A novel lncRNA-mediated signaling axis governs cancer stemness and splicing reprogramming in hepatocellular carcinoma with therapeutic potential.

IF 12.8 1区医学 Q1 ONCOLOGY

Journal of Experimental & Clinical Cancer Research Pub Date : 2025-10-09 DOI:10.1186/s13046-025-03546-w

Ke Si, Lantian Zhang, Zehang Jiang, Zhiyong Wu, Zhanying Wu, Yubin Chen, Weifei Liang, Xiaoren Zhang, Wenliang Zhang

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引用次数: 0

Abstract

Background: Aberrant alternative splicing (AS) contributes to cancer stemness and progression in hepatocellular carcinoma (HCC). However, the regulatory roles of long noncoding RNAs (lncRNAs) in linking AS dysregulation to tumor stemness remain elusive.

Methods: We performed integrated bulk and single-cell RNA-Seq analyses combined with functional assays to identify key lncRNAs associated with splicing regulation and cancer stemness in HCC. Mechanistic studies were conducted to elucidate the molecular interplay between lncRNAs, splicing factors, and transcriptional regulators. Drug sensitivity assays were used to evaluate therapeutic potential.

Results: Global analysis revealed increased splicing regulator activity during hepatocellular carcinoma (HCC) progression, which correlated with poor prognosis. This splicing dysregulation led us to identify 28 lncRNAs that connect aberrant splicing with cancer stemness. Among these, RAB30-DT was significantly overexpressed in malignant epithelial cells and associated with advanced tumor stage, stemness features, genomic instability, and poor patient prognosis. Functional assays demonstrated that RAB30-DT promotes proliferation, migration, invasion, colony and sphere formation in vitro, and tumor growth in vivo. Mechanistically, RAB30-DT is transcriptionally activated by CREB1 and directly binds and stabilizes the splicing kinase SRPK1, facilitating its nuclear localization. This interaction broadly reshapes the AS landscape, including splicing of the cell cycle regulator CDCA7, to drive tumor stemness and malignancy. Importantly, pharmacological disruption of the CREB1-RAB30-DT-SRPK1 axis sensitizes HCC cells to targeted therapies.

Conclusions: Our study reveals a novel lncRNA-mediated signaling axis that integrates transcriptional regulation and splicing reprogramming to sustain cancer stemness and progression in HCC. Targeting this axis offers promising therapeutic opportunities for HCC treatment.

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一种新的lncrna介导的信号轴调控肝癌干细胞和剪接重编程，具有治疗潜力。

背景：异常选择性剪接（AS）有助于肝细胞癌（HCC）的发生和进展。然而，长链非编码rna （lncRNAs）在AS失调与肿瘤干性之间的调节作用仍然难以捉摸。方法：我们进行了整体和单细胞RNA-Seq分析，并结合功能分析，以鉴定与HCC剪接调节和癌性相关的关键lncrna。机制研究是为了阐明lncrna、剪接因子和转录调控因子之间的分子相互作用。采用药物敏感性试验评价治疗潜力。结果：全球分析显示，在肝细胞癌（HCC）进展过程中剪接调节因子活性增加，这与不良预后相关。这种剪接失调使我们鉴定出28个将异常剪接与癌症干细胞联系起来的lncrna。其中，RAB30-DT在恶性上皮细胞中显著过表达，并与肿瘤分期晚期、干性特征、基因组不稳定性和患者预后差相关。功能实验表明RAB30-DT在体外促进肿瘤的增殖、迁移、侵袭、集落和球形成以及体内肿瘤的生长。在机制上，RAB30-DT被CREB1转录激活，直接结合并稳定剪接激酶SRPK1，促进其核定位。这种相互作用广泛地重塑了AS的格局，包括细胞周期调节因子CDCA7的剪接，以驱动肿瘤的干性和恶性。重要的是，CREB1-RAB30-DT-SRPK1轴的药理学破坏使HCC细胞对靶向治疗敏感。结论：我们的研究揭示了一种新的lncrna介导的信号轴，该信号轴整合了转录调控和剪接重编程，以维持HCC的癌症发生和进展。靶向这一轴为HCC治疗提供了有希望的治疗机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.