The CK1δ/ε-AES axis regulates tumorigenesis and metastasis in colorectal cancer.
The CK1δ/ε-AES axis regulates tumorigenesis and metastasis in colorectal cancer.
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CK1δ/δ-AES 轴调节结直肠癌的肿瘤发生和转移
作者：
Wang Z;Zhou L;Wang Y;Peng Q;Li H;Zhang X;Su Z;Song J;Sun Q;Sayed S;Liu S;Lu D
背景：分裂的氨基末端增强子(AES)在包括结直肠癌(CRC)在内的某些肿瘤中被认为是一种肿瘤和转移抑制因子，但对其表达的调控知之甚少。方法：应用生物信息学方法研究细胞周期蛋白1、细胞周期蛋白1δ和细胞周期蛋白1ε的表达模式。采用免疫共沉淀法、谷胱甘肽转移酶下拉法、Western Blot法、实时定量聚合酶链式反应和免疫组织化学等方法，研究细胞角蛋白1δ/ε调控血管紧张素转换酶基因表达的机制。通过体外集落形成、转运、球体形成、肿瘤器官形成、体内肿瘤转移模型和患者源性结直肠癌异种移植(PDTX)模型评价其生物学功能。结果：ACEs的表达与CK1δ/ε的表达呈显著负相关。从机制上讲，ASAs可以通过其Q结构域与CK1、δ/ε和Skp2相互作用。Skp2以CK1δ/ε依赖的方式介导ACEs的泛素化和降解。CK1δ/ε在SER121位上磷酸化aES，加速Skp2介导的aES泛素化和降解。在结肠癌细胞中，CK1AES拮抗野生型δ/ε对Wnt和Notch信号的影响，但不能拮抗其突变体(S121a)的作用，导致Wnt靶基因和Notch靶基因表达增加。通过下调ACEs的表达，CK1δ/ε促进了结肠癌细胞的非锚定生长、迁移、侵袭和球体的形成。CK1APCMIN还通过调节δ/ε的降解，促进APCMIN/+结直肠癌细胞生长，促进结肠癌小鼠肝转移。此外，CK1抑制剂SR3029治疗通过稳定APCmin/+结直肠癌器官和患者来源的结直肠癌异种移植瘤(PDTX)中的AES来抑制肿瘤生长。结论：我们的结果表明CK1δ/ε-AES轴在结直肠癌的发生和转移中起重要作用，靶向抑制这一轴可能是结直肠癌潜在的治疗策略。
Background: Amino-terminal enhancer of split (AES) has been identified as a tumor and metastasis suppressor in some cancers including colorectal cancer (CRC), but very little is known about the regulation of AES expression. Methods: Bioinformatics analysis was used to investigate the expression patterns of AES, CK1δ and CK1ε. The co-immunoprecipitation, GST pull-down, Western Blot, real-time PCR and immunohistochemistry were performed to study the mechanism underlying the regulation of AES expression by CK1δ/ε. The biological function was assessed by in vitro colony formation, transwell, sphere formation, tumor organoids, in vivo tumor metastasis model and patient-derived colorectal tumor xenografts (PDTX) model. Results: A strong inverse relationship was observed between the expression of AES and the expression of CK1δ/ε. Mechanically, AES could interact with CK1δ/ε and SKP2 using its Q domain. SKP2 mediated the ubiquitination and degradation of AES in a CK1δ/ε-dependent manner. CK1δ/ε phosphorylated AES at Ser121 and accelerated the SKP2-mediated ubiquitination and degradation of AES. In colon cancer cells, CK1δ/ε antagonized the effect of wild-type AES but not that of its mutant (S121A) on Wnt and Notch signaling, leading to an increase in the expression of Wnt target genes and Notch target genes. By downregulating the expression of AES, CK1δ/ε enhanced anchorage-independent growth, migration, invasion and sphere formation in colon cancer cells. CK1δ/ε also promoted the growth of APCmin/+ colorectal tumor organoids and liver metastasis in colon cancer mouse models through the regulation of AES degradation. Furthermore, CK1 inhibitor SR3029 treatment suppressed tumor growth via stabilizing AES in APCmin/+ colorectal tumor organoids and patient-derived colorectal tumor xenografts (PDTX). Conclusions: Our results revealed that the CK1δ/ε-AES axis is important for CRC tumorigenesis and metastasis, and targeted inhibition of this axis may be a potential therapeutic strategy for CRC.
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影响因子：
82.9
作者：
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通讯作者：
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50.3
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11.2
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