Journal Article

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

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

2025

Overview

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. Graphical abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alternative Splicing / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer stem cell / Cancer therapies / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / CDCA7 / Cell cycle / Cell Line, Tumor / Cell Proliferation / Clinical outcomes / Data analysis / Gene expression / Gene Expression Regulation, Neoplastic / Health aspects / Hepatocellular carcinoma / Hepatoma / Humans / Immunology / Kinases / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / LncRNA RAB30-DT / Male / Medical prognosis / Metastasis / Mice / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Oncology / Prognosis / Quality control / RNA / RNA sequencing / RNA, Long Noncoding - genetics / Signal Transduction / SRPK1 / Stem cells / Survival analysis