表观遗传分子JMJD2B在幽门螺杆菌感染促进恶性转化中的作用与机制研究

Gastric cancer is a serious disease to human health, involving multiple factors, multiple genes interactions, infection with Helicobacter pylori (H. pylori) inducing gastric malignant transformation in gastritis - precancerous lesions - gastric malignancy by deregulation of host cell genes，which provides an ideal model for the study of the interaction mechanism of the pathogen -host interaction. JMJD2B is a carcinogenic factor newly discovered, early research has been published: JMJD2B promotes gastric carcinogenesis and metastasis (IF = 8.193), based on this study, we further explore the role and molecular mechanism of JMJD2B in the malignant evolution from precancerous lesions to gastric cancer. Our preliminary finding was that the expression of JMJD2B was found to increase in malignant transformation of gastric tissue, meanwhile, H. pylori infection upregulated JMJD2B expression, and inhibiting JMJD2B blocked cell proliferation induced by H. pylori, suggesting that JMJD2B was involved in the early stages of the disease. Based on the previous research works, further studies focus on the role and mechanism of JMJD2B in the malignant transformation of gastric tissue caused by Helicobacter pylori infection at the integral, cellular and molecular levels, providing theoretical basis for targeted therapy of gastric cancer.

胃癌是严重危害人类健康的重大疾病，其发生涉及多因素、多基因相互作用，幽门螺杆菌（Helicobacter pylori，H. pylori）感染导致宿主细胞基因异常引发胃炎-癌前病变-胃癌的恶性转化，为病原-宿主多因素相互作用致癌机制研究提供了一个理想模型。JMJD2B是新发现的致癌因子,申请者前期已发表JMJD2B促进胃癌发生和转移的研究成果（IF= 8.193），在此基础上，进一步探究JMJD2B在癌前病变到胃癌恶性转化过程的作用及分子机制。初步发现JMJD2B表达在恶性转化过程胃组织中不断升高，同时H. pylori感染上调JMJD2B表达，抑制JMJD2B阻碍H. pylori诱导细胞的增殖能力，提示JMJD2B参与疾病早期事件。本课题组拟在前期工作基础上，从分子、细胞和整体三层面解析JMJD2B在H. pylori感染导致胃组织恶性转化中的作用和机制，为胃癌靶向治疗提供理论基础。

胃癌是世界范围内最常见的恶性肿瘤之一，位居全球癌症相关的死亡率第三位。胃癌的发生涉及多因素、多基因相互作用，幽门螺杆菌定植于胃粘膜长期慢性的（Helicobacter pylori，H.pylori）感染导致宿主细胞基因异常从而引发胃炎-癌前病变-胃癌的恶性转化，本研究揭示表观遗传分子JMJD2B在H.pylori慢性感染导致胃炎-癌前病变-胃癌的恶性转化中的作用及分子机制，对寻找新的药物治疗靶点进行有针对性的治疗至关重要。研究发现：1.细胞水平：幽门螺杆菌感染胃黏膜上皮细胞，上调JMJD2B表达，抑制JMJD2B阻碍了H.pylori诱导的细胞增殖能力，JMJD2B加速幽门螺杆菌感染引发的炎症的恶性转化，幽门螺杆菌感染胃黏膜上皮细胞，上调TGFβ、Wnt/β-catenin信号通路，增强β-catenin核聚集激活β-catenin转录，β-catenin/TCF/LEF结合至JMJD2B的启动子区，介导JMJD2B转录表达，上调的JMJD2B又在TGFβ1/β-catenin介导下促进β-catenin核聚集并激活其转录，激活Wnt/β-catenin信号通路，形成JMJD2B/β-catenin正反馈环，不断激活β-catenin/TCF/LEF转录，激活COX-2的转录表达，从而促进了胃黏膜上皮细胞的恶性转化。2、动物水平：JMJD2B、COX-2在幽门螺杆菌感染的小鼠胃粘膜组织中表达升高。3、人体组织标本水平：免疫组化结果显示JMJD2B和COX-2在胃癌组织中普遍高表达，且从正常胃组织、胃炎、胃癌及恶性程度高的转移性胃癌的恶性转化病理组织标本中，JMJD2B和COX-2的表达水平不断升高，且JMJD2B的表达与COX-2的表达、幽门螺杆菌的感染状态相关。本研究从细胞水平、动物水平和人体组织水平三方面揭示了JMJD2B在胃黏膜上皮细胞恶性转化的作用及相关分子机制，提示JMJD2B有可能作为一种新的胃癌治疗的靶点，为胃癌靶向药物的开发提供思路。