Lin28B-ARID3A促PGE2合成的机制及其在阿司匹林防治肠癌中的作用研究

Colon cancer is an inflammation associated cancer. Nonsterile anti-inflammation drug aspirin could decrease the morbidity and mortality of colon cancer, however the mechanisms of aspirin anti-colon cancer is largely unknown. Lin28B has been well documented to promote the carcinogenesis and progression of colon cancer by inducing inflammation in tumor tissues, however, whether Lin28B is a potential target of aspirin in colon cancer chemopreventiation and treatment is unknown. We have shown that aspirin could inhibit the promoting effect of Lin28B on the malignant transformation of colon cells and on the proliferation and invasion of colon cancer cells. Further studies suggest that Lin28B may promote the expression of transfection factor ARID3A by directly binding its mRNA, and then elevate the transcription of PTGES, an enzyme catalyzing the synthesis of PGE2, and finally enhance the generation of PGE2, which facilitates the carcinogenesis and progression of colon cancer. Aspirin could inhibit the synthesis of PGE2, which may contribute to suppress the function of Lin28B in the carcinogenesis and progression of colon cancer. We will employ functional studies in vivo and in vitro to demonstrate that aspirin could block the oncogenic function of Lin28B in colon cancer, and reveal the molecular mechanisms underlying aspirin inhibiting the functions of Lin28B. This study will not only reveal novel mechanisms of Lin28B promoting carcinogenesis and progression of colon cancer as well as aspirin preventing and treating colon cancer, but also provide theoretical and experimental evidences to support the strategy of targeting Lin28B in the prevention and treatment of colon cancer.

结肠癌是炎症相关性肿瘤。抗炎药阿司匹林能降低结肠癌的发生率和死亡率，但机制不清。原癌基因Lin28B可通过炎症反应促进结肠癌的发生和演进，但Lin28B可否作为阿司匹林防治肠癌的靶点，目前尚无报道。我们证实阿司匹林能抑制Lin28B对肠上皮细胞恶性转化和对肠癌细胞增殖及侵袭能力的促进作用；进一步研究提示Lin28B可直接结合转录因子ARID3A的mRNA并增强其表达，继而增加PTGES的转录，后者催化前列腺素E2（PGE2）合成，进而促进结肠癌的发生和演进。阿司匹林能阻断PGE2的合成，故可借此抑制Lin28B的原癌基因功能。我们将通过体内外功能实验证明阿司匹林能抑制Lin28B的原癌基因功能，并通过分子生物学实验阐明其中的分子机制。本研究不仅将揭示Lin28B促进结肠癌发生和演进以及阿司匹林防治肠癌的新机制，而且还会为Lin28B作为肠癌预防和治疗的新靶点提供理论和实验依据。

基因组不稳定性是恶性肿瘤发生和进展的使能性特征，通过累积驱动基因突变而使细胞获得其它癌症特征。而且，由于同时造成DNA损伤修复缺陷，因此基因组不稳定性也为增强癌细胞的化疗敏感性带来契机。RNA结合蛋白LIN28B在多种癌症类型中表达升高，并被证实可作为癌基因促进癌症的发生和进展。然而，LIN28B是否调控了基因组不稳定性尚不清楚。本研究证实，LIN28B通过诱导基因组不稳定性促进了肠上皮细胞恶性转化和结肠癌进展，同时也提高了结肠癌对化疗药物的敏感性。机制研究发现，LIN28B通过直接抑制GCLC、G6PD、GSTM4和GSTT2B四种谷胱甘肽代谢酶的翻译，降低了谷胱甘肽（GSH）的产生和活性，并因此削弱了细胞清除活性氧（ROS）的能力。同时，LIN28B通过增强转录因子ARID3A的翻译而转录激活两种前列腺素E合成酶PTGES1和PTGES2，从而促进PGE2的产生。而PGE2作为一种关键的炎症介质，增加了ROS的产生。经典的环氧合酶（COX）抑制剂阿司匹林，通过阻断PGE2的产生来降低ROS生成，进而抑制了LIN28B的促癌作用。总之，通过促进基因组不稳定和癌症相关性炎症，LIN28B在降低ROS清除能力的同时也增加了ROS的生成，最终促进了结肠癌的发生和进展。本研究不仅揭示了LIN28B对两个癌症使能特征的促进作用，而且表明LIN28B是结肠癌化学预防和化疗的潜在标志物。