E3泛素连接酶HECTD3促进乳腺癌转移及其机制研究

Tumor metastasis, which commonly occurs at the late stage, is responsible for the majority of cancer deaths. Tumor microenvironment plays a critical role in metastasis. The colonization of circulating tumor cells in distant organs depends on adhesion by vascular endothelium. Here we demonstrated that Hectd3 KO mice significantly reduced breast cancer cell lung metastasis. When HECTD3 was knocked down in HUVEC (human umbilical vein endothelial cell), inflammation factors, including LPS, TNFα and IL-1β, induced adhesion molecules (VCAM-1, ICAM-1 and E-selectin) expression were inhibited. Subsequently, the adhesion of breast cancer cells to HUVEC was decreased significantly. In this study, we propose that HECTD3 interacts with and ubiquitinates IKKα with non-degradative poly-ubiquitin chains, which stabilize IKKα and promotes expression of adhesion molecules and breast cancer metastasis. Completion of this study will reveal the mechanism by which HECTD3 promotes breast cancer metastasis and identify potential HECTD3 small molecule inhibitors for breast cancer prevention and treatment.

肿瘤转移是大多数癌症患者的死亡原因，肿瘤微环境在转移中扮演重要角色。血管内皮细胞对肿瘤细胞的粘附能力，决定了循环肿瘤细胞是否转移并定居远端器官。我们在多种小鼠肿瘤转移模型上发现，敲除E3泛素连接酶HECTD3能显著降低乳腺癌的肺转移。在炎症因子LPS，TNFα和IL-1β刺激下，HECTD3能促进人脐静脉内皮细胞（HUVEC）粘附分子VCAM-1，ICAM-1和E-selectin的表达，增加HUVEC对乳腺癌细胞的粘附能力。本研究将验证一个假说：HECTD3与NF-κB信号通路关键分子IKKα相互作用，通过非降解型泛素化修饰增加其稳定性，从而诱导下游粘附分子表达增强乳腺癌的远端器官转移。探索HECTD3在转移中的分子机制，确定其作为乳腺癌转移靶点的生物学功能，筛选针对HECTD3的特异性小分子抑制剂，将为乳腺癌转移的防治提供新的策略。

肿瘤转移是大多数癌症患者的死亡原因，手术作为去除原位实体肿瘤的有效方法，往往造成了系统性炎症因子风暴，促进血管内皮细胞对肿瘤细胞的粘附能力，导致循环肿瘤细胞转移并定居远端器官。目前没有有效手段阻止原位肿瘤像远端器官的转移，这项研究中我们发现，敲除血管上皮细胞的E3泛素连接酶HECTD3能显著降低乳腺癌的肺转移，在炎症因子LPS刺激以及MMTV-Neu小鼠转移模型中，HECTD3敲除在体内外的模型均能降低粘附分子VCAM-1，ICAM-1和E-selectin的表达，抑制HUVEC对乳腺癌细胞的粘附能力。深入研究其机制为HECTD3泛素化修饰NF-κB信号通路关键分子IKKα，通过K27和K63链的非降解型泛素化修饰其K296位点增加IKKα的稳定性，促进组蛋白H3的Ser10位点磷酸化修饰来促进NF-κB下游靶基因转录，从而诱导下游粘附分子表达增强乳腺癌的远端器官转移。另外，我们还发现IKKα 的激酶抑制剂可以阻断LPS诱导的乳腺癌肺转移。这一系列发现揭示了HECTD3-IKKα信号轴在促进乳腺癌远端转移的机制，提供了潜在的预防策略。