SENP1靶向调控HIF1α促进前列腺癌瓦伯格效应的机制研究

The Warburg effect, a phenomenon known as increased aerobic glycolysis in cancer, promote carcinoma (PCa) progression. Accumulating Evidence shows that hypoxia-induced factor 1α (HIF1α) promote the Warburg effect by activating the transcription of several genes such as GLUT1, LDHA, PDK1, et al. SUMO-specific protease 1 (SENP1) is essential for HIF1α stabilization and activity through targeting its oxygen-depend-degradation (ODD) domain. We, therefore, hypothesize that SENP1 played a vital role in PCa progression and metastasis by promoting the Warburg effect through the HIF1α signal pathway. In our study, the association of between SENP1 and PCa clinical pathological characteristics will be evaluated, then the effect of tumor microenvironment on the Warburg effect and expression of SENP1 and HIF1α, in PCa cells will be further clarified. Next the effect of SENP1 on SUMOylation of HIF1α will be detected, and signal transduction pathway of SENP1 in regulating the Warburg effect in PCa will be explored. Finally the effect of SENP1 on PCa progression and metastasis by regulating the Warburg effect will be investigated in vivo. Based on the data, we aim to provide a new perspective to the molecular mechanisms of PCa invasion and metastasis and explore the diagnostic and therapeutic potential of SENP1 in PCa.

瓦伯格（Warburg）效应即肿瘤细胞对糖酵解通路产能依赖增强现象，可促进前列腺癌（PCa）疾病进展，但机制不明。HIF1α通过转录活化GLUT1、LDHA、PDK1等糖酵解途径限速酶来增强Warburg效应，而SUMO特异性蛋白酶1（SENP1）可直接靶向作用于HIF1α氧依赖性降解结构域，使HIF1α去SUMO化而不被降解。我们假设：PCa中SENP1表达升高使HIF1α去SUMO化而增加其活性，再通过HIF1α调控的糖酵解途径增强Warburg效应，最终促进PCa进展和转移。因此，本研究将从临床病理、肿瘤微环境、去SUMO化修饰及信号转导通路、动物实验方面论证SENP1依赖HIF1α通路提升Warburg效应促进PCa进展和转移的分子机制，拓展我们对SUMO化修饰和能量代谢在PCa发病中的新认识，并为SENP1成为PCa肿瘤标记物和治疗靶点提供理论依据。

前列腺癌（Prostate cancer, PCa）是发达国家男性最常见的恶性肿瘤，其发病机制是肿瘤研究领域的热点问题。首先，我们进行了微小核苷酸-145下调小泛素相关修饰物特异性蛋白酶1（Small ubiquitin-related modifier-specific protease 1，SENP1）抑制PCa细胞增殖的机制研究。我们发现，与正常细胞和癌旁相比，miR-145和SENP1在PCa中呈显著差异表达。随后的研究证实，miR-145可与SENP1 mRNA 3’非编码区特异性结合。体内和体外实验表明，miR-145可通过与SENP1作用，导致PCa细胞增殖抑制。这些结果说明，miR-145作为肿瘤抑制因子，下调SENP1表达并抑制PCa细胞增殖。接下来，我们开展了SENP1通过靶向调控HIF1ɑ参与PCa瓦伯格效应，进而促进细胞增殖的实验研究。大家知道，缺氧环境下实体肿瘤有氧糖酵解增强，进而改变肿瘤代谢模式，以更好地为肿瘤供能以适应肿瘤微环境。这又被称为“瓦伯格效应”。 这部分中，我们观察多种PCa细胞在低氧、缺氧、低PH、低血清状态下，乳糖、ATP、葡萄糖等产物的代谢情况，结果发现在模拟肿瘤微环境条件下，不同肿瘤细胞展现出类似“瓦伯格效应”的趋势；同时，研究数据说明，SENP1可促进PCa细胞增殖，其中机制之一可能与低氧条件下SENP1通过去SUMO化HIF1ɑ，导致HIF1ɑ表达升高，进而与MCT4结合促进“瓦伯格效应”发生有关。上述研究为阐明PCa发病分子机制提供新的理论依据，为开发新的肿瘤标记物和治疗靶向奠定基础。