Jiang Lei, Wang Justin, Liu Ze, Zhang Qian, Yang Xiang-Lei
Department of Molecular Medicine, Scripps Research Institute, La Jolla, California, USA.
FASEB J. 2025 Jan 15;39(1):e70294. doi: 10.1096/fj.202401720R.
Tumors require ample protein synthesis to grow, and aminoacyl-tRNA synthetases, as critical translation factors, are expected to support cancer progression. Unexpectedly, overexpression of seryl-tRNA synthetase (SerRS) suppresses primary tumor growth of breast cancer. However, the effects of SerRS on metastasis have not been studied. We observe a decrease in SerRS expression in breast cancer patient metastases compared with matched primary tumors, suggesting an inhibitory role of SerRS in metastasis. Through mouse metastasis models using breast cancer cell lines overexpressing SerRS, we show that SerRS impedes not only primary tumor growth but also establishment of metastases, and the effect of SerRS on metastasis can be independent of its impact on the primary tumor. SerRS also inhibits tumor growth with induced, post-tumor-onset overexpression, demonstrating its potential as an anticancer therapeutic. Tumor RNA-seq analysis identified Wnt signaling among the top SerRS-regulated pathways. Using cell-based studies, we confirm SerRS suppresses Wnt signaling and metastatic processes in breast cancer cells. To the best of our knowledge, this is the first study to show a component of the translation machinery can act as both a tumor and metastasis suppressor.
肿瘤生长需要充足的蛋白质合成，而氨酰 - tRNA合成酶作为关键的翻译因子，有望促进癌症进展。出乎意料的是，丝氨酰 - tRNA合成酶（SerRS）的过表达会抑制乳腺癌原发肿瘤的生长。然而，SerRS对转移的影响尚未得到研究。我们观察到，与配对的原发肿瘤相比，乳腺癌患者转移灶中SerRS的表达降低，这表明SerRS在转移过程中具有抑制作用。通过使用过表达SerRS的乳腺癌细胞系建立小鼠转移模型，我们发现SerRS不仅阻碍原发肿瘤生长，还抑制转移灶的形成，并且SerRS对转移的影响可能独立于其对原发肿瘤的作用。SerRS在肿瘤发生后诱导过表达也能抑制肿瘤生长，证明了其作为抗癌治疗药物的潜力。肿瘤RNA测序分析确定Wnt信号通路是SerRS调控的主要通路之一。通过细胞实验，我们证实SerRS抑制乳腺癌细胞中的Wnt信号通路和转移过程。据我们所知，这是第一项表明翻译机制的一个组成部分可以同时作为肿瘤和转移抑制因子的研究。
