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Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients

SIMPLE SUMMARY: Natural killer (NK) cells normally respond to tumor cells and virally infected cells by killing them via the innate immune system. However, the functional impairment of NK cells has been observed in hepatocellular carcinoma. The NK-cell phenotype is partially mediated through the bin...

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Autores principales: Umemura, Takeji, Joshita, Satoru, Saito, Hiromi, Wakabayashi, Shun-ichi, Kobayashi, Hiroyuki, Yamashita, Yuki, Sugiura, Ayumi, Yamazaki, Tomoo, Ota, Masao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267716/
https://www.ncbi.nlm.nih.gov/pubmed/34209910
http://dx.doi.org/10.3390/cancers13133267
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author Umemura, Takeji
Joshita, Satoru
Saito, Hiromi
Wakabayashi, Shun-ichi
Kobayashi, Hiroyuki
Yamashita, Yuki
Sugiura, Ayumi
Yamazaki, Tomoo
Ota, Masao
author_facet Umemura, Takeji
Joshita, Satoru
Saito, Hiromi
Wakabayashi, Shun-ichi
Kobayashi, Hiroyuki
Yamashita, Yuki
Sugiura, Ayumi
Yamazaki, Tomoo
Ota, Masao
author_sort Umemura, Takeji
collection PubMed
description SIMPLE SUMMARY: Natural killer (NK) cells normally respond to tumor cells and virally infected cells by killing them via the innate immune system. However, the functional impairment of NK cells has been observed in hepatocellular carcinoma. The NK-cell phenotype is partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This study evaluated the involvement of KIR–HLA pairs in hepatocellular carcinoma development in 211 patients with hepatitis C virus-associated cirrhosis. HLA-Bw4 and the KIR3DL1+HLA-Bw4 pair were significantly associated with hepatocellular carcinoma onset during a median follow-up of 6.6 years, which suggested that functional interactions between KIR and HLA or HLA-Bw4 may influence the risk of cancer development. ABSTRACT: Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.
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spelling pubmed-82677162021-07-10 Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients Umemura, Takeji Joshita, Satoru Saito, Hiromi Wakabayashi, Shun-ichi Kobayashi, Hiroyuki Yamashita, Yuki Sugiura, Ayumi Yamazaki, Tomoo Ota, Masao Cancers (Basel) Article SIMPLE SUMMARY: Natural killer (NK) cells normally respond to tumor cells and virally infected cells by killing them via the innate immune system. However, the functional impairment of NK cells has been observed in hepatocellular carcinoma. The NK-cell phenotype is partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This study evaluated the involvement of KIR–HLA pairs in hepatocellular carcinoma development in 211 patients with hepatitis C virus-associated cirrhosis. HLA-Bw4 and the KIR3DL1+HLA-Bw4 pair were significantly associated with hepatocellular carcinoma onset during a median follow-up of 6.6 years, which suggested that functional interactions between KIR and HLA or HLA-Bw4 may influence the risk of cancer development. ABSTRACT: Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset. MDPI 2021-06-29 /pmc/articles/PMC8267716/ /pubmed/34209910 http://dx.doi.org/10.3390/cancers13133267 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Umemura, Takeji
Joshita, Satoru
Saito, Hiromi
Wakabayashi, Shun-ichi
Kobayashi, Hiroyuki
Yamashita, Yuki
Sugiura, Ayumi
Yamazaki, Tomoo
Ota, Masao
Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
title Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
title_full Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
title_fullStr Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
title_full_unstemmed Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
title_short Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
title_sort investigation of the effect of kir–hla pairs on hepatocellular carcinoma in hepatitis c virus cirrhotic patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267716/
https://www.ncbi.nlm.nih.gov/pubmed/34209910
http://dx.doi.org/10.3390/cancers13133267
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