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CSN6-TRIM21 轴在肿瘤发生过程中引发癌症干性。

CSN6-TRIM21 axis instigates cancer stemness during tumorigenesis.

机构信息

Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China.

Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China.

出版信息

Br J Cancer. 2020 May;122(11):1673-1685. doi: 10.1038/s41416-020-0779-9. Epub 2020 Mar 30.

DOI:10.1038/s41416-020-0779-9
PMID:32225170
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7250844/
Abstract

BACKGROUND

Cancer 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.

METHODS

The 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.

RESULTS

The 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.

CONCLUSIONS

In 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.

摘要

背景

癌症干细胞（CSC）是肿瘤起始、转移和复发的原因。然而，结直肠癌（CRC）中 CSC 的形成、维持和扩增的机制仍未得到很好的描述。

方法

通过类器官形成和有限稀释分析评估 COP9 信号osome 亚基 6（CSN6）在调节癌症干性中的作用。在体外和体内评估 CSN6-TRIM21-OCT1-ALDH1A1 轴在 CSC 形成中的作用。通过包含 267 例 CRC 患者的组织微阵列验证 CSN6、TRIM21 和 ALDH1A1 表达的相关性。

结果

结果表明 CSN6 对于球体形成和维持患者来源的类器官（PDOs）的生长至关重要。我们描述了 CSN6 在调节癌症干性中的作用，该作用涉及 TRIM21 E3 泛素连接酶、转录因子 POU 类 2 同源框 1（OCT1）和癌症干细胞标志物醛脱氢酶 1 A1（ALDH1A1）。我们的数据表明，CSN6 促进 TRIM21 的泛素介导降解，这反过来又减少了 TRIM21 介导的 OCT1 泛素化，随后稳定了 OCT1。因此，OCT1 稳定导致 ALDH1A1 表达并促进癌症干性。我们进一步表明，CSN6、TRIM21 和 ALDH1A1 的蛋白表达水平可作为人类 CRC 的预后标志物。

结论

总之，我们验证了一条涉及 ALDH1A1 水平的通过 CSN6-TRIM21 轴的癌症干性调节途径，该途径可作为 CRC 分子标志物，并可作为癌症治疗干预的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/427b5f628949/41416_2020_779_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/1915b55e53c0/41416_2020_779_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/fac1fd86fc75/41416_2020_779_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/b45a5fa362cd/41416_2020_779_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/0fc19c40f8c7/41416_2020_779_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/37526ad68603/41416_2020_779_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/427b5f628949/41416_2020_779_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/1915b55e53c0/41416_2020_779_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/fac1fd86fc75/41416_2020_779_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/b45a5fa362cd/41416_2020_779_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/0fc19c40f8c7/41416_2020_779_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/37526ad68603/41416_2020_779_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5bd/7250844/427b5f628949/41416_2020_779_Fig6_HTML.jpg

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