Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan.
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.
Int J Mol Sci. 2021 Mar 1;22(5):2480. doi: 10.3390/ijms22052480.
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.
越来越多的证据表明，在某些癌症（如结肠癌和肝癌）中，高表达的 Ephrin-A1 与预后不良呈正相关。Ephrin-A1 表达水平升高导致预后不良的确切机制仍有待充分阐明。我们之前曾报道，ADAM12 切割的 Ephrin-A1 增强了肺血管通透性，从而诱导了肺转移。然而，目前尚不清楚 Ephrin-A1 的切割形式是否来自原发性肿瘤并具有生物学活性。我们通过基质辅助激光解吸电离质谱鉴定了 Ephrin-A1 的 ADAM12 介导的切割位点，并通过使用小鼠模型检查了源自原发性肿瘤的血清和尿液中 Ephrin-A1 的水平。我们发现荷瘤小鼠的血清和尿液中 Ephrin-A1 水平升高。此外，抑制 Ephrin-A1 的 ADAM 介导的切割或拮抗 EphA 受体导致肺转移显著减少。这些结果表明，肿瘤衍生的 Ephrin-A1 不仅是预测高表达 Ephrin-A1 的原发性肿瘤发生肺转移的潜在生物标志物，也是肺转移的治疗靶点。
