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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
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 processe...
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Published in: | Cellular and molecular life sciences : CMLS 2020-10, Vol.77 (20), p.4093-4115 |
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creator | Arasu, Uma Thanigai Deen, Ashik Jawahar Pasonen-Seppänen, Sanna Heikkinen, Sami Lalowski, Maciej Kärnä, Riikka Härkönen, Kai Mäkinen, Petri Lázaro-Ibáñez, Elisa Siljander, Pia R-M Oikari, Sanna Levonen, Anna-Liisa Rilla, Kirsi |
description | 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. |
doi_str_mv | 10.1007/s00018-019-03399-5 |
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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.</description><identifier>ISSN: 1420-682X</identifier><identifier>EISSN: 1420-9071</identifier><identifier>DOI: 10.1007/s00018-019-03399-5</identifier><identifier>PMID: 31820036</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; c-Myc protein ; Cancer ; CD44 antigen ; Cell Biology ; Cell interactions ; Cell Line ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - genetics ; Cell signaling ; Communication ; Epithelial-Mesenchymal Transition - genetics ; Extracellular vesicles ; Extracellular Vesicles - genetics ; Hedgehog protein ; Hedgehog Proteins - genetics ; Humans ; Hyaluronan Receptors - genetics ; Hyaluronan synthase ; Hyaluronan Synthases - genetics ; Hyaluronic acid ; Keratinocytes ; Kinases ; Life Sciences ; Melanoma ; Melanoma - genetics ; Mesenchyme ; Metastases ; Myc protein ; Original ; Original Article ; Proto-Oncogene Proteins c-myc - genetics ; Signal transduction ; Signal Transduction - genetics ; Signaling ; Up-Regulation - genetics ; Vesicles</subject><ispartof>Cellular and molecular life sciences : CMLS, 2020-10, Vol.77 (20), p.4093-4115</ispartof><rights>The Author(s) 2019</rights><rights>The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-ad454b7377cdfdcf4f16159e693009d7afe43c40923003e6601313a9ddedcaef3</citedby><cites>FETCH-LOGICAL-c474t-ad454b7377cdfdcf4f16159e693009d7afe43c40923003e6601313a9ddedcaef3</cites><orcidid>0000-0002-5211-1007</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532973/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532973/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31820036$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arasu, Uma Thanigai</creatorcontrib><creatorcontrib>Deen, Ashik Jawahar</creatorcontrib><creatorcontrib>Pasonen-Seppänen, Sanna</creatorcontrib><creatorcontrib>Heikkinen, Sami</creatorcontrib><creatorcontrib>Lalowski, Maciej</creatorcontrib><creatorcontrib>Kärnä, Riikka</creatorcontrib><creatorcontrib>Härkönen, Kai</creatorcontrib><creatorcontrib>Mäkinen, Petri</creatorcontrib><creatorcontrib>Lázaro-Ibáñez, Elisa</creatorcontrib><creatorcontrib>Siljander, Pia R-M</creatorcontrib><creatorcontrib>Oikari, Sanna</creatorcontrib><creatorcontrib>Levonen, Anna-Liisa</creatorcontrib><creatorcontrib>Rilla, Kirsi</creatorcontrib><title>HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell. Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>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.</description><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>c-Myc protein</subject><subject>Cancer</subject><subject>CD44 antigen</subject><subject>Cell Biology</subject><subject>Cell interactions</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - genetics</subject><subject>Cell signaling</subject><subject>Communication</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Extracellular vesicles</subject><subject>Extracellular Vesicles - genetics</subject><subject>Hedgehog protein</subject><subject>Hedgehog Proteins - genetics</subject><subject>Humans</subject><subject>Hyaluronan Receptors - genetics</subject><subject>Hyaluronan synthase</subject><subject>Hyaluronan Synthases - genetics</subject><subject>Hyaluronic acid</subject><subject>Keratinocytes</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Melanoma</subject><subject>Melanoma - genetics</subject><subject>Mesenchyme</subject><subject>Metastases</subject><subject>Myc protein</subject><subject>Original</subject><subject>Original Article</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Signaling</subject><subject>Up-Regulation - 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extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells</title><author>Arasu, Uma Thanigai ; Deen, Ashik Jawahar ; Pasonen-Seppänen, Sanna ; Heikkinen, Sami ; Lalowski, Maciej ; Kärnä, Riikka ; Härkönen, Kai ; Mäkinen, Petri ; Lázaro-Ibáñez, Elisa ; Siljander, Pia R-M ; Oikari, Sanna ; Levonen, Anna-Liisa ; Rilla, Kirsi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-ad454b7377cdfdcf4f16159e693009d7afe43c40923003e6601313a9ddedcaef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>c-Myc protein</topic><topic>Cancer</topic><topic>CD44 antigen</topic><topic>Cell Biology</topic><topic>Cell interactions</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell 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Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>77</volume><issue>20</issue><spage>4093</spage><epage>4115</epage><pages>4093-4115</pages><issn>1420-682X</issn><eissn>1420-9071</eissn><abstract>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.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>31820036</pmid><doi>10.1007/s00018-019-03399-5</doi><tpages>23</tpages><orcidid>https://orcid.org/0000-0002-5211-1007</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Biochemistry Biomedical and Life Sciences Biomedicine c-Myc protein Cancer CD44 antigen Cell Biology Cell interactions Cell Line Cell Line, Tumor Cell proliferation Cell Proliferation - genetics Cell signaling Communication Epithelial-Mesenchymal Transition - genetics Extracellular vesicles Extracellular Vesicles - genetics Hedgehog protein Hedgehog Proteins - genetics Humans Hyaluronan Receptors - genetics Hyaluronan synthase Hyaluronan Synthases - genetics Hyaluronic acid Keratinocytes Kinases Life Sciences Melanoma Melanoma - genetics Mesenchyme Metastases Myc protein Original Original Article Proto-Oncogene Proteins c-myc - genetics Signal transduction Signal Transduction - genetics Signaling Up-Regulation - genetics Vesicles |
title | HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells |
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