Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation
Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation
复制标题
Siah1 下调通过调节 AKT 和 YAP 泛素化和蛋白酶体降解促进结直肠癌细胞增殖和迁移
DOI：
10.1186/s12935-020-1124-3
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发表时间：
2020-02-13
影响因子：
5.8
通讯作者：
Jiao, Hongli
中科院分区：
文献类型：
--
作者：
Xiao, Zhiyuan;Wei, Zhigang;Jiao, Hongli
研究背景结直肠癌(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)是一种肿瘤抑制基因，在恶性肿瘤的发生发展中起重要作用。为了探讨Siah1在结直肠癌发生发展中的作用及其分子机制，我们检测了Siah1在结直肠癌组织中的表达，并分析了其与结直肠癌进展及预后的关系。此外，还利用Siah1的过表达和敲除来研究其在结直肠癌细胞中的活性。结果发现Siah1在结直肠癌组织中的表达显著下调，其低表达与结直肠癌患者的TNM分期和预后密切相关。此外，我们还发现Siah1在结直肠癌细胞中的过表达明显抑制了结直肠癌细胞的增殖和侵袭，而Siah1基因的敲除则促进了结直肠癌细胞的增殖和侵袭。此外，我们还发现Siah1通过促进AKT(丝氨酸-苏氨酸蛋白激酶)和YAP(YES相关蛋白)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)和河马信号通路，从而部分地抑制了结直肠癌细胞的增殖和侵袭。结论Siah1是一种新的潜在的预后生物标志物，在结直肠癌的发生发展过程中发挥着肿瘤抑制作用。
BackgroundColorectal 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.MethodsTo 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.ResultsWe 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.ConclusionsThese findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.