Linc00210 通过 CTNNBIP1 依赖性方式驱动 Wnt/β-catenin 信号激活和肝肿瘤进展。
Linc00210 drives Wnt/β-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner.
机构信息
Department of Cancer Biology Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, Henan, 450003, China.
Department of Histology and Embryology, College of Basic Medicine, Zhengzhou University, 100 Kexue Road, Zhengzhou, Henan, 450052, China.
出版信息
Mol Cancer. 2018 Mar 14;17(1):73. doi: 10.1186/s12943-018-0783-3.
BACKGROUND
Liver tumor initiating cells (TICs) have self-renewal and differentiation properties, accounting for tumor initiation, metastasis and drug resistance. Long noncoding RNAs are involved in many physiological and pathological processes, including tumorigenesis. DNA copy number alterations (CNA) participate in tumor formation and progression, while the CNA of lncRNAs and their roles are largely unknown.
METHODS
LncRNA CNA was determined by microarray analyses, realtime PCR and DNA FISH. Liver TICs were enriched by surface marker CD133 and oncosphere formation. TIC self-renewal was analyzed by oncosphere formation, tumor initiation and propagation. CRISPRi and ASO were used for lncRNA loss of function. RNA pulldown, western blot and double FISH were used to identify the interaction between lncRNA and CTNNBIP1.
RESULTS
Using transcriptome microarray analysis, we identified a frequently amplified long noncoding RNA in liver cancer termed linc00210, which was highly expressed in liver cancer and liver TICs. Linc00210 copy number gain is associated with its high expression in liver cancer and liver TICs. Linc00210 promoted self-renewal and tumor initiating capacity of liver TICs through Wnt/β-catenin signaling. Linc00210 interacted with CTNNBIP1 and blocked its inhibitory role in Wnt/β-catenin activation. Linc00210 silencing cells showed enhanced interaction of β-catenin and CTNNBIP1, and impaired interaction of β-catenin and TCF/LEF components. We also confirmed linc00210 copy number gain using primary hepatocellular carcinoma (HCC) samples, and found the correlation between linc00210 CNA and Wnt/β-catenin activation. Of interest, linc00210, CTNNBIP1 and Wnt/β-catenin signaling targeting can efficiently inhibit tumor growth and progression, and liver TIC propagation.
CONCLUSION
With copy-number gain in liver TICs, linc00210 is highly expressed along with liver tumorigenesis. Linc00210 drives the self-renewal and propagation of liver TICs through activating Wnt/β-catenin signaling. Linc00210 interacts with CTNNBIP1 and blocks the combination between CTNNBIP1 and β-catenin, driving the activation of Wnt/β-catenin signaling. Linc00210-CTNNBIP1-Wnt/β-catenin axis can be targeted for liver TIC elimination.
背景
肝肿瘤起始细胞（TICs）具有自我更新和分化的特性，参与肿瘤的起始、转移和耐药性。长链非编码 RNA 参与许多生理和病理过程，包括肿瘤发生。DNA 拷贝数改变（CNA）参与肿瘤的形成和进展，而 lncRNA 的 CNA 及其作用在很大程度上尚不清楚。
方法
通过微阵列分析、实时 PCR 和 DNA FISH 确定 lncRNA 的 CNA。通过表面标记物 CD133 和类器官形成来富集肝 TICs。通过类器官形成、肿瘤起始和增殖来分析 TIC 的自我更新。CRISPRi 和 ASO 用于 lncRNA 功能丧失。RNA 下拉、Western blot 和双 FISH 用于鉴定 lncRNA 和 CTNNBIP1 之间的相互作用。
结果
使用转录组微阵列分析，我们在肝癌中鉴定出一种经常扩增的长链非编码 RNA，称为 linc00210，它在肝癌和肝 TICs 中高表达。肝癌和肝 TICs 中 linc00210 拷贝数增加与其高表达相关。Linc00210 通过 Wnt/β-catenin 信号通路促进肝 TICs 的自我更新和肿瘤起始能力。Linc00210 与 CTNNBIP1 相互作用并阻止其对 Wnt/β-catenin 激活的抑制作用。Linc00210 沉默细胞显示出 β-catenin 和 CTNNBIP1 之间增强的相互作用，以及 β-catenin 和 TCF/LEF 成分之间受损的相互作用。我们还使用原发性肝细胞癌（HCC）样本证实了 linc00210 拷贝数增加，并发现了 linc00210 CNA 与 Wnt/β-catenin 激活之间的相关性。有趣的是，linc00210、CTNNBIP1 和 Wnt/β-catenin 信号通路靶向治疗可以有效地抑制肿瘤生长和进展以及肝 TIC 增殖。
结论
在肝 TIC 中，linc00210 随着肝肿瘤的发生而获得拷贝数增加，高表达。Linc00210 通过激活 Wnt/β-catenin 信号通路驱动肝 TIC 的自我更新和增殖。Linc00210 与 CTNNBIP1 相互作用并阻止 CTNNBIP1 与 β-catenin 结合，从而驱动 Wnt/β-catenin 信号通路的激活。Linc00210-CTNNBIP1-Wnt/β-catenin 轴可作为肝 TIC 消除的靶点。
Zotero 插件