While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.

中文翻译：

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Isthmin-1 通过与 EGFR 和 YBX-1 相互作用促进结直肠癌的生长和进展

虽然之前的研究表明 Isthmin 1 (ISM1)（一种分泌蛋白）参与癌症的发展，但确切的机制仍然难以捉摸。在这项研究中，我们发现 ISM1 在结直肠癌 (CRC) 患者的血液和组织样本中显着过度表达，这与他们的不良预后相关。功能实验表明，强制 ISM1 表达可显着增强 CRC 增殖、迁移、侵袭和肿瘤生长。值得注意的是，我们的研究揭示了 ISM1 与表皮生长因子受体 (EGFR) 的相互作用，表皮生长因子受体 (EGFR) 是 CRC 细胞受体酪氨酸激酶 (RTK) 家族的成员。 ISM1 的结合触发 EGFR 激活并启动下游信号通路。同时，细胞内的ISM1与Y-box结合蛋白1（YBX1）相互作用，增强其对EGFR的转录调节。此外，我们的研究揭示了CRC细胞中缺氧诱导转录因子HIF-1α对ISM1表达的调节。从机制上讲，我们确定 HIF-1α 是 ISM1 的直接调节因子，与其启动子上的缺氧反应元件结合。这种新机制阐明了潜在的治疗靶点，为抑制 HIF-1α/ISM1/EGFR 驱动的 CRC 进展和转移提供了见解。