Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma
Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with the liver fluke is a major risk factor for cholangiocarcinoma (CCA). The liver fluke Opisthorchis viverrini secretes a growth factor termed liver fluke granulin, a homologue of the human progr...
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Format: | Article |
Language: | English |
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Elsevier
2020-05-01
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Series: | Neoplasia: An International Journal for Oncology Research |
Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558620300221 |
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doaj-3799a2516bc54006934f1b0afa1bd439 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patpicha Arunsan Apisit Chaidee Christina J. Cochran Victoria H. Mann Toshihiko Tanno Chutima Kumkhaek Michael J. Smout Shannon E. Karinshak Rutchanee Rodpai Javier Sotillo Alex Loukas Thewarach Laha Paul J. Brindley Wannaporn Ittiprasert |
spellingShingle |
Patpicha Arunsan Apisit Chaidee Christina J. Cochran Victoria H. Mann Toshihiko Tanno Chutima Kumkhaek Michael J. Smout Shannon E. Karinshak Rutchanee Rodpai Javier Sotillo Alex Loukas Thewarach Laha Paul J. Brindley Wannaporn Ittiprasert Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma Neoplasia: An International Journal for Oncology Research |
author_facet |
Patpicha Arunsan Apisit Chaidee Christina J. Cochran Victoria H. Mann Toshihiko Tanno Chutima Kumkhaek Michael J. Smout Shannon E. Karinshak Rutchanee Rodpai Javier Sotillo Alex Loukas Thewarach Laha Paul J. Brindley Wannaporn Ittiprasert |
author_sort |
Patpicha Arunsan |
title |
Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma |
title_short |
Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma |
title_full |
Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma |
title_fullStr |
Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma |
title_full_unstemmed |
Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma |
title_sort |
liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 |
publishDate |
2020-05-01 |
description |
Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with the liver fluke is a major risk factor for cholangiocarcinoma (CCA). The liver fluke Opisthorchis viverrini secretes a growth factor termed liver fluke granulin, a homologue of the human progranulin, which contributes significantly to biliary tract fibrosis and morbidity. Here, extracellular vesicle (EV)-mediated transfer of mRNAs from human cholangiocytes to naïve recipient cells was investigated following exposure to liver fluke granulin. To minimize the influence of endogenous progranulin, its cognate gene was inactivated using CRISPR/Cas9-based gene knock-out. Several progranulin-depleted cell lines, termed ΔhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of specific transcript and progranulin, both in gene-edited cells and within EVs released by these cells. Profiles of extracellular vesicle RNAs (evRNA) from ΔhuPGRN-H69 for CCA-associated characteristics revealed a paucity of transcripts for estrogen- and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific evRNAs including MAPK/AKT pathway members were induced by exposure to liver fluke granulin. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 cells exposed to liver fluke granulin. Of these, CCA-associated evRNAs modified the CCA microenvironment in naïve cells co-cultured with EVs from ΔhuPGRN-H69 cells exposed to liver fluke granulin, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells in comparison with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCA-conducive disposition. Keywords: Opisthorchis viverrini, Liver fluke granulin, Extracellular vesicle, Cellular crosstalk |
url |
http://www.sciencedirect.com/science/article/pii/S1476558620300221 |
work_keys_str_mv |
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doaj-3799a2516bc54006934f1b0afa1bd4392020-11-25T02:04:16ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862020-05-01225203216Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinomaPatpicha Arunsan0Apisit Chaidee1Christina J. Cochran2Victoria H. Mann3Toshihiko Tanno4Chutima Kumkhaek5Michael J. Smout6Shannon E. Karinshak7Rutchanee Rodpai8Javier Sotillo9Alex Loukas10Thewarach Laha11Paul J. Brindley12Wannaporn Ittiprasert13Department of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandDepartment of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandDepartment of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USADepartment of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USADepartment of Surgery and the Institute of Human Virology, University of Maryland, Baltimore, MD 21201, USACellular and Molecular Therapeutics Laboratory, National Heart, Lungs and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USACentre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, AustraliaDepartment of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USADepartment of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandCentre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia; Laboratorio de Helmintos, Laboratorio de Referencia e Investigación en Enfermedades Parasitarias, Centro Nacional de Microbiología, Madrid, SpainCentre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, AustraliaDepartment of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandDepartment of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; Corresponding author: George Washington University, 2300 Eye Street NW, Washington, D.C., 20037Department of Microbiology, Immunology & Tropical Medicine, & Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; Corresponding author: George Washington University, 2300 Eye Street NW, Washington, D.C., 20037Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with the liver fluke is a major risk factor for cholangiocarcinoma (CCA). The liver fluke Opisthorchis viverrini secretes a growth factor termed liver fluke granulin, a homologue of the human progranulin, which contributes significantly to biliary tract fibrosis and morbidity. Here, extracellular vesicle (EV)-mediated transfer of mRNAs from human cholangiocytes to naïve recipient cells was investigated following exposure to liver fluke granulin. To minimize the influence of endogenous progranulin, its cognate gene was inactivated using CRISPR/Cas9-based gene knock-out. Several progranulin-depleted cell lines, termed ΔhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of specific transcript and progranulin, both in gene-edited cells and within EVs released by these cells. Profiles of extracellular vesicle RNAs (evRNA) from ΔhuPGRN-H69 for CCA-associated characteristics revealed a paucity of transcripts for estrogen- and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific evRNAs including MAPK/AKT pathway members were induced by exposure to liver fluke granulin. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 cells exposed to liver fluke granulin. Of these, CCA-associated evRNAs modified the CCA microenvironment in naïve cells co-cultured with EVs from ΔhuPGRN-H69 cells exposed to liver fluke granulin, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells in comparison with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCA-conducive disposition. Keywords: Opisthorchis viverrini, Liver fluke granulin, Extracellular vesicle, Cellular crosstalkhttp://www.sciencedirect.com/science/article/pii/S1476558620300221 |