CSN6-TRIM21 axis instigates cancer stemness during tumorigenesis
CSN6-TRIM21 axis instigates cancer stemness during tumorigenesis
复制标题
CSN6-TRIM21 轴在肿瘤发生过程中引发癌症干性
DOI：
10.1038/s41416-020-0779-9
复制
发表时间：
2020-03-30
影响因子：
8.8
通讯作者：
Lee, Mong-Hong
中科院分区：
文献类型：
--
作者：
Qin, Baifu;Zou, Shaomin;Lee, Mong-Hong
研究背景肿瘤干细胞（Cancer stem cells，CSCs）是肿瘤发生、转移和复发的重要细胞.然而，CSC的形成，维护和扩展在结直肠癌（CRC）的机制仍然很差characterized.MethodsThe COP 9信号体亚基6（CSN 6）在调节癌症干细胞的作用进行了评估类器官的形成和有限稀释分析。在体外和体内评价CSN 6-TRIM 21-OCT 1-ALDH 1A 1轴在CSC形成中的作用。CSN 6，TRIM 21和ALDH 1A 1表达的协会进行了验证，通过组织芯片与267 CRC patients.ResultsThe结果表明，CSN 6是球的形成和维持患者源性类器官（PDO）的生长至关重要。我们表征了CSN 6在调节癌症干细胞性中的作用，其涉及TRIM 21 E3泛素连接酶、转录因子POU 2类同源框1（OCT 1）和癌症干细胞标志物醛脱氢酶1A 1（ALDH 1A 1）。我们的数据表明，CSN 6促进泛素介导的TRIM 21降解，从而降低TRIM 21介导的OCT 1泛素化，随后稳定OCT 1。因此，OCT 1稳定导致ALDH 1A 1表达并促进癌症的干性。我们进一步表明，CSN 6，TRIM 21和ALDH 1A 1的蛋白质表达水平可以作为人类CRC.ConclusionsIn结论的预后标志物，我们验证了癌症干细胞调节途径涉及ALDH 1A 1水平通过CSN 6-TRIM 21轴，这可能是利用CRC分子标记物，并有针对性地为癌症的治疗干预。
BackgroundCancer stem cells (CSCs) are responsible for tumour initiation, metastasis and recurrence. However, the mechanism of CSC formation, maintenance and expansion in colorectal cancer (CRC) remains poorly characterised.MethodsThe role of COP9 signalosome subunit 6 (CSN6) in regulating cancer stemness was evaluated by organoid formation and limited dilution analysis. The role of CSN6–TRIM21–OCT1–ALDH1A1 axis in CSC formation was evaluated in vitro and in vivo. The association of CSN6, TRIM21 and ALDH1A1 expression was validated by a tissue microarray with 267 CRC patients.ResultsThe results showed that CSN6 is critical for sphere formation and maintaining the growth of patient-derived organoids (PDOs). We characterised the role of CSN6 in regulating cancer stemness, which involves the TRIM21 E3 ubiquitin ligase, transcription factor POU class 2 homeobox 1 (OCT1) and cancer stem cell marker aldehyde dehydrogenase 1 A1 (ALDH1A1). Our data showed that CSN6 facilitates ubiquitin-mediated degradation of TRIM21, which in turn decreases TRIM21-mediated OCT1 ubiquitination and subsequently stabilises OCT1. Consequently, OCT1 stabilisation leads to ALDH1A1expression and promotes cancer stemness. We further showed that the protein expression levels of CSN6, TRIM21 and ALDH1A1 can serve as prognostic markers for human CRC.ConclusionsIn conclusion, we validate a pathway for cancer stemness regulation involving ALDH1A1 levels through the CSN6–TRIM21 axis, which may be utilised as CRC molecular markers and be targeted for therapeutic intervention in cancers.