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HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells.

  • Arasu, Uma Thanigai1
  • Deen, Ashik Jawahar2
  • Pasonen-Seppänen, Sanna3
  • Heikkinen, Sami3, 4
  • Lalowski, Maciej5
  • Kärnä, Riikka3
  • Härkönen, Kai3
  • Mäkinen, Petri2
  • Lázaro-Ibáñez, Elisa6
  • Siljander, Pia R-M6, 7
  • Oikari, Sanna3
  • Levonen, Anna-Liisa2
  • Rilla, Kirsi3
  • 1 Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. [email protected] , (Finland)
  • 2 A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. , (Finland)
  • 3 Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. , (Finland)
  • 4 Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. , (Finland)
  • 5 Faculty of Medicine, Biochemistry and Developmental Biology, Meilahti Clinical Proteomics Core Facility, HiLIFE, University of Helsinki, Helsinki, Finland. , (Finland)
  • 6 Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, Helsinki, Finland. , (Finland)
  • 7 EV Group and EV Core, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland. , (Finland)
Published Article
Cellular and Molecular Life Sciences
Publication Date
Oct 01, 2020
DOI: 10.1007/s00018-019-03399-5
PMID: 31820036


Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.

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