens Röhrl, Markus Hengstschläger, Herbert Stangl, Mario Mikula

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article number1063
JournalInternational Journal of Molecular Sciences
Volume20
Issue number5
DOIs
Publication statusPublished - 1 Mar 2019
Externally publishedYes

Keywords

  • cMET
  • Extracellular vesicles
  • Melanoma metastasis
  • Pigmentation
  • SCARB1
  • Secretory pathway
  • Microphthalmia-Associated Transcription Factor/genetics
  • Down-Regulation
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Extracellular Vesicles/metabolism
  • Scavenger Receptors, Class B/genetics
  • Cell Line, Tumor
  • Melanoma/genetics
  • rab GTP-Binding Proteins/genetics
  • Synaptosomal-Associated Protein 25/genetics
  • Vesicular Transport Proteins/genetics

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