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Volume 22
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10.3390/ijms22052480
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Article

Analysis of ADAM12-Mediated Ephrin-A1 Cleavage and Its Biological Functions

by
Katsuaki Ieguchi
1,2,*,
Takeshi Tomita
3,
Toshifumi Takao
4,
Tsutomu Omori
1,
Taishi Mishima
1, 5,
Massimiliano Tognolini
6,
Alessio Lodola
6,
Takuya Tsunoda
7,
Shinichi Kobayashi
8,
Satoshi Wada
2,7,8 and
Yoshiro Maru
1,*
1
Department of Pharmacology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan
2
Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya, Tokyo 157-8777, Japan
3
Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Department of Biochemistry and Molecular Biology, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
4
Laboratory of Protein Profiling and Functional Proteomics, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 567-0871, Japan
5
Department of Applied Chemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan
6
Department of Food and Drug, University of Parma, Viale delle Scienze 27/a, 43124 Parma, Italy
7
Department of Medicine, Division of Medical Oncology, School of Medicine, Showa University, 1-5-8, Hatanodai, Shinagawa, Tokyo 142-8555, Japan
8
Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya, Tokyo 157-8777, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: Dimitar B. Nikolov
Int. J. Mol. Sci. 2021, 22(5), 2480; https://doi.org/10.3390/ijms22052480
Received: 12 January 2021 / Revised: 19 February 2021 / Accepted: 24 February 2021 / Published: 1 March 2021
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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Abstract

Accumulating evidence indicates that an elevated ephrin-A1 expression is positively correlated with a worse prognosis in some cancers such as colon and liver cancer. The detailed mechanism of an elevated ephrin-A1 expression in a worse prognosis still remains to be fully elucidated. We previously reported that ADAM12-cleaved ephrin-A1 enhanced lung vascular permeability and thereby induced lung metastasis. However, it is still unclear whether or not cleaved forms of ephrin-A1 are derived from primary tumors and have biological activities. We identified the ADAM12-mediated cleavage site of ephrin-A1 by a Matrix-assisted laser desorption ionization mass spectrometry and checked levels of ephrin-A1 in the serum and the urine derived from the primary tumors by using a mouse model. We found elevated levels of tumor-derived ephrin-A1 in the serum and the urine in the tumor-bearing mice. Moreover, inhibition of ADAM-mediated cleavage of ephrin-A1 or antagonization of the EphA receptors resulted in a significant reduction of lung metastasis. The results suggest that tumor-derived ephrin-A1 is not only a potential biomarker to predict lung metastasis from the primary tumor highly expressing ephrin-A1 but also a therapeutic target of lung metastasis. View Full-Text
Keywords: Eph; ephrin; ADAM; MMP; cancer; metastasis; biomarker; poor prognosis; urinalysis Eph; ephrin; ADAM; MMP; cancer; metastasis; biomarker; poor prognosis; urinalysis
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MDPI and ACS Style

Ieguchi, K.; Tomita, T.; Takao, T.; Omori, T.; Mishima, T.; Shimizu, I.; Tognolini, M.; Lodola, A.; Tsunoda, T.; Kobayashi, S.; Wada, S.; Maru, Y. Analysis of ADAM12-Mediated Ephrin-A1 Cleavage and Its Biological Functions. Int. J. Mol. Sci. 2021, 22, 2480. https://doi.org/10.3390/ijms22052480

AMA Style

Ieguchi K, Tomita T, Takao T, Omori T, Mishima T, Shimizu I, Tognolini M, Lodola A, Tsunoda T, Kobayashi S, Wada S, Maru Y. Analysis of ADAM12-Mediated Ephrin-A1 Cleavage and Its Biological Functions. International Journal of Molecular Sciences. 2021; 22(5):2480. https://doi.org/10.3390/ijms22052480

Chicago/Turabian Style

Ieguchi, Katsuaki, Takeshi Tomita, Toshifumi Takao, Tsutomu Omori, Taishi Mishima, Isao Shimizu, Massimiliano Tognolini, Alessio Lodola, Takuya Tsunoda, Shinichi Kobayashi, Satoshi Wada, and Yoshiro Maru. 2021. "Analysis of ADAM12-Mediated Ephrin-A1 Cleavage and Its Biological Functions" International Journal of Molecular Sciences 22, no. 5: 2480. https://doi.org/10.3390/ijms22052480

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