title: Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs.
abstract: Exosomes are increasingly recognized as important mediators of cell-cell communication in cancer progression through the horizontal transfer of RNAs and proteins to neighboring or distant cells. Hepatocellular carcinoma (HCC) is a highly malignant cancer, whose metastasis is largely influenced by the tumor microenvironment. The possible role of exosomes in the interactions between HCC tumor cell and its surrounding hepatic milieu are however largely unknown. In this study, we comprehensively characterized the exosomal RNA and proteome contents derived from three HCC cell lines (HKCI-C3, HKCI-8 and MHCC97L) and an immortalized hepatocyte line (MIHA) using Ion Torrent sequencing and mass spectrometry, respectively. RNA deep sequencing and proteomic analysis revealed exosomes derived from metastatic HCC cell lines carried a large number of protumorigenic RNAs and proteins, such as MET protooncogene, S100 family members and the caveolins. Of interest, we found that exosomes from motile HCC cell lines could significantly enhance the migratory and invasive abilities of non-motile MIHA cell. We further demonstrated that uptake of these shuttled molecules could trigger PI3K/AKT and MAPK signaling pathways in MIHA with increased secretion of active MMP-2 and MMP-9. Our study showed for the first time that HCC-derived exosomes could mobilize normal hepatocyte, which may have implication in facilitating the protrusive activity of HCC cells through liver parenchyma during the process of metastasis.
authors.affiliation: Department of Anatomical and Cellular Pathology and.
authors.forename: Mian
authors.initials: M
authors.lastname: He
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Qin
authors.affiliation: Pilot Laboratory and Proteomics Core, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China and.
authors.forename: Terence C W
authors.initials: TC
authors.lastname: Poon
authors.affiliation: Department of Anatomical and Cellular Pathology and.
authors.forename: Siu-Ching
authors.initials: SC
authors.lastname: Sze
authors.affiliation: Department of Anatomical and Cellular Pathology and.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Anatomical and Cellular Pathology and.
authors.forename: Ngai Na
authors.initials: NN
authors.lastname: Co
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Sai-Ming
authors.initials: SM
authors.lastname: Ngai
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Ting-Fung
authors.initials: TF
authors.lastname: Chan
authors.affiliation: Department of Anatomical and Cellular Pathology and State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China natwong@cuhk.eud.hk.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000096:biosynthesis / Q000235:genetics; D051243:Caveolin 2 / Q000096:biosynthesis / Q000235:genetics; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics; D017423:Sequence Analysis, RNA; D059016:Tumor Microenvironment
chemical_list: C495540:CAV1 protein, human; C495544:CAV2 protein, human; D051242:Caveolin 1; D051243:Caveolin 2; D034741:RNA, Small Interfering; D009418:S100 Proteins; D012313:RNA; D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9