Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma.
Animals
Bile Duct Neoplasms
/ genetics
Bile Ducts
/ cytology
Cell Line
Cell Proliferation
/ drug effects
Cell Transformation, Neoplastic
/ pathology
Cholangiocarcinoma
/ genetics
Clustered Regularly Interspaced Short Palindromic Repeats
Extracellular Vesicles
/ metabolism
Gene Expression Regulation, Neoplastic
Granulins
/ metabolism
Mutation
Opisthorchis
/ metabolism
Progranulins
/ genetics
RNA, Messenger
/ metabolism
Tumor Microenvironment
Cellular crosstalk
Extracellular vesicle
Liver fluke granulin
Opisthorchis viverrini
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
16
01
2020
revised:
25
02
2020
accepted:
29
02
2020
pubmed:
4
4
2020
medline:
29
5
2021
entrez:
4
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32244128
pii: S1476-5586(20)30022-1
doi: 10.1016/j.neo.2020.02.004
pmc: PMC7118280
pii:
doi:
Substances chimiques
GRN protein, human
0
Granulins
0
Progranulins
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
203-216Subventions
Organisme : NCI NIH HHS
ID : R01 CA164719
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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