File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity

TitleGranulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity
Authors
Issue Date2014
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerimmunolres.aacrjournals.org/
Citation
Cancer Immunology Research, 2014, v. 2 n. 12, p. 1209-1219 How to Cite?
AbstractImmunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin–epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain–related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n = 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P = 0.089) expression was observed when compared with those in nontumor (n = 80) and normal livers (n = 10). Serum GEP (P = 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n = 80) than in healthy individuals (n = 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P = 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy. Cancer Immunol Res; 2(12); 1209–19. ©2014 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/207315
ISSN
2015 Impact Factor: 6.665
2015 SCImago Journal Rankings: 3.648
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorCheung, PFY-
dc.contributor.authorYip, CW-
dc.contributor.authorWong, NCL-
dc.contributor.authorFong, DYT-
dc.contributor.authorNg, LWC-
dc.contributor.authorWan, AMY-
dc.contributor.authorWong, CK-
dc.contributor.authorCheung, TT-
dc.contributor.authorNg, IOL-
dc.contributor.authorPoon, RTP-
dc.contributor.authorFan, ST-
dc.contributor.authorCheung, ST-
dc.date.accessioned2014-12-19T10:20:50Z-
dc.date.available2014-12-19T10:20:50Z-
dc.date.issued2014-
dc.identifier.citationCancer Immunology Research, 2014, v. 2 n. 12, p. 1209-1219-
dc.identifier.issn2326-6066-
dc.identifier.urihttp://hdl.handle.net/10722/207315-
dc.description.abstractImmunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin–epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain–related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n = 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P = 0.089) expression was observed when compared with those in nontumor (n = 80) and normal livers (n = 10). Serum GEP (P = 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n = 80) than in healthy individuals (n = 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P = 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy. Cancer Immunol Res; 2(12); 1209–19. ©2014 AACR.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerimmunolres.aacrjournals.org/-
dc.relation.ispartofCancer Immunology Research-
dc.titleGranulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity-
dc.typeArticle-
dc.identifier.emailCheung, PFY: cphyllis@hkucc.hku.hk-
dc.identifier.emailYip, CW: wallacey@hku.hk-
dc.identifier.emailWong, NCL: h0894166@connect.hku.hk-
dc.identifier.emailFong, DYT: dytfong@hku.hk-
dc.identifier.emailNg, LWC: lindanwc@hku.hk-
dc.identifier.emailWan, AMY: anguswan@hku.hk-
dc.identifier.emailCheung, TT: cheung68@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailPoon, RTP: poontp@hku.hk-
dc.identifier.emailFan, ST: stfan@hku.hk-
dc.identifier.emailCheung, ST: stcheung@hkucc.hku.hk-
dc.identifier.authorityFong, DYT=rp00253-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityPoon, RTP=rp00446-
dc.identifier.authorityFan, ST=rp00355-
dc.identifier.authorityCheung, ST=rp00457-
dc.identifier.doi10.1158/2326-6066.CIR-14-0096-
dc.identifier.pmid25315249-
dc.identifier.scopuseid_2-s2.0-84937511490-
dc.identifier.hkuros241970-
dc.identifier.volume2-
dc.identifier.issue12-
dc.identifier.spage1209-
dc.identifier.epage1219-
dc.identifier.isiWOS:000346135500010-
dc.publisher.placeUnited States-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats