HIF1-α调控NFκB/Survivin信号通路对结肠癌凋亡的作用研究

Colon cancer is one of the most common gastrointestinal tumors. Hypoxia-inducible factor 1-α (HIF1-α) was proved playing an important role in resisting the apoptosis of cancer cells. Our preliminary studies demonstrated that HIF1-α inhibited the apoptosis of colon cancer cells and was significantly related to PLD2 and Survivin, which also had significantly related to NFκB. These findings provided evidence that HIF1-α may regulate NFκB directly or by PLD2, increased the expression of Survivin and affected apoptosis. In this proposed study, we will prove the expression of HIF1-α, PLD2, NFκB and Survivin in colon carcer and find the relationship between them; determine the alteration of NFκB activity, cell apoptosis and Survivin expression under the modulating of HIF1-α and other factors involved in HIF1-α-regulated NFκB/Survivin pathways. This study will clarify the signaling pathway by which HIF1-α regulate NFκB/Survivin in colon cancer, and the mechanism of how HIF1-α effect on apoptosis, though which we expect to find a novel regulator for the prevention and treatment of colon cancer.

结肠癌是最常见的消化道恶性肿瘤之一，缺氧诱导因子1-α(HIF1-α)在肿瘤细胞抗凋亡过程中发挥了重要作用。本项目在初步证实HIF1-α增强了结肠癌细胞抗凋亡能力，并与PLD2、Survivin关系密切的基础上，结合各项文献报道PLD2与NFκB以及NFκB与Survivin之间也存在着密切的联系。由此推测出HIF1-α可直接或通过PLD2间接调控NFκB，使Survivin高表达，从而影响细胞凋亡。本研究拟通过：HIF1-α、PLD2、NFκB及Survivin在结肠癌组织中的表达情况及其表达间的相关性；HIF1-α表达的变化及特异性阻断HIF1-α调控NFκB/Survivin信号通路中关键因子的表达对NFκB的活性、细胞凋亡情况以及Survivin表达的影响等3部分的研究，以期阐明HIF1-α通过何种信号通路调控NFκB/Survivin，并对结肠癌凋亡产生影响这一科学问题。

结肠癌是常见的消化道恶性肿瘤之一，缺氧微环境是结肠癌等实体肿瘤的重要特征。缺氧诱导因子1-α(hypoxia inducible factor 1-α, HIF1-α)作为主要的缺氧反应因子可以调控上百种基因从而影响结肠癌细胞的增殖、凋亡、血管形成、侵袭、迁移等，以促进结肠癌的发生和发展。.课题组在前期实验已证实：结直肠癌组织中HIF1-α 的表达与磷脂酶D2(phospholipase D2, PLD2)之间具有相关性；随着HIF1-α 的表达升高，Survivin 的表达明显升高；沉默HIF1-α 可导致PLD2、Survivin 的表达明显降低。综合分析国内外相关领域的研究及课题组的前期工作结果，我们提出在结肠癌中，HIF1-α通过调控PLD2 的表达、再通过PI3K/AKT/NFκB或PKC/PKA/NFκB信号通路，最终使Survivin 高表达，从而对肿瘤细胞的凋亡产生影响。.本课题在实施中发现：1. HIF1-α、PLD2及Survivin在结肠癌组织和细胞中均呈明显的高表达。HIF1-α与PLD2、PLD2与Survivin的表达均具有明显的相关性；2. 体内外的研究发现干扰HIF1-α使PLD2表达明显降低，并能够抑制肿瘤的生长；3. HIF1-α/PLD2通过PI3K/ΑKT/NF-kB信号通路，调控Survivin和Bcl2的表达，从而抑制结肠癌细胞凋亡。.本项目的研究结果，进一步阐明了HIF1-α/PLD2对结肠癌凋亡的作用及其作用机制，为结肠癌的治疗提供了理论基础及新的思路。