Immunoevasion is an emerging hallmark of cancers. Impairment of natural killer (NK) cytotoxicity is one of the mechanisms that evade host immunosurveillance. Granulin-epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion and chemoresistance in hepatocellular carcinoma (HCC). Here, we examined the role of GEP in conferring HCC cells ability to evade NK cytotoxicty. In cell line models, GEP over-expression reduced, while suppression enhanced, NK cytotoxicity against HCC cells. GEP down-regulated surface expression of MHC class I chain-related molecule A (MICA), ligand for NK stimulatory receptor natural killer group 2 member D; while up-regulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. MMP2 and MMP9 activities were shown to be 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) expressions were observed when compared to non-tumors (n=80) and normal livers (n=10). Serum GEP (p=0.010) and MICA (p<0.001) levels were higher in HCC patients (n=80) than healthy individuals (n=30). Patients with high serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, p=0.042). Importantly, GEP blockage by monoclonal antibody 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 blockage using antibody. Serum GEP and MICA levels provided prognostic information and could stratify patients for targeted therapy.
- Received May 15, 2014.
- Revision received September 10, 2014.
- Accepted September 27, 2014.
- Copyright © 2014, American Association for Cancer Research.