GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Death Dis. 2024 Aug 28;15(8):631. doi: 10.1038/s41419-024-07021-w.
Angiogenesis is critical for colorectal cancer (CRC) progression, but its mechanisms remain unclear. Here, we reveal that ethylmalonic encephalopathy protein 1 (ETHE1), an essential enzyme in hydrogen sulfide catabolism, inhibits VEGF-A expression and tumor angiogenesis in vitro and in vivo. Moreover, we find that this biological function of ETHE1 depends on the STAT3/VEGF-A pathway. Further investigation demonstrates that ETHE1 promotes the interaction between T cell protein tyrosine phosphatase (TC45) and STAT3, resulting in decreased STAT3 phosphorylation and inhibition of the STAT3 signaling pathway. In clinical samples, we find that ETHE1 is downregulated in CRC and positively correlates with survival outcomes of CRC patients. Meanwhile, the negative correlation of ETHE1 and VEGF-A expression is verified in CRC specimens, and the patients with low ETHE1 and high VEGF-A expression exhibits poorer prognosis. Collectively, our study identifies ETHE1 as a novel regulator of tumor angiogenesis, implying its potential as a prognostic biomarker and promising antiangiogenic target for CRC patients.
血管生成对于结直肠癌（CRC）的进展至关重要，但其中的机制尚不清楚。在这里，我们揭示了乙二酸脑病蛋白 1（ETHE1），一种在硫化氢代谢中必不可少的酶，可在体外和体内抑制 VEGF-A 的表达和肿瘤血管生成。此外，我们发现 ETHE1 的这种生物学功能依赖于 STAT3/VEGF-A 通路。进一步的研究表明，ETHE1 促进了 T 细胞蛋白酪氨酸磷酸酶（TC45）和 STAT3 之间的相互作用，导致 STAT3 磷酸化减少和 STAT3 信号通路的抑制。在临床样本中，我们发现 ETHE1 在 CRC 中下调，与 CRC 患者的生存结果呈正相关。同时，在 CRC 标本中验证了 ETHE1 与 VEGF-A 表达的负相关，低表达 ETHE1 和高表达 VEGF-A 的患者预后较差。总之，我们的研究确定 ETHE1 是肿瘤血管生成的一个新的调节因子，表明其作为 CRC 患者的预后生物标志物和有前途的抗血管生成靶点的潜力。
