title: Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity.
abstract: Immunoevasion 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.
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China. Center for Cancer Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Phyllis F Y
authors.initials: PF
authors.lastname: Cheung
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China. Center for Cancer Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Yip
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Nicholas C L
authors.initials: NC
authors.lastname: Wong
authors.affiliation: School of Nursing, The University of Hong Kong, Hong Kong, China.
authors.forename: Daniel Y T
authors.initials: DY
authors.lastname: Fong
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Linda W C
authors.initials: LW
authors.lastname: Ng
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Angus M Y
authors.initials: AM
authors.lastname: Wan
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
authors.forename: Chun Kwok
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China. Department of Surgery, Queen Mary Hospital, Hong Kong, China.
authors.forename: Tan To
authors.initials: TT
authors.lastname: Cheung
authors.affiliation: Center for Cancer Research, The University of Hong Kong, Hong Kong, China. Department of Pathology, The University of Hong Kong, Hong Kong, China. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Irene O L
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China. Center for Cancer Research, The University of Hong Kong, Hong Kong, China. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China. Center for Cancer Research, The University of Hong Kong, Hong Kong, China. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China. Center for Cancer Research, The University of Hong Kong, Hong Kong, China. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China. stcheung@hku.hk.
authors.forename: Siu Tim
authors.initials: ST
authors.lastname: Cheung
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D000077153:Progranulins; D000097625:HLA-E Antigens
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D020782:Matrix Metalloproteinases; D000077153:Progranulins; D000097625:HLA-E Antigens; C099187:MHC class I-related chain A