炎症激酶IKBKE磷酸化并稳定snail促进乳腺癌肺转移

Breast cancer is one of the deadliest cancers in women because of its aggressiveness and poor survival rate. Early metastasis is the major caution of death for breast cancer, thus discovery of the novel biomarkers for breast cancer early diagnosis, investigation of the key oncogenes governing breast cancer metastasis and the target therapy for these key oncoproteins are the urgent question desired to be solved. The pivotal roles of IKBKE, a well-defined inflammatory kinase, in promoting breast cancer growth in culture cells, has been explored recently, however, the important roles of IKBKE in breast tumorigenesis and metastasis in vivo have not been identified. Our preliminary study revealed that IKBKE is significantly up-regulated in breast cancer samples and associated with poor patient survival. More importantly, IKBKE could phosphorylate and stabilize EMT-associated transcriptional factor Snail, to promote breast cancer cell EMT phenotype and metastasis. Furthermore, IKBKE functions in promoting breast tumorigenesis and metastasis in early stage have been evaluated in breast cancer mouse models. Therefore, we propose to uncover the mechanism of IKBKE high expression in breast cancer, and the mechanism of IKBKE regulation the stability of snail in a phosphorylation-dependent manner, as well as the important role of IKBKE/Snail axis in breast cancer initiation and metastasis. Ultimately, the small molecular inhibitors for IKBKE will be employed for combating high IKBKE-induced breast cancer tumorigenesis and metastasis in vitro and in mouse models. Completion of this project will identify novel mechanisms of IKBKE in regulating metastasis of breast cancer and provide new insights for the breast cancer metastasis diagnostics and targets treatment.

乳腺癌是一种危害女性健康的重大疾病，乳腺癌的早期转移是病人死亡的主要原因。因此发现新的乳腺癌转移相关标记物及针对乳腺癌转移关键癌基因性的靶向治疗是目前急需解决的问题。近期研究显示，慢性炎症是癌症发生的重要原因。IKBKE作为炎症相关的蛋白激酶，在乳腺癌的发生和转移中起着重要的作用。我们的研究发现，IKBKE通过磷酸化转录因子snail，来增强snail蛋白的稳定性，从而促进乳腺癌细胞EMT和转移。在乳腺癌小鼠模型上中IKBKE可以促进乳腺癌的早期发生和肺转移。本课题将进一步研究IKBKE在乳腺癌中高表达的机制、IKBKE磷酸化snail对snail稳定性进行调控的机理，及IKBKE-Snail这一通路路在乳腺癌转移中的重要作用，最终揭示IKBKE的特异性小分子抑制剂对乳腺癌发生、转移的治疗效效果。从而为乳腺癌的早期诊断、转移诊断和针对乳腺癌转移的治疗提供有效的理论支持和潜在方案。

乳腺癌是一种危害女性健康的重大疾病，其的早期转移和治疗耐药是病人死亡的主要原因。因此发现新的乳腺癌转移及耐药相关标记物、研究乳腺癌转移关键癌基因及针对性的靶向治疗是目前急需解决的问题。我们研究发现IKBKE作为炎症相关的蛋白激酶通过磷酸化转移相关的转录因子snail，来增强snail蛋白的稳定性，从而促进乳腺癌细胞EMT和转移。在乳腺癌小鼠模型上，我们证实了IKBKE可以通过稳定snail蛋白来促进乳腺癌的早期发生和早期转移。并揭示了IKBKE的特异性小分子抑制剂对乳腺癌发生、转移的治疗效效果，提出了通过靶向IKBKE进行乳腺癌转移治疗的策略。之后的研究中，我们发现IKBKE下游激酶AKT可以通过被不同信号调控，从而影响肿瘤的发生和耐药，包括SPOP介导的PDK1降解、S6K磷酸化介导的PDK1反馈抑制等因素起作用来调控肿瘤的发生，对此我们发现多种PDK1突变可以影响AKT的激酶活性，通过逃脱抑制来促进肿瘤的发生和耐药，提出靶向突变PDK1进行肿瘤治疗的策略；同时我们通过分析发现铜离子及其受体在乳腺癌发生和转移中通过调控PDK1-AKT通路起到重要的作用，提出可以通过利用铜离子螯合剂进行潜在的乳腺癌治疗的策略。