RHBDF1对上皮细胞癌变重要蛋白的调控机理研究

Loss of normal tissue architecture, cell polarity, and growth arrest are important primary characteristics of epithelial carcinogenesis. HIF1α is an important factor in tumor development and progression. We recently discovered that 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. 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. We also found that overexpressed-RHBDF1 in mammary cell line MCF-10A may inhibit apoptotic signal, increase growth signals, prevent the formation of the mammary acinar normal architecture and growth arrest. In addition, overexpressed-RHBDF1 in mammary cell line MCF-10A can misregulated epithelial cell polarity proteins (Par3 and Par6), enhance the stabilization of HIF1α, and reduce caspase3 and increase pAKT in the graft cells of the immunodeficient nude mice. Based on these findings, we will focus on researching that RHBDF1 how to modulate the key proteins, HIF1α, Par3, and Par6, for epithelial carcinogenesis and the primary characteristics of cell carcinogenesis from the level of molecular, cellular, tissue, and the overall. Findings from these studies should not only give rise to important insights into the relationships of RHBDF1, HIF1α, loss cell polarity, and epithelial tumorigenesis, but also provide a novel target for the development of new anticancer approaches.

丧失正常组织结构、细胞极性和生长抑制是上皮细胞癌变早期发生的重要特征。HIF1α是肿瘤发生和发展的重要因子。我们发现，RHBDF1 在临床乳腺癌中的表达水平与癌症的发展、转移、复发及不良预后密切相关，并能促进HIF1α的稳定性，其siRNA 可引起癌细胞凋亡或自噬，抑制肿瘤模型生长；RHBDF1 过表达能够误调细胞极性蛋白Par3 和Par6，抑制乳腺腺泡正常结构形成和生长抑制，降低凋亡信号，增加生长信号。本项目将从分子、细胞、组织、整体等层次，对RHBDF1 如何调节HIF1α、Par3 和Par6 及其促进上皮细胞癌变早期特征发生的分子机理进行深入研究，为揭示癌变机理、确立抗癌新靶标及治疗和预防癌症提供新理论、新策略。

丧失正常组织结构、细胞极性和生长抑制是上皮细胞癌变早期发生的重要特征。本项目的研究内容是阐明RHBDF1调控HIF1α、Par3 和Par6等上皮细胞癌变重要蛋白促进上皮细胞组织早期癌变发生的分子机理。我们发现，过表达RHBDF1上调EGFR和HIF 1α等信号促进乳腺腺泡增殖，抑制细胞凋亡，造成腺泡生长抑制丧失；进一步，RHBDF1可调控顶底部极性蛋白Par3 和Par6表达，并能够直接与Par6结合，干扰Rac1/Cdc42-Par3-Par6极性复合物形成，扰乱乳腺腺泡顶底部极性的形成。为揭示癌变机理、确立抗癌新靶标及治疗和预防癌症提供了新理论、新策略。