Anticancer Chemotherapy Inhibits MHC Class I–Related Chain A Ectodomain Shedding by Downregulating ADAM10 Expression in Hepatocellular Carcinoma

Kohga, Keisuke; Takehara, Tetsuo; Tatsumi, Tomohide; Miyagi, Takuya; Ishida, Hisashi; Ohkawa, Kazuyoshi; Kanto, Tatsuya; Hiramatsu, Naoki; Hayashi, Norio

doi:10.1158/0008-5472.can-09-0789

Cited by 81 publications

(91 citation statements)

References 27 publications

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“…Similar to our observations, etoposide, a topoisomerase II inhibitor able to activate the response to DNA damage, was demonstrated to enhance ADAM10 expression (47). However, at variance with our results, Kohga et al (48) observed that MICA shedding upon epirubicin treatment in hepatocarcinoma cells was accompanied by reduced ADAM10 expression. These discrepancies may depend on the different cellular systems and/or experimental conditions used.…”

Section: Discussionsupporting

confidence: 87%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses

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Section: Discussionsupporting

confidence: 87%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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“…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%

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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“…Exponentially growing HepG2 cells were harvested and a tumorigenic dose of 2x10 6 cells was injected intraperitoneally into the BALB mice. When tumors grew to an average volume of 75 mm 3 , the mice were randomly divided into ADAM10-RNAi, control (untreated) and NC-RNAi groups (n=8 in each group).…”

Section: Terminal Deoxynucleotidyl Transferase-mediated Nick End Labementioning

confidence: 99%

“…These proteins are involved in a range of human disease processes, such as cancer metastasis, inflammation and asthma (4,5). ADAM10, an important member of the ADAM family, is frequently upregulated in various types of cancer, including HCC, and is involved in cancer progression and metastasis (6)(7)(8)(9)(10)(11)(12). ADAM10 has been reported to exert an important role in cell migration, tumor development and metastasis by proteolytic shedding of cell surface proteins (13,14).…”

Section: Introductionmentioning

confidence: 99%

Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells

Liu

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract.A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein associated with metastasis in a number of types of cancer. Little is known, however, regarding the role of ADAM10 in hepatocellular carcinoma (HCC). The aim of the present study was to evaluate whether downregulation of ADAM10 effects HCC cell proliferation, cell cycle, cell migration and cell invasion. A recombinant small hairpin RNA expression vector carrying ADAM10 was constructed and then transfected into the HepG2 human HCC cell line. In vitro cell proliferation, cell cycle, cell migration and cell invasion, and in vivo tumor growth were determined following the downregulation of ADAM10 by RNA interference. The results revealed that downregulation of ADAM10 expression in HepG2 tumor cells using the RNA silencing approach significantly suppressed cell proliferation, cell migration and cell invasion in vitro, and tumor growth in vivo. Furthermore, ADAM10 silencing was able to significantly reduce constitutive phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt, which implies that ADAM10 is, at least partially, involved in the activation of the PI3K/Akt signaling pathway. These results suggest that ADAM10 is important in regulating the proliferation and metastasis of HCC. Thus, ADAM10 is a promising therapeutic target for the prevention of tumor metastases in HCC.

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Anticancer Chemotherapy Inhibits MHC Class I–Related Chain A Ectodomain Shedding by Downregulating ADAM10 Expression in Hepatocellular Carcinoma

Cited by 81 publications

References 27 publications

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

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

Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells

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