Xiao Zhiyuan, Wei Zhigang, Deng Danling, Zheng Zhe, Zhao Yali, Jiang Shenglu, Zhang Dan, Zhang Ling-Jie, Fan Mingmei, Chen Siqi, Wang ShuYang, Ding Yanqing, Ye Yaping, Jiao Hongli
1Department of Pathology, Nanfang Hospital and School of Basic Medical Science, Southern Medical University, Guangzhou, 510515 China.
2Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
Cancer Cell Int. 2020 Feb 13;20:50. doi: 10.1186/s12935-020-1124-3. eCollection 2020.
Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Siah E3 ubiquitin protein ligase 1 (Siah1) has been identified as a tumor suppressor gene and plays an important role in the development of malignant tumors. However, the potential role and molecular mechanism of Siah1 in the development and progression of CRC is still unclear.
To explore the role and molecular mechanism of Siah1 in the development and progression of CRC, we examined the expression of Siah1 in CRC tissue samples and analyzed its association with progression and prognosis in CRC. In addition, overexpression and knockdown of Siah1 was used to investigate its activity in CRC cells. We also use bioinformatics to analyze and verify the significant roles of Siah1 in critical signaling pathways of CRC.
We found that the expression of Siah1 was significantly downregulated in CRC tissues, and low expression of Siah1 was associated with aggressive TNM staging and poor survival of CRC patients. Moreover, we revealed that overexpression of Siah1 in CRC cells markedly inhibited CRC cell proliferation and invasion in vitro and in vivo, while knockdown of Siah1 enhanced CRC cell proliferation and invasion. Furthermore, we found that Siah1 prohibited cell proliferation and invasion in CRC partially through promoting AKT (the serine-threonine protein kinase) and YAP (yes associated protein) ubiquitylation and proteasome degradation to regulate the activity of MAPK(mitogen-activated protein kinase 1), PI3K-AKT (phosphatidylinositol 3-kinase-the serine-threonine protein kinase) and Hippo signaling pathways.
These findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.
结直肠癌（CRC）是世界上最常见的恶性肿瘤之一。Siah E3泛素蛋白连接酶1（Siah1）已被鉴定为一种肿瘤抑制基因，在恶性肿瘤的发生发展中起重要作用。然而，Siah1在CRC发生发展中的潜在作用和分子机制仍不清楚。
为了探究Siah1在CRC发生发展中的作用和分子机制，我们检测了CRC组织样本中Siah1的表达，并分析其与CRC进展和预后的关系。此外，通过Siah1的过表达和敲低来研究其在CRC细胞中的活性。我们还利用生物信息学分析并验证Siah1在CRC关键信号通路中的重要作用。
我们发现CRC组织中Siah1的表达显著下调，Siah1低表达与CRC患者的侵袭性TNM分期和不良生存相关。此外，我们发现CRC细胞中Siah1的过表达在体外和体内均显著抑制CRC细胞增殖和侵袭，而Siah1的敲低则增强了CRC细胞的增殖和侵袭。此外，我们发现Siah1部分通过促进AKT（丝氨酸 - 苏氨酸蛋白激酶）和YAP（Yes相关蛋白）的泛素化和蛋白酶体降解来调节MAPK（丝裂原活化蛋白激酶1）、PI3K - AKT（磷脂酰肌醇3 - 激酶 - 丝氨酸 - 苏氨酸蛋白激酶）和Hippo信号通路的活性，从而抑制CRC细胞增殖和侵袭。
这些发现表明Siah1是一种新型潜在的预后生物标志物，在CRC的发生发展中起肿瘤抑制作用。
