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.
Analysis of adam12-mediated ephrin-a1 cleavage and its biological functions / Ieguchi, K.; Tomita, T.; Takao, T.; Omori, T.; Mishima, T.; Shimizu, I.; Tognolini, M.; Lodola, A.; Tsunoda, T.; Kobayashi, S.; Wada, S.; Maru, Y.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:5(2021), pp. 1-17. [10.3390/ijms22052480]
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