Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.
Signal Transduct Target Ther. 2022 Aug 3;7(1):264. doi: 10.1038/s41392-022-01057-0.
Metastasis is the leading cause of cancer-related death. The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis. Surgery is a common intervention for most primary solid tumors. However, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells (ECs). Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization, nuclear localization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 to promote NF-κB target gene transcription. Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization, while conditional knockin promotes that. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention.
转移是癌症相关死亡的主要原因。循环肿瘤细胞与远处器官内皮黏附分子的相互作用是血源性转移中外渗的关键步骤。手术是大多数原发性实体瘤的常见干预措施。然而，与手术创伤相关的全身炎症通过增加肿瘤细胞向血管内皮细胞 (ECs) 的扩散和黏附，促进远处肿瘤转移。目前，没有有效的干预措施来预防远处转移。在这里，我们表明 ECs 中的 HECTD3 缺乏显着减少了多种小鼠模型中的肿瘤转移。HECTD3 耗竭下调了黏附分子的表达，例如炎性因子刺激的小鼠原代 ECs 和 HUVECs 中的 VCAM-1、ICAM-1 和 E-选择素，并抑制了肿瘤细胞在体外和体内与 ECs 的黏附。我们证明 HECTD3 通过 K27 和 K63 连接的多泛素链在 K296 处泛素化 IKKα，从而促进 IKKα 的稳定、核定位和激酶活性，增加组蛋白 H3 的磷酸化，从而促进 NF-κB 靶基因转录。内皮细胞中 HECTD3 的敲除显着抑制了肿瘤细胞的肺定植，而条件性敲入则促进了肿瘤细胞的肺定植。IKKα 激酶抑制剂可阻止 LPS 诱导的肺转移。这些发现揭示了 HECTD3-IKKα 轴在肿瘤血源性转移中的促进作用，并为肿瘤转移预防提供了一种潜在策略。
