(P)RR通过抑制Wnt3泛素化降解诱发结直肠癌肝转移的机制研究

Liver metastasis is the main death cause of colorectal cancer. However, the key driving molecule(s) of colorectal cancer liver metastasis is/are still unclear. Recent studies indicated that the Wnt3/β-catenin/Ascl2/c-Myc signaling transduction promotes the directed liver metastasis of colorectal cancer by endowing cancer cells with the characters of migrating cancer stem cells. However, the regulatory mechanism of Wnt3, as a critical upstream molecule, has not been reported yet. We have previously demonstrated, for the first time, that (pro)renin receptor ((P)RR) induces carcinogenesis of colorectal cancer by increasing Wnt3 protein level and the activity of Wnt3/β-catenin signaling pathway. In the preliminary experiments of the present project, we further found that (P)RR inhibits Wnt3 ubiquitination and degradation, promotes in vitro migration and invasion of colorectal cancer cell lines and in vivo colon-liver metastasis in nude mice; furthermore, high expression of (P)RR in the patients’ cancer tissues is positively associated with cancer progression and metastasis. Based on these previous findings, the present project hypothesized and aims to demonstrate that (P)RR inhibits Wnt3 ubiquitination and degradation, thus promotes the Wnt3-induced colorectal cancer liver metastasis. Moreover, we will take the lead in investigating the molecular mechanism by which (P)RR regulates the Wnt3 ubiquitination and looking for the key E3 ubiquitin ligase(s) that mediate(s) this effect. We will conduct the project at multi-levels of molecular interaction, cell, animal and clinical data. We aim to provide novel therapeutic theory and molecular target for the disease by the present study.

肝转移是结直肠癌患者最主要的死亡原因,而其关键驱动分子尚不明确。新近发现Wnt3/β-catenin/Ascl2/c-Myc信号转导通过介导癌细胞获得迁移干细胞特性等行为诱发结直肠癌定向肝转移,然而上游关键分子Wnt3的调控机制尚未见报道。我们已率先报道肾素（原）受体(P)RR通过上调Wnt3蛋白水平、激活Wnt3/β-catenin通路介导结直肠癌发生。本项目预实验进一步发现(P)RR可抑制Wnt3泛素化降解、促进人结直肠癌细胞体外迁移侵袭及裸鼠体内结肠-肝转移;且患者癌组织(P)RR高表达与结直肠癌进展转移正相关。基于前期发现,我们推断并拟证实(P)RR通过抑制Wnt3泛素化降解,促进Wnt3介导的结直肠癌进展及肝转移。我们也将率先探寻在(P)RR调控Wnt3泛素化过程中起关键作用的E3泛素连接酶。我们将从分子互作、细胞、动物及临床等多水平进行验证,以期为该病的治疗提供新理论、新靶点。

肝转移是结直肠癌患者最主要的死亡原因,而其关键驱动分子尚不明确。新近发现Wnt3/β-catenin信号转导通过介导癌细胞获得迁移干细胞特性等行为诱发结直肠癌定向肝转移,然而上游关键分子Wnt3的调控机制尚未见报道。我们已率先报道肾素（原）受体(P)RR通过上调Wnt3蛋白水平、激活Wnt3/β-catenin通路介导结直肠癌发生。本项目前期预实验发现(P)RR可抑制Wnt3泛素化降解、促进人结直肠癌细胞体外迁移侵袭及裸鼠体内结肠-肝转移;且患者癌组织(P)RR高表达与结直肠癌进展转移正相关。基于前期发现,我们推断并拟证实(P)RR通过抑制Wnt3泛素化降解,促进Wnt3介导的结直肠癌进展及肝转移,同时率先探寻了在(P)RR调控Wnt3泛素化过程中起关键作用的E3泛素连接酶。本项目从分子互作、细胞、动物及临床等多水平进行了验证,以期为该病的治疗提供新理论、新靶点。本项目研究发现结直肠癌原发灶中(P)RR表达升高与Wnt3高表达及疾病进展特别是肝转移呈正相关;进展期特别是发生肝转移的结直肠癌原发灶组织中Wnt3和E3泛素连接酶NEDD4L的共定位明显低于非进展期结直肠癌;在结肠癌细胞中，(P)RR显著抑制NEDD4L介导的Wnt3蛋白泛素化降解;肠上皮特异性(P)RR过表达的基因编辑小鼠相较于野生型小鼠,其肠上皮细胞Wnt3-NEDD4L共定位明显降低,且对结直肠癌具有保护作用的Lachnospiraceae_NK4A136和Bacteroides菌群明显受抑。因此,本研究发现(P)RR通过抑制NEDD4L介导的Wnt3泛素化降解并调节肠道菌群促进结直肠癌进展特别是肝转移。本项目成果未来有望转化为治疗结肠肠癌的新型治疗策略。