Soluble MICA and a MICA Variation as Possible Prognostic Biomarkers for HBV-Induced Hepatocellular Carcinoma

Kumar, Vinod; Lo, Paulisally Hau Yi; Sawai, Hiromi; Kato, Naoya; Takahashi, Atsushi; Deng, Zhenzhong; Urabe, Yuji; Mbarek, Hamdi; Tokunaga, Katsushi; Tanaka, Yasuhito; Sugiyama, Masaya; Mizokami, Masashi; Muroyama, Ryosuke; Tateishi, Ryosuke; Omata, Masao; Koike, Kazuhiko; Tanikawa, Chizu; Kamatani, Naoyuki; Kubo, Michiaki; Nakamura, Yusuke; Matsuda, Koichi

doi:10.1371/journal.pone.0044743

Cited by 80 publications

(97 citation statements)

References 38 publications

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“…We observed that serum GEP levels significantly correlated with tumor size (Supplementary Table S1; Spearman r correlation coefficient ¼ 0.569; P < 0.001). A previous study has reported serum MICA levels as a potential prognostic marker for HCC (27). Here, we showed that patients with high levels of serum GEP or MICA trended toward poor recurrence-free survival, though statistical significance had not been reached with single molecule (Supplementary Fig.…”

Section: Association Of Serum Gep and Mica Levels With Clinicopatholomentioning

confidence: 62%

“…sMICA levels were frequently elevated in patients with advanced HCC (3,27,(30)(31)(32), and such elevation was associated with downregulated NKG2D expression and impaired NK activity in HCC (3). sMICA was reported as predictive and prognostic marker in hepatitis B virus (HBV)-induced HCC and advanced HCC (27,30).…”

Section: Discussionmentioning

confidence: 99%

“…sMICA was reported as predictive and prognostic marker in hepatitis B virus (HBV)-induced HCC and advanced HCC (27,30). To investigate the potential of sGEP and sMICA as predictive or prognosis markers for HCC, we determined the association of sGEP and sMICA levels with clinicopathologic parameters in patients with HCC (n ¼ 80).…”

Section: Discussionmentioning

confidence: 99%

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Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

Cheung

Yip

Wong

et al. 2014

Cancer Immunology Research

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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 ¼ 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P ¼ 0.089) expression was observed when compared with those in nontumor (n ¼ 80) and normal livers (n ¼ 10). Serum GEP (P ¼ 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n ¼ 80) than in healthy individuals (n ¼ 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P ¼ 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.

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Section: Association Of Serum Gep and Mica Levels With Clinicopatholomentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

Cheung

Yip

Wong

et al. 2014

Cancer Immunology Research

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“…Survival analysis also showed that higher sMICA levels were related with poor prognosis in HCC patients, and sMICA is regarded as a predictive biomarker for HBV-induced HCC. 96,97 Significantly higher levels of sMICA/B were also observed in patients with chronic liver disease compared with healthy volunteers. 98 Reduced expression of another NKG2D ligand, ULBP1, has also been observed in HCC, and soluble ULBP1 prevented effective NKG2D-mediated killing and led to early recurrence of HCC after hepatectomy.…”

Section: Soluble Ligands Of Nkg2dmentioning

confidence: 99%

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono-and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC. Keywords: activating receptor; hepatocellular carcinoma; inhibitory receptor; natural killer cell; natural killer receptor INTRODUCTION Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. 1 Common clinical risk factors for HCC include hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, heavy alcohol intake, steatohepatitis and diabetes. 2 Approximately 50% of HCC cases worldwide can be attributed to chronic HBV infection (CHB) and almost 75% of HCC cases occur in developing countries where HBV is endemic. 3,4 According to statistics, older male patients who are infected with HBV genotype C or co-infected with HCV, have high levels of viral load and have been exposed to the aflatoxin, or older male patients who have a family history of HCC tend to have a high risk of developing HCC. [5][6][7] Accumulating clinical and epidemiological evidence shows a significant correlation between chronic HBV infection and hepatocarcinogenesis. However, the underlying mechanisms

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“…There is an association of MICA rs2596542G/A promoter variant and substitutions MICA129Met/Val, MICA-251Gln/Arg, MICA175Gly/Ser with HBV-induced hepatocellular carcinoma and HBV persistence (Kumar V, 2012). Disease Hepatitis B and C are viral infections that can chronically predispose to hepatocellular carcinoma.…”

Section: Notementioning

confidence: 99%

MICA (MHC class I polypeptide-related sequence A)

Ahmed¹,

Askar²

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Human Major Histocompatibility Complex (MHC) Class I Chain-Related gene A (MICA) is located 46 Kb centromeric to the HLA-B locus on the short arm of human chromosome 6 and encodes for a 62-kda cell surface glycoprotein. It is expressed on endothelial cells, dendritic cells, fibroblasts, epithelial cells, and many tumours and serves as target for both cellular and humoral immune responses in transformed cells. MICA protein at normal states has a low level of expression in epithelial tissues but is upregulated in response to various stimuli of cellular stress. MICA also functions as a ligand recognized by the activating receptor NKG2D that is expressed on the surface of NK, NKT, CD8+ and TCRγδ+ T cells. Allelic variants of MICA due to a single amino acid substitution at position 129 in the α2 domain have been reported to result in large differences in NKG2D binding. These variable affinities have been suggested to affect thresholds of NK cell triggering and T cell modulation in autoimmune diseases and malignancies. MICA molecules exist also in soluble forms (sMICA) and altered serum levels of sMICA have been reported in multiple states of health and disease.

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Soluble MICA and a MICA Variation as Possible Prognostic Biomarkers for HBV-Induced Hepatocellular Carcinoma

Cited by 80 publications

References 38 publications

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

MICA (MHC class I polypeptide-related sequence A)

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