CEACAM1 Is Associated With the Suppression of Natural Killer Cell Function in Patients With Chronic Hepatitis C

Suda, Takahiro; Tatsumi, Tomohide; Nishio, Akira; Kegasawa, Tadashi; Yoshioka, Teppei; Yamada, Ryotaro; Furuta, Kunimaro; Kodama, Tatsuhiko; Shigekawa, Minoru; Sakamori, Ryotaro; Fukuhara, Takasuke; Matsuura, Yoshiharu; Takehara, Tetsuo

doi:10.1002/hep4.1240

Cited by 12 publications

(18 citation statements)

References 30 publications

(55 reference statements)

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“…Similar results were presented in a recent report in which the authors demonstrated that levels of CEACAM1 on the cell surface, levels of CEACAM1 mRNA, and levels of soluble CEACAM1 in supernatants were significantly higher in Huh7.5.1 cells infected with HCV than in uninfected Huh7.5.1 cells. 26 Furthermore, patients with CHC were shown to have higher serum CEACAM1 levels in comparison with healthy individuals. 26 These findings are corroborated in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…26 Furthermore, patients with CHC were shown to have higher serum CEACAM1 levels in comparison with healthy individuals. 26 These findings are corroborated in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…25 ELISA for CEACAM1 protein in patients' sera was performed as previously described. 26 Cell culture Huh-7, HepG2, K562, and Hepa1-6 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM; Invitrogen, Carlsbad, CA, USA) with 10% fetal bovine serum (Invitrogen), 100 µg/mL penicillin, and 0.25 µg/mL streptomycin (Invitrogen). Hep3B cells were grown in minimum essential medium (MEM; Invitrogen, Carlsbad, CA, USA) with 10% fetal bovine serum (Invitrogen), 100 µg/mL penicillin, and 0.25 µg/mL streptomycin (Invitrogen).…”

Section: Patient Samples and Clinical Informationmentioning

confidence: 99%

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EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

Park

Sung

Kim

et al. 2020

J Immunother Cancer

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BackgroundNatural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhighCSCs in HCC.MethodsEpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhighand EpCAMlowHuh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice.ResultsThe frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhighHCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhighHuh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1highcells. In mouse experiments with Hepa1–6 cells, EpCAMhighHepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+HCC.ConclusionOur data demonstrated that EpCAMhighliver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.

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Section: Discussionmentioning

confidence: 99%

“…26 Furthermore, patients with CHC were shown to have higher serum CEACAM1 levels in comparison with healthy individuals. 26 These findings are corroborated in the current study.…”

Section: Discussionmentioning

confidence: 99%

Section: Patient Samples and Clinical Informationmentioning

confidence: 99%

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EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

Park

Sung

Kim

et al. 2020

J Immunother Cancer

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“…In addition, carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein that belongs to the CEA family of highly glycosylated cellular adhesion molecules, and is implicated in hepatocyte differentiation and liver regeneration . It has been reported that CEACAM1 was involved in the progression of hepatocellular carcinoma and chronic hepatitis C . Nevertheless, roles of miR‐30b, miR‐30d, and CEACAM1 in FHF have not been revealed prior to this study.…”

Section: Introductionmentioning

confidence: 87%

Up‐regulation of microRNA‐30b/30d cluster represses hepatocyte apoptosis in mice with fulminant hepatic failure by inhibiting CEACAM1

et al. 2020

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Recently, impacts of microRNAs have been unraveled in human diseases, and we aimed to confirm the role of miR‐30b/30d in fulminant hepatic failure (FHF). Expression of miR‐30b/30d and CEACAM1 in serum of FHF patients and healthy people was measured by reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and Western blot analysis. Mice FHF models were established by injection of D‐Galn and lipopolysaccharide, and were treated with miR‐30b/30d mimics. Oxidative stress, liver injury, and inflammatory reaction in mouse liver tissues were measured using oxidative stress‐related factor kits, hematoxylin–eosin staining and enzyme‐linked immunosorbent assay, respectively. Moreover, cell cycle distribution and apoptosis of hepatocytes of mice were determined by flow cytometry, and the target relation between miR‐30b/30d and CEACAM1 was confirmed by bioinformatic method and dual luciferase reporter gene assay. MiR‐30b/30d expression was positively, and CEACAM1 expression was negatively related to prognosis of FHF patients. Up‐regulation of miR‐30b/30d attenuated oxidative stress, liver injury, and inflammatory reaction, and improved survival rate of FHF mice. Furthermore, elevated miR‐30b/30d ameliorated apoptosis and cell cycle arrest of hepatocytes of FHF mice. CEACAM1 was a target gene of miR‐30b/30d. This study highlights that up‐regulated miR‐30b/30d attenuates the progression of FHF by targeting CEACAM1, which may be helpful to FHF treatment.

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“…The HCV core protein stimulates NK cells to increase release of IFN-γ, which in turn results in increased PD-1 expression that is associated with diminished NK cell responsiveness, and higher viral loads [93,94]. Levels of other inhibitory factors, including CEACAM-1/CD66a and CD81 are similarly elevated in persons chronically infected with HCV [95,96,97]. These molecules, in turn, support viral persistence and progression of infection to hepatocellular carcinoma [95,98].…”

Section: Resetting the Balance To Favor Inhibition Over Activationmentioning

confidence: 99%

The Evolutionary Arms Race between Virus and NK Cells: Diversity Enables Population-Level Virus Control

Savoy

Boudreau

2019

Viruses

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Viruses and natural killer (NK) cells have a long co-evolutionary history, evidenced by patterns of specific NK gene frequencies in those susceptible or resistant to infections. The killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) ligands together form the most polymorphic receptor-ligand partnership in the human genome and govern the process of NK cell education. The KIR and HLA genes segregate independently, thus creating an array of reactive potentials within and between the NK cell repertoires of individuals. In this review, we discuss the interplay between NK cell education and adaptation with virus infection, with a special focus on three viruses for which the NK cell response is often studied: human immunodeficiency virus (HIV), hepatitis C virus (HCV) and human cytomegalovirus (HCMV). Through this lens, we highlight the complex co-evolution of viruses and NK cells, and their impact on viral control.

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CEACAM1 Is Associated With the Suppression of Natural Killer Cell Function in Patients With Chronic Hepatitis C

Cited by 12 publications

References 30 publications

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

Up‐regulation of microRNA‐30b/30d cluster represses hepatocyte apoptosis in mice with fulminant hepatic failure by inhibiting CEACAM1

The Evolutionary Arms Race between Virus and NK Cells: Diversity Enables Population-Level Virus Control

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