缺氧诱导的HIF-1α/STAT3通路在胃癌干细胞“干性”维持中的作用及其机制

Cancer stem cells exist in the gastric cancer, namely gastric cancer stem cells，which are the origin of the occurrence and recurrence of gastric cancer. Stem cell character-'stemness' is the decisive factor for malignant behavior of cancer stem cells, its maintenance is closely related to the microenvironment, and hypoxia is the most significant character of tumor microenvironment. Our preliminary experiments found that hypoxia can induce gastric cancer cells with high expression of HIF-1α, and transformed into stem-like cancer cells; and also previous studies found that HIF-1α can activate the STAT3 pathway, this pathway has a regulatory role of cancer stem cells stemness. We also confirmed that the existence of the activation of STAT3 pathway in some kinds of gastric cancer cells. Accordingly, based on the above research, we hypothesized that: hypoxia play a role in the maintenance of gastric cancer stem cells stemness; this effect is achieved through the activation of HIF/stat3 pathway. In this study, we use the proposed methods such as：clone screening, RNA interference,and human gastric cancer-derived gastric cancer stem cells as the main study object, observe the effection of hypoxia on gastric cancer stem cell self-renewal, proliferation, differentiation, invasion and in vivo tumor anti-angiogenic effect, and also investigate the role of HIF-1α/STAT3 pathway in maintaining stemness of gastric cancer stem cells and its mechanism. The highlights of the project are: The findings will preliminary reveal the mechanism between gastric cancer stem cells stemness and the hypoxic microenvironment, it is possible to find effective target against tumor hypoxia or a chain reaction triggered by hypoxia, help us to further understanding the mechanisms of cancer resistance to anti-angiogenic therpy, and providing a theoretical basis and experimental evidence for targeting gastric cancer stem cells and enhancing the efficacy of anti-angiogenesis in treatment gastric cancer.

胃癌中存在肿瘤干细胞，是胃癌发生发展的根源。干细胞特性-"干性"是肿瘤干细胞恶性行为的决定性因素，其维持与微环境密切相关，而缺氧是肿瘤微环境的显著特征。我们预实验发现，缺氧可诱导胃癌细胞高表达HIF-1α，使其转化为干细胞样癌细胞；同时，以往研究提示HIF-1α能激活STAT3通路，该通路对肿瘤干细胞的干性具有调节作用，而我们也观察到某些胃癌细胞存在STAT3通路活化的现象。因此，我们推测：缺氧对胃癌干细胞的干性有维持作用；该作用是通过活化HIF/stat3通路实现的。本研究拟采用克隆筛选、RNA干扰等方法，观测缺氧对胃癌干细胞自我更新、增殖分化、侵袭及抗血管生成治疗等的影响，探讨缺氧诱导的HIF-1α/STAT3途径在维持胃癌干细胞干性的作用及机制。该项目突出意义在于：揭示胃癌干细胞的微环境调控机制，明确针对癌组织缺氧的有效靶点，阐明抗血生成治疗抵抗的新机制，为靶向治疗胃癌提供实验依据。

胃癌中存在肿瘤干细胞，是肿瘤发生和复发根源。无血清培养基悬浮培养获得胃癌干细胞，胃癌干细胞具有较强的自我更新、增殖、迁移、侵袭能力和多向分化潜能，对化疗药物更易产生耐药性。干细胞特性—“干性”是肿瘤干细胞恶性行为的决定性因素，其维持与微环境密切相关，而缺氧是肿瘤微环境的显著特征。缺氧可诱导胃癌细胞高表达HIF-1α，使胃癌细胞转化为干细胞样癌细胞，HIF-1α能激活STAT3 通路，该通路对肿瘤干细胞的干性具有调节作用。缺氧对胃癌干细胞干性具有维持作用，该作用通过HIF-1α/STAT3实现。本研究采用克隆筛选、RNA 干扰等方法，观测缺氧对胃癌干细胞自我更新、增殖分化、侵袭及抗血管生成治疗等的影响，探讨缺氧诱导的HIF-1α/STAT3 途径在维持胃癌干细胞干性的作用及机制。该项目突出意义在于：揭示胃癌干细胞的微环境调控机制，明确针对癌组织缺氧的有效靶点，阐明抗血生成治疗抵抗的新机制，为靶向治疗胃癌提供实验依据。