PDF(Pubmed)
Abstract：
Desmosomes are essential structures for ensuring tissue functions, and their deregulation is involved in the development of colorectal cancer (CRC). JUP (γ-catenin) is a desmosome adhesion component that also acts as a signaling hub, suggesting its potential involvement in CRC progression. In this context, we recently demonstrated that miR-195-5p regulated JUP and desmosome cadherins expression. In addition, miR-195-5p gain of function indirectly modulated the expression of key effectors of the Wnt pathway involved in JUP-dependent signaling. Here, our purpose was to demonstrate the aberrant expression of miR-195-5p and JUP in CRC patients and to functionally characterize the role of miR-195-5p in the regulation of desmosome function. First, we showed that miR-195-5p was downregulated in CRC tumors compared to adjacent normal tissue. Then, we demonstrated that JUP expression was significantly increased in CRC tissues compared to adjacent normal tissues. The effects of miR-195-5p on CRC progression were assessed using in vitro transient transfection experiments and in vivo miRNA administration. Increased miR-195-5p in colonic epithelial cells strongly inhibits cell proliferation, viability, and invasion via JUP. In vivo gain of function of miR-195-5p reduced the numbers and sizes of tumors and significantly ameliorated the histopathological changes typical of CRC. In conclusion, our findings indicate a potential pharmacological target based on miR-195-5p replacement as a new therapeutic approach in CRC.
摘要：
桥粒是确保组织功能的重要结构，它们的失调与结直肠癌（CRC）的发展有关。JUP（γ-catenin）是桥粒粘附组件，也充当信号集线器，提示其可能参与CRC进展。在这种情况下，我们最近证明miR-195-5p调节JUP和桥粒钙黏着蛋白的表达.此外,miR-195-5p的功能获得间接调节参与JUP依赖性信号传导的Wnt途径的关键效应子的表达。这里,我们的目的是证明miR-195-5p和JUP在CRC患者中的异常表达,并在功能上表征miR-195-5p在桥粒功能调节中的作用.首先,我们显示,与邻近正常组织相比,miR-195-5p在CRC肿瘤中下调.然后，我们证实,与邻近正常组织相比,JUP在CRC组织中的表达显著增加.使用体外瞬时转染实验和体内miRNA施用评估miR-195-5p对CRC进展的影响。结肠上皮细胞中增加的miR-195-5p强烈抑制细胞增殖，生存能力，并通过JUP入侵。体内miR-195-5p的功能获得减少了肿瘤的数量和大小，并显着改善了CRC典型的组织病理学变化。总之,我们的研究结果表明,基于miR-195-5p替代作为CRC新治疗方法的潜在药理学靶点.
