title: Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy.
abstract: Hepatocellular cancer (HCC) is a highly treatment-refractory cancer and is also highly resistant to adverse cellular stress. Although cell behavior can be modulated by noncoding RNAs (ncRNA) within extracellular vesicles (EV), the contributions of long noncoding RNAs (lncRNAs) are largely unknown. To this end, the involvement and functional roles of lncRNAs contained within EVs during chemotherapeutic stress in human HCC were determined. Expression profiling identified a subset of lncRNAs that were enriched in tumor cell-derived vesicles released from two different cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was significantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell-cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, subfamily G member 2), whereas overexpression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an EV-enriched lncRNA that contributes to cellular stress responses.
  
  
  CONCLUSIONS
  These findings provide new insight into the role of EVs and demonstrate the capacity of lncRNAs to mediate chemotherapeutic stress response in HCC.
authors.affiliation: Department of Internal Medicine, Department of Transplantation, and Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Internal Medicine, Department of Transplantation, and Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Irene K
authors.initials: IK
authors.lastname: Yan
authors.affiliation: Department of Internal Medicine, Department of Transplantation, and Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wood
authors.affiliation: Department of Internal Medicine, Department of Transplantation, and Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Haga
authors.affiliation: Department of Internal Medicine, Department of Transplantation, and Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. patel.tushar@mayo.edu.
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; C000599618:linc-VLDLR long noncoding RNA, human