DLC1 in inflammation-driven gastric carcinogenesis

Caveolin-1（Cav 1）是质膜中的支架蛋白和病原体受体，其组织信号分子以控制上皮完整性和细胞命运决定，例如增殖和存活。我们在BU 2285/1-2中表明Cav 1存在于正常人和小鼠胃中，在那里它作为促进分化的核受体PPARgamma的共激活剂。Cav 1和PPARgamma的药理学活化在体外和体内抑制胃癌（GC）细胞的生长。Cav 1在原发性GC患者中下调，在感染幽门螺杆菌（HP）的小鼠和细胞系中下调，幽门螺杆菌是人类GC的主要危险因素，导致其肿瘤抑制功能丧失。Cav 1基因敲除小鼠对HP相关胃炎和组织损伤表现出增强的易感性，Cav 1通过招募肝癌缺失型1（DLC 1）（一种小GTP酶和细胞-细胞/基质接触的调节因子）保护人胃上皮细胞免受HP致癌毒力因子CagA的侵害。我们确定DLC 1作为Cav 1的一种新型胃特异性相互作用伴侣，其抵消HP诱导的细胞骨架重排和粘着斑。与Cav 1类似，DLC 1是正常组织中的肿瘤抑制因子，其在人类原发性肿瘤中经常丢失，但在晚期癌症中重新获得，例如在转移期间。在3年的延长期内，我们计划深入研究Cav 1/DLC 1复合物的功能。在人类GC细胞中的功能分子研究的翻译方法，炎症驱动的小鼠模型GC和表达/临床数据从GC患者的预期阐述的Cav 1/DLC 1复合物在胃癌发生中的致病作用。胃癌的生存预后差，可用的治疗方案有限。因此，我们的研究旨在将DLC 1作为GC中潜在的新靶点或HP诱导的胃炎向肿瘤转变的未来早期诊断标志物。

Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the plasma membrane which organizes signaling molecules to control epithelial integrity and cell fate decisions such as proliferation and survival. We showed in BU2285/1-2 that Cav1 is present in the normal human and murine stomach, where it acts as a coactivator of the differentiation-promoting nuclear receptor PPARgamma. Cav1 and pharmacological activation of PPARgamma inhibited growth of gastric cancer (GC) cells in vitro and in vivo. Cav1 was down-regulated in patients with primary GC, and in mice and cell lines infected with Helicobacter pylori (HP), a major risk factor for GC in humans, resulting in loss of its tumor suppressor functions. Cav1 knockout mice showed an enhanced susceptibility against HP-related gastritis and tissue damage, and Cav1 protected human gastric epithelial cells against HPs oncogenic virulence factor CagA by recruiting deleted in liver cancer-1 (DLC1), a regulator of small GTPases and cell-cell/matrix contacts. We identified DLC1 as a novel stomach-specific interaction partner of Cav1 which counteracted HP-induced rearrangements of the cytoskeleton and focal adhesions. Similar to Cav1, DLC1 is a tumor suppressor in normal tissue which is frequently lost in human primary tumors but regained in advanced stage cancer, e.g. during metastasis. In the 3 year extension period, we plan to investigate in depth the function of the Cav1/DLC1 complex. A translational approach of functional molecular studies in human GC cells, an inflammation-driven mouse model of GC and expression/clinical data from GC patients is expected to elaborate the causative role of the Cav1/DLC1 complex in gastric carcinogenesis. Survival prognosis of GC is poor and available treatment options limited. Therefore, our research aims to contribute to the characterisation of DLC1 as a potential novel target in GC or future early diagnostic marker for the transition of HP-induced gastritis to neoplasia.