lncrna - ccat5介导的Wnt/β-Catenin与STAT3信号之间的串扰提示了高Wnt活性转移性胃癌的新治疗方法。

IF 20.1 1区 医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2023-11-27 DOI:10.1002/cac2.12507
Chenchen Liu, Aiwen Shen, Junquan Song, Lei Cheng, Meng Zhang, Yanong Wang, Xiaowen Liu
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引用次数: 0

摘要

背景:虽然组成性激活的Wnt/β-catenin信号通路在胃癌(GC)的进展中起着至关重要的作用,但很少有Wnt抑制剂被批准用于临床。此外,长链非编码rna (lncRNAs)在GC腹腔播散(IPD)中的临床意义尚不明确。在这里,我们研究了wnt转激活的lncRNA结肠癌相关转录物5 (CCAT5)在胃癌转移中的功能和治疗潜力。方法:采用lncrna测序法,记录Wnt家族成员3A (Wnt3a)和抗降解β-catenin (S33Y突变)在Wnt活性低的腹水源性GC细胞中诱导的lncrna丰度变化。采用荧光素酶报告基因、染色质免疫沉淀(ChIP)-re-ChIP测定CCAT5的转录方式。在两组胃癌患者中检测CCAT5的临床意义。CCAT5的生物学功能通过功能获得和功能丧失研究进行了研究。通过rna测序、质谱分析和CRISPR/ cas9敲除系统探索其分子机制。通过基于rnai的细胞异种移植模型和IPD患者源异种移植(PDX)模型检测CCAT5的治疗潜力。结果:我们发现了一个新的wnt调控lncRNA CCAT5,它被β-catenin/转录因子3 (TCF3)复合物反激活。CCAT5在GC中显著上调,预示预后不良。功能研究证实了CCAT5在胃癌生长和转移中的促进作用。在机制上,CCAT5结合到信号换能器和转录激活子3 (STAT3)的c端结构域,阻断含有Src同源2结构域的蛋白酪氨酸磷酸酶1 (SHP-1)介导的STAT3Y705去磷酸化,导致STAT3进入核并转激活,从而加速GC的进展。此外,我们证明Wnt3a和β-catenin都是STAT3信号通路的激活剂,并且CCAT5和STAT3之间的相互作用对于wnt驱动的STAT3信号传导和肿瘤进化在功能上是必不可少的。最后,我们发现体内si-CCAT5选择性地抑制Wnthigh GC的生长和转移,但对wnlow GC没有作用。si-CCAT5联合奥沙利铂对Wnthigh PDX小鼠有明显的协同治疗作用。结论:我们发现了一种新的wnt转激活lncRNA CCAT5。我们的研究揭示了STAT3信号通过典型Wnt信号调控的机制,以及CCAT5作为关键中介的功能意义。我们提供了lncrna作为逆转GC进展的治疗靶点的概念进展。
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LncRNA-CCAT5-mediated crosstalk between Wnt/β-Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity

Background

Although the constitutively activated Wnt/β-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis.

Methods

LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant β-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD.

Results

We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the β-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnthigh GC, but not Wntlow GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnthigh PDX mice.

Conclusions

We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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