人类长菱家族1号基因RHBDF1在癌细胞中调控缺氧诱导因子HIF-1α氧非依赖型降解的机理

Chronic inflammation and associated angiogenesis are critically attributed to tumorigenesis. Hypoxia inducible factor-1 (HIF-1) is a key transcription factor that modulates angiogenesis and cancer development. We recently discovered that HIF-1 activity was regulated by human rhomboid family-1 gene (RHBDF1). We showed that RHBDF1 was an essential component of the signaling pathway involved in G-protein coupled receptor (GPCR)-mediated transactivation of epidermal growth factor receptor (EGFR). Treatment of breast cancer or head and neck cancer cells with RHBDF1 siRNA resulted in apoptosis or autophagy. Treatment of tumor-bearing mice with the siRNA led to tumor growth inhibition. Elevated RHBDF1 expression levels in invasive breast cancer under clinical conditions exhibited a strong correlation with increased lymph node and distant metastasis, more frequent local recurrence, and poorer prognosis. We also found that RHBDF1 may directly participate in the modulation of oxygen-independent degradation of HIF-1α. Based on these findings, we propose two Specific Aims in this grant: 1) To determine the role of RHBDF1 phosphorylation in the regulation of its activities, and 2) To delineate the molecular mechanism by which RHBDF1 modulates HIF-1α stability in hypoxia. We will focus on the potential phosphorylation sites of the RHBDF1 protein to analyze its structure-function relationships and identify the kinases and signaling pathways involved. We have developed a transgenic mouse model in which RHBDF1 is highly expressed in the lung. We will use this model to study RHBDF1 modulation of HIF-1α stability under inflammatory conditions as well as cancer metastasis to the lung. Findings from these studies should not only give rise to important insights into the relationships between inflammation, angiogenesis, and tumorigenesis, but also provide a novel target for the development of new anticancer approaches.

慢性炎症及伴随的血管新生是癌变的重要诱因，缺氧诱导因子HIF-1在这些过程中起核心作用。我们发现，新近鉴定功能的人类基因RHBDF1在临床乳腺癌组织中的表达水平与癌转移、复发及不良预后显著相关，并参与调控HIF-1α氧非依赖型降解；RHBDF1是GPCR介导的EGFR跨位激活途径的重要组成部分，其siRNA可引起癌细胞凋亡或自噬，抑制肿瘤模型生长；RHBDF1活性受蛋白磷酸化调控。本项目力图揭示RHBDF1的磷酸化与活性的关系及机理，阐明RHBDF1参与调控HIF-1α氧非依赖型降解的分子机制。我们将针对RHBDF1潜在的磷酸化位点开展结构与功能分析，鉴定可能涉及到的磷酸激酶及信号通路，并利用已建立的转基因小鼠模型探讨炎症和癌转移条件下RHBDF1对HIF-1α的调控。研究目标的实现将深化对癌变过程的认识，确立抗癌新靶标，开拓癌症研究的新领域，为研发癌症治疗新途径提供生物学和临床医学基础。

慢性炎症及伴随的血管新生是癌变的重要诱因，HIF-1在这些过程中起核心作用。我们发现，人类基因RHBDF1在临床乳腺癌组织中的表达水平与癌转移、复发及不良预后显著相关，并参与调控HIF-1α氧非依赖型降解；RHBDF1是GPCR介导的EGFR跨位激活途径的重要组成部分，其siRNA可引起癌细胞凋亡或自噬，并抑制肿瘤模型生长；RHBDF1活性受蛋白磷酸化调控。本项目力图揭示RHBDF1的磷酸化与活性的关系及机理，阐明RHBDF1参与调控HIF-1α氧非依赖型降解的分子机制。我们将针对RHBDF1潜在的磷酸化位点开展结构与功能分析，鉴定可能涉及到的磷酸激酶及信号通路，并利用已建立的转基因小鼠模型探讨炎症和癌转移条件下RHBDF1对HIF-1α的调控。本项目通过对大量乳腺癌临床样本的分析，发现RHBDF1与乳腺癌恶化程度及不良预后正相关，并且与乳腺癌的组织中HIF1α的水平正相关。我们组利用分子生物学和细胞生物学方法，在乳腺癌细胞模型中对RHBDF1促进缺氧诱导转录因子HIF1α稳定性的机理进行了探讨，揭示了RHBDF1抑制HIF1α氧非依赖降解的机制，为肿瘤治疗提供了潜在的新药物靶点。研究目标的实现将深化对癌变过程的认识，确立抗癌新靶标，开拓癌症研究的新领域，为研发癌症治疗新途径提供生物学和临床医学基础。

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