Abstract：
Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with a poor prognosis due to a lack of early detection. Indeed, the mechanisms underlying ESCC progression remain unclear. Here, we discovered that abnormal arginine metabolism contributes to ESCC progression. Based on transcriptomic and metabolomic analyses, we found that argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) levels were increased in primary tumor tissues but decreased in lymph-metastatic tumor tissues. Intriguingly, FOXO3a was inversely correlated with ASS1 and ASL in primary and metastatic tumor tissues, suggesting that FOXO3a dissimilarly regulates ASS1 and ASL at different stages of ESCC. Silencing ASS1/ASL inhibited primary tumor growth and promoted metastasis. Conversely, overexpression of ASS1/ASL or increased arginine supply promoted tumor proliferation but suppressed metastasis. In addition, FOXO3a activation inhibited primary tumor growth by repressing ASS1 and ASL transcription, whereas inactivation of FOXO3a impeded metastasis by releasing ASS1 and ASL transcription. Together, the finding sheds light on metastatic reprogramming in ESCC.
摘要：
食管鳞状细胞癌（ESCC）是一种常见的恶性肿瘤，由于缺乏早期检测，预后较差。的确,ESCC进展的潜在机制仍不清楚.这里,我们发现精氨酸代谢异常有助于ESCC进展。基于转录组学和代谢组学分析，我们发现精氨酰琥珀酸合成酶1(ASS1)和精氨酰琥珀酸裂解酶(ASL)水平在原发肿瘤组织中升高,但在淋巴转移肿瘤组织中降低.有趣的是，FOXO3a在原发和转移肿瘤组织中与ASS1和ASL呈负相关。这表明FOXO3a在ESCC的不同阶段对ASS1和ASL的调控不同。沉默ASS1/ASL抑制原发肿瘤生长，促进转移。相反，ASS1/ASL过表达或精氨酸供应增加可促进肿瘤增殖但抑制转移。此外,FOXO3a激活通过抑制ASS1和ASL转录抑制原发性肿瘤生长，而FOXO3a的失活通过释放ASS1和ASL转录来阻碍转移。一起,这一发现揭示了ESCC中的转移重编程。
