YARS通过E2F1及PI3K-Akt信号通路促进胃癌恶性进展的机制研究

As a catalyzer in mediating the integration between Tyrosyl and tRNA, YARS (Tyrosyl-tRNA synthetase) has long been considered as a classic gatekeeper for protein translation. Surprisingly, our recent exploration observed an elevation of YARS in gastric cancer tissues, whose high-expression positively correlated with poor prognosis, impaired chromosomal integrity and enhanced tumor mutation burden. YARS knockdown inhibited gastric cancer cell proliferation/metastasis, enhanced apoptosis, specifically downregulated E2F1 expression, inactivated PI3K-Akt as well as DNA-damage repair (homologues recombination) pathways. These findings suggested that apart from its role in protein translation, YARS was also a novel gastric cancer progression related gene. By combing our preliminary works and current reports, we hypothesized that YARS exerted its carcinogenic functions through an E2F1-PI3K-Akt axis. Hence, we plan to unveil YARS’s impact on gastric cancer phenotypes and to validate whether YARS exerted its malignant function through an E2F1-PI3K-Akt signaling axis. Our work may hopefully shed a new light upon the mechanisms of gastric cancer progression, and broaden the horizon for current anticancer therapies.

YARS为酪氨酰氨tRNA合成酶，具有介导蛋白翻译的经典作用，而我们发现YARS在胃癌组织中表达升高，与患者不利预后、染色体不稳定性和肿瘤高突变频率正相关。YARS敲降显著抑制胃癌细胞增殖转移，促进凋亡，对E2F1，PI3K-Akt和DNA损伤同源重组修复通路具有下调抑制作用。这些结果提示除经典的生物学功能外，YARS亦为全新胃癌进展相关基因。结合以上前期结果和文献报道，我们猜测YARS可通过E2F1及PI3K-Akt信号轴促进胃癌恶性进展。由此，本课题计划明确YARS对胃癌恶性表型的影响，研究YARS通过E2F1及PI3K-Akt信号通路促进胃癌恶性进展的机制，以加深对胃癌发生发展的认识，为其防治提供全新思路。

aaRS (氨基酸-tRNA合成酶)具有介导蛋白翻译的经典作用，其中 YARS (tyrosyl-tRNA synthetase)为酪氨酰氨tRNA合成酶，调控酪胺酰胺与相关tRNA的结合，从而发挥关键的生物学作用。一些研究已经提示YARS突变与发育性异常和疾病的相关性，但其与肿瘤的联系至今未见报道。在本项目中，我们结合了生物信息分析、细胞分子生物学和动物学实验，探索了YARS在胃癌中的表达特征和生物学功能。我们通过分析数据库信息和检测患者标本评估了YARS的表达特征，并在建立YARS敲低/过表达的细胞株后进行了RNA-sequencing、表型检测和分子机制研究。研究结果显示，YARS在胃癌组织中表达普遍高于正常组织。下调YARS的表达抑制细胞增殖和迁移侵袭、促进凋亡，而上调YARS促进细胞增殖。通过对YARS敲低后的分子通路变化进行分析，我们锁定了多个与肿瘤相关的潜在分子通路，并通过实验证实YARS通过激活PI3K-Akt信号通路促进胃癌发生恶性表型并发生同源重组。我们的工作首次报道了YARS在肿瘤中发挥的作用，提示其为全新的促癌基因，并且具有在未来成为治疗靶点的潜在价值。