COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of β-catenin signaling.

IF 4.9 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2024-10-01 Epub Date: 2024-07-30 DOI:10.1007/s13402-024-00972-4

Mei-Na Cai, Dong-Mei Chen, Xin-Ru Chen, Yu-Rong Gu, Chun-Hong Liao, Le-Xin Xiao, Jia-Liang Wang, Bing-Liang Lin, Yue-Hua Huang, Yi-Fan Lian

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引用次数: 0

Abstract

Background: Liver cancer stem cells (CSCs) contribute to tumor initiation, progression, and recurrence in hepatocellular carcinoma (HCC). The Wnt/β-catenin pathway plays a crucial role in liver cancer stemness, progression, metastasis, and drug resistance, but no clinically approved drugs have targeted this pathway efficiently so far. We aimed to elucidate the role of COLEC10 in HCC stemness.

Methods: The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases were employed to search for the association between COLEC10 expression and HCC stemness. Colony formation, sphere formation, side population, and limiting dilution tumor initiation assays were used to identify the regulatory role of COLEC10 overexpression in the stemness of HCC cell lines. Wnt/β-catenin reporter assay and immunoprecipitation were performed to explore the underlying mechanism.

Results: COLEC10 level was negatively correlated with HCC stemness. Elevated COLEC10 led to decreased expressions of EpCAM and AFP (alpha-fetoprotein), two common markers of liver CSCs. Overexpression of COLEC10 inhibited HCC cells from forming colonies and spheres, and reduced the side population numbers in vitro, as well as the tumorigenic capacity in vivo. Mechanically, we demonstrated that overexpression of COLEC10 suppressed the activity of Wnt/β-catenin signaling by upregulating Wnt inhibitory factor WIF1 and reducing the level of cytoplasmic β-catenin. COLEC10 overexpression promoted the interaction of β-catenin with the component of destruction complex CK1α. In addition, KLHL22 (Kelch Like Family Member 22), a reported E3 ligase adaptor predicted to interact with CK1α, could facilitate COLEC10 monoubiquitination and degradation.

Conclusion: COLEC10 inhibits HCC stemness by downregulating the Wnt/β-catenin pathway, which is a promising target for liver CSC therapy.

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COLEC10通过抑制β-catenin信号的活性来抑制肝细胞癌的干性。

背景：肝癌干细胞（CSCs）在肝细胞癌（HCC）的肿瘤发生、进展和复发中起着重要作用。Wnt/β-catenin通路在肝癌干细胞的形成、进展、转移和耐药性中起着至关重要的作用，但迄今为止还没有临床批准的药物能有效地靶向这一通路。我们旨在阐明COLEC10在HCC干性中的作用：方法：利用癌症基因组图谱（TCGA）和临床肿瘤蛋白质组学分析联盟（CPTAC）数据库搜索 COLEC10 表达与 HCC 干性之间的关联。研究人员利用集落形成、球形形成、侧群和极限稀释肿瘤启动试验来确定 COLEC10 过表达在 HCC 细胞系干性中的调控作用。研究人员还进行了Wnt/β-catenin报告实验和免疫沉淀以探索其潜在机制：结果：COLEC10水平与HCC干性呈负相关。COLEC10的升高导致EpCAM和AFP（甲胎蛋白）这两种肝脏造血干细胞常见标志物的表达降低。COLEC10的过表达抑制了HCC细胞形成集落和球体，减少了体外的侧群数量和体内的致瘤能力。从机理上讲，我们发现过表达COLEC10可通过上调Wnt抑制因子WIF1和降低胞质β-catenin水平来抑制Wnt/β-catenin信号转导的活性。COLEC10 的过表达促进了β-catenin 与破坏复合体 CK1α 的相互作用。此外，KLHL22（Kelch Like Family Member 22）是一种已报道的E3连接酶适配体，据预测可与CK1α相互作用，可促进COLEC10的单泛素化和降解：结论：COLEC10通过下调Wnt/β-catenin通路抑制HCC干细胞，是肝脏CSC治疗的一个有前景的靶点。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.