PDF(Pubmed)
Abstract：
Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson\'s disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.
摘要：
富含亮氨酸的重复激酶2(LRRK2)是属于ROCO蛋白家族的丝氨酸-苏氨酸蛋白激酶。在LRRK2的激酶域中，称为LRRK2G2019S的点突变已成为与帕金森氏病相关的最普遍的变体。最近的临床研究表明，G2019S携带者患癌症的风险较高，包括结肠癌.尽管有这样的观察,LRRK2G2019S与结肠癌相关的潜在机制仍然难以捉摸.在这项研究中,采用结肠炎相关癌症（CAC）模型和LRRK2G2019S敲入（KI）小鼠模型，我们证明LRRK2G2019S促进结肠癌的发病机制，以KI小鼠肿瘤数量和大小增加为特征。此外，LRRK2G2019S增强肿瘤微环境内的肠上皮细胞增殖和炎症。机械上,KI小鼠对DSS诱导的结肠炎表现出更高的易感性，抑制LRRK2激酶活性改善结肠炎严重程度和CAC进展。我们的研究还显示，在结肠炎模型中，LRRK2G2019S促进炎症小体激活并加剧肠上皮坏死。值得注意的是,GSDMD抑制剂减轻LRRK2G2019SKI小鼠的结肠炎。一起来看,我们的发现提供了实验证据，表明LRRK2中激酶活性的增加促进了结直肠肿瘤发生，表明LRRK2是结肠癌患者表现出高LRRK2激酶活性的潜在治疗靶标。
