Enzymatic inhibition of MICA sheddase ADAM17 by lomofungin in hepatocellular carcinoma cells

Arai, Jun; Goto, Kaku; Tanoue, Yasushi; Ito, Sayaka; Muroyama, Ryosuke; Matsubara, Yasuo; Nakagawa, Ryo; Kaise, Yoshimi; Lim, Lay Ahyoung; Yoshida, Hitoshi; Kato, Naoya

doi:10.1002/ijc.31615

Cited by 27 publications

(34 citation statements)

References 31 publications

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“…At each time-point, ISG mRNA level was adjusted to the level of the internal control and quantified, as previously described. 16 There was no significant difference in the male/female ratio, age, log HCV RNA in the serum (log/mL), platelet count, and levels of alanine aminotransferase (ALT) and γ-GTP between the patients with HCV genotypes 1 and 2 ( Table 1). The positive rates of HCV RNA in B cells were significantly higher in CH-C patients with G1 than in those with G2 (P < 0.001) [G1, 110/132 (83.3%); G2, 20/40 (50.0%)].…”

Section: Evaluation Of Levels Of the Isg Mrnamentioning

confidence: 91%

Decreased expression of interferon‐stimulated genes in B cells of patients with chronic hepatitis C during interferon‐free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study

Arai

Ito

Shimozuma

et al. 2020

Health Science Reports

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Aims Hepatitis C virus (HCV) infection is monitored by the host innate immunity that includes the endogenous interferon (IFN), which up‐regulates IFN‐stimulated genes (ISGs). HCV is both hepatotropic and lymphotropic, but HCV replication in lymphoid cells is a controversial issue. Here, we analyzed the mRNA levels of the ISGs in B cells of HCV‐infected patients during antiviral therapy and investigated the effects of viral eradication. Methods One hundred and eighty‐one patients with chronic hepatitis C and 26 healthy volunteers were enrolled in this study. Levels of HCV RNA and mRNA of ISGs in B cells isolated from the patients were monitored before, during, and after antiviral therapy. Results HCV RNA was detected in B cells of 133/175 (76.0%) patients who achieved sustained virologic response (SVR) before therapy was started. The positive ratio of HCV RNA in B cells was higher in patients with genotype 1 and the non‐major genotype of interleukin 28B. HCV RNA in B cells of most patients disappeared 1 week after antiviral therapy was started. The baseline expression of ISG mRNA was significantly higher in the patients than in the healthy volunteers. Levels of ISG mRNA were increased and remained high throughout the IFN‐based therapy. In contrast, levels of ISG mRNA in patients who achieved SVR were significantly decreased 1 week after the IFN‐free therapy was started and remained low during the therapy. Conclusions These results suggested that IFN‐free therapy potentially eradicated HCV in the B cells, leading to the down‐regulation of endogenous ISGs. The level of ISG mRNA could be used as a marker for viral eradication in B cells.

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Section: Evaluation Of Levels Of the Isg Mrnamentioning

confidence: 91%

Decreased expression of interferon‐stimulated genes in B cells of patients with chronic hepatitis C during interferon‐free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study

Arai

Ito

Shimozuma

et al. 2020

Health Science Reports

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“…According to Jinushi et al, the amount of soluble MICA was high in several patients with HCC, and their respective peripheral NK cells had reduced amounts of NKG2D expression and showed impaired activation [ 82 ]. This detrimental function of soluble MICA, enables cancer cells to evade the NK cell-mediated immune surveillance [ 83 ]. Among the MICA-shedding proteases, the roles of a disintegrin and metalloproteases 17 (ADAM17), were emphasized recently [ 83 ].…”

Section: Nk Cell Dysfunction In Hccmentioning

confidence: 99%

“…This detrimental function of soluble MICA, enables cancer cells to evade the NK cell-mediated immune surveillance [ 83 ]. Among the MICA-shedding proteases, the roles of a disintegrin and metalloproteases 17 (ADAM17), were emphasized recently [ 83 ]. ADAM17 knockdown reduced the soluble MICA levels and increased the membrane-bound MICA expression in HCC cell lines, thereby allowing for the cells to be killed by NK cells ( Figure 1 ) [ 83 ].…”

Section: Nk Cell Dysfunction In Hccmentioning

confidence: 99%

Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

Sung

Jang

2018

IJMS

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Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

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“…In the HCC setting, it has been shown that ADAM9, which is overexpressed in HCC tissue, was involved in MICA shedding at the level of an intracellular cleavage resulting in the release of the soluble form of MICA [49]. Interestingly, decreased sMICA levels and increased membrane-bound MICA expression in HCC could be attained by ADAM17 knockdown [50], an enzymatic pathway which is also involved in the control of FcγRIII shedding in chronic HCV infection [51]. Regorafenib, a small molecule inhibitor of multiple kinases approved for treatment of sorafenib-resistant HCC, inhibited mRNA and protein expression of ADAM9 and ADAM10 in HCC cell lines, resulting in higher membrane MICA expression and conversely lower sMICA levels [52], similarly to the popular aldehyde dehydrogenase inhibitor disulfiram which suppresses ADAM10 activity [53].…”

Section: Alteration Of the Nkg2d-mica/b Axis In Hccmentioning

confidence: 99%

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Mantovani

Oliviero

Varchetta

et al. 2020

Cancers

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Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri-and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

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Enzymatic inhibition of MICA sheddase ADAM17 by lomofungin in hepatocellular carcinoma cells

Cited by 27 publications

References 31 publications

Decreased expression of interferon‐stimulated genes in B cells of patients with chronic hepatitis C during interferon‐free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study

Decreased expression of interferon‐stimulated genes in B cells of patients with chronic hepatitis C during interferon‐free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study

Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

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