鞣花鞣质代谢物urolithins通过 NF-κB/PRL-3反馈环路抑制肝癌淋巴道转移机制研究

Based on channel tropism theories, numerous ellagitannins-rich Chinese herbal medicines are considered to distribute to liver and intestines. In previous studies, ellagitannins suffer extensive metabolism to generate ellagic acid in digestive fluid, and are further metabolized by the gut microbiota to produce urolithins that are much better absorbed as the real beneficial substances for anti-oxidation, anti-inflammation, and anti-carcinogenesis in vivo. The failure of surgery and/or postoperative radiotherapy and chemotherapy of hepatocellular carcinoma is generally attributed to lymphatic metastasis of hepatocellular carcinoma, which is recognized as an unresolved case in clinical practice. The pathogenesis of lymphatic metastasis of hepatocellular carcinoma is involved in epithelial-mesenchymal transition mediated by activation of nuclear factor κB (NF-κB) and overexpression of phosphatase of regenerating liver 3 (PRL-3). According to the literature research on antineoplastic activity of urolithins and our previous experimental research, the present project aims to investigate the inhibiting effects of urolithins on lymphatic metastasis of hepatocellular carcinoma both in vitro and in vivo. The regulatory mechanism of urolithins on NF-κB/PRL-3 feedback loop will also be demonstrated. The preclinical evidences revealed in this project could clarify whether urolithins are the metabolic pharmacodynamic materials of ellagictannins from Chinese herbal medicine against lymphatic metastasis of hepatocellular carcinoma.

中医归经理论认为富含鞣花鞣质的中药归肝、大肠经。研究表明，鞣花鞣质类化合物在胃肠代谢成鞣花酸，再经肠道菌群代谢生成urolithins后进入机体内发挥抗氧化、抗炎及抗肿瘤作用。肝癌淋巴道转移导致的肝癌外科手术及术后放化疗失败已成为临床肝癌治疗的公认性难题，其发病机制与核转录因子NF-κB活化及促肝细胞再生磷酸酶PRL-3过表达而介导上皮间充质转化相关。本项目拟在已有报道的urolithins抗肿瘤活性研究成果及前期研究工作基础上，研究鞣花鞣质代谢物urolithins对肝细胞癌淋巴道转移的抑制作用，阐明urolithins对肝癌细胞中NF-κB/PRL-3反馈环路的调控机制，并通过小鼠体内肝癌淋巴道转移模型深入研究鞣花鞣质代谢物urolithins治疗肝细胞癌淋巴道转移的动态机制。本项目能够为鞣花鞣质代谢物urolithins治疗肝细胞癌淋巴道转移提供临床前研究依据。

本项目研究鞣花鞣质代谢物urolithins调控NF-κB/PRL-3轴抑制肝癌淋巴道转移恶性进展的作用机制。运用分子生物学和分子药理学研究方法，在细胞模型和动物模型中研究urolithins对肝癌细胞侵袭转移的抑制作用，并阐明其作用机制。研究表明，urolithins能够显著降低肝癌细胞的细胞活力并诱导肝癌细胞凋亡；urolithin A能够抑制肝癌细胞恶性进展的潜能较其他urolithins化合物高；urolithins能够抑制肝癌细胞侵袭转移；urolithin A抑制肝癌细胞与人淋巴管内皮细胞间的相互作用；体外机制研究证实urolithin A能够调控NF-κB/PRL-3反馈环路并抑制其下游促进肝癌细胞恶性转化相关靶标的表达；鞣花酸/urolithin A对小鼠肝癌模型中肝细胞恶性转化具有抑制作用，其机制与urolithin A调控NF-κB/PRL-3反馈环路抑制下游恶性转化相关靶标的表达有关。本项目研究结果可为临床运用鞣花鞣质及其代谢物防治肝脏疾病提供依据。