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Volume 12
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10.3390/cancers12030745
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Article

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

by
Sooyeon Oh
1,
YoungJoon Park
2,
Hyun-Jung Lee
3,
Jooho Lee
4,*,
Soo-Hyeon Lee
5,
Young-Seok Baek
5,
Su-Kyung Chun
6,
Seung-Min Lee
3,
Mina Kim
4,
Young-Eun Chon
4,
Yeonjung Ha
4,
Yuri Cho
7,
Gi Jin Kim
2,
Seong-Gyu Hwang
4 and
KyuBum Kwack
2
1
Chaum Life Center, CHA University School of Medicine, Seoul 06062, Korea
2
Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, Korea
3
Center for Research & Development, CHA Advanced Research Institute, Seongnam 13488, Korea
4
Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Korea
5
Immunotherapy Development Team, R & D Division, CHA Biolab, Seongnam 13488, Korea
6
Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam 13488, Korea
7
Department of Gastroenterology, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul 06135, Korea
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(3), 745; https://doi.org/10.3390/cancers12030745
Submission received: 28 January 2020 / Revised: 15 March 2020 / Accepted: 19 March 2020 / Published: 21 March 2020
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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Abstract

The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings.
Keywords: hepatocellular carcinoma; a disintegrin and metalloprotease 9; nivolumab; natural killer; immunotherapy hepatocellular carcinoma; a disintegrin and metalloprotease 9; nivolumab; natural killer; immunotherapy

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MDPI and ACS Style

Oh, S.; Park, Y.; Lee, H.-J.; Lee, J.; Lee, S.-H.; Baek, Y.-S.; Chun, S.-K.; Lee, S.-M.; Kim, M.; Chon, Y.-E.; et al. A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy. Cancers 2020, 12, 745. https://doi.org/10.3390/cancers12030745

AMA Style

Oh S, Park Y, Lee H-J, Lee J, Lee S-H, Baek Y-S, Chun S-K, Lee S-M, Kim M, Chon Y-E, et al. A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy. Cancers. 2020; 12(3):745. https://doi.org/10.3390/cancers12030745

Chicago/Turabian Style

Oh, Sooyeon, YoungJoon Park, Hyun-Jung Lee, Jooho Lee, Soo-Hyeon Lee, Young-Seok Baek, Su-Kyung Chun, Seung-Min Lee, Mina Kim, Young-Eun Chon, and et al. 2020. "A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy" Cancers 12, no. 3: 745. https://doi.org/10.3390/cancers12030745

APA Style

Oh, S., Park, Y., Lee, H.-J., Lee, J., Lee, S.-H., Baek, Y.-S., Chun, S.-K., Lee, S.-M., Kim, M., Chon, Y.-E., Ha, Y., Cho, Y., Kim, G. J., Hwang, S.-G., & Kwack, K. (2020). A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy. Cancers, 12(3), 745. https://doi.org/10.3390/cancers12030745

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