Key Takeaways & Executive Findings
- •• RP11-439C15.4 is significantly downregulated in hepatocellular carcinoma (HCC) and its low expression correlates with poor patient prognosis. • Overexpression of RP11-439C15.4 suppresses HCC cell proliferation, invasion, migration, and sorafenib resistance in vitro and in vivo. • Mechanistically, RP11-439C15.4 binds to DHX9, promoting its ubiquitination and proteasomal degradation, thereby inhibiting HCC progression. • The RP11-439C15.4/DHX9 axis represents a novel therapeutic target and potential biomarker for HCC diagnosis and treatment.
Abstract
Long noncoding RNAs (lncRNAs) play crucial roles in the occurrence and progression of hepatocellular carcinoma (HCC), but the functions and molecular mechanisms of large lncRNAs remain unclear. In this study, HCC data from The Cancer Genome Atlas (TCGA) and 116 HCC cases from our clinical center are used to identify a novel lncRNA, RP11-439C15.4, which is significantly downregulated in HCC. This downregulation is associated with poor prognosis in HCC patients. A series of in vitro and in vivo experiments demonstrate that RP11-439C15.4 significantly inhibits the proliferation, invasion, migration and sorafenib resistance of HCC cells. Further mechanistic investigations reveal that RP11-439C15.4 interacts with DExH-Box Helicase 9 (DHX9) to increase its ubiquitination and accelerate the degradation of DHX9, ultimately suppressing HCC progression. Modulation of DHX9 significantly reverses the effects of RP11-439C15.4 in HCC. In conclusion, this study identifies RP11-439C15.4 as a tumor suppressor and elucidates the regulatory mechanism of the RP11-439C15.4/DHX9 axis in HCC, providing valuable insights into the mechanisms of HCC progression and potential therapeutic targets.
1. Introduction
Hepatocellular carcinoma (HCC), the main type of primary liver cancer, is characterized by high morbidity, high mortality, and a poor prognosis, making it a leading cause of cancer-related deaths worldwide [1]. Projections suggest that the incidence of HCC will surpass one million cases annually after 2025, with an estimated one million deaths attributed to the disease each year by 2030 [2]. The insidious onset of HCC and the absence of effective early diagnostic methods have resulted in many patients being diagnosed at advanced stages with metastasis, contributing to the poor prognosis and a five-year survival rate of only 18% [3,4]. Thus, there is an urgent need for improved early detection, treatment, and research into the biological mechanisms underlying HCC.
Long non-coding RNA (lncRNA) is a class of non-coding RNA molecules exceeding 200 nucleotides in length that lack protein-coding capacity. Previous studies have demonstrated the importance of lncRNAs in diverse biological processes, including epigenetic regulation, cell cycle regulation, and cell differentiation regulation, establishing them as prominent areas of genetics research. Similarly, lncRNAs have been implicated in the development and progression of various cancers, including HCC. Research has indicated that lncRNAs can modulate HCC cell proliferation, migration, and invasion through interactions with DNA, proteins, or other RNAs, suggesting their potential as biomarkers for tumor diagnosis and treatment [5]. However, the lncRNAs currently identified in HCC represent only a fraction of the total, and the functions of many remain to be elucidated. A comprehensive investigation of lncRNA functions and their underlying molecular mechanism in HCC is essential for a deeper understanding of HCC pathogenesis and the identification of novel diagnostic and therapeutic targets.
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Xuejiao Li, Zhongying Hu, Yina Sun, Tingting Wang, Xijing Yan, Qiang You, Kunhua Hu, Jia Yao, Xiaofeng Yuan, Rong Li (2026). RP11-439C15.4 inhibits the malignant progression of hepatocellular carcinoma via binding to DHX9 and facilitating its degradation. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025122
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Frequently Asked Questions
What is the role of RP11-439C15.4 in hepatocellular carcinoma?
RP11-439C15.4 is a long noncoding RNA that is significantly downregulated in HCC. It acts as a tumor suppressor by inhibiting proliferation, invasion, migration, and sorafenib resistance of HCC cells.
How does RP11-439C15.4 exert its tumor-suppressive effects?
RP11-439C15.4 binds to the RNA helicase DHX9, promoting its ubiquitination and subsequent degradation via the proteasome pathway, which ultimately suppresses HCC progression.
What is the clinical significance of RP11-439C15.4 in HCC?
Low expression of RP11-439C15.4 is associated with poor prognosis in HCC patients, suggesting its potential as a prognostic biomarker and therapeutic target.
What are the implications of this study for HCC treatment?
The RP11-439C15.4/DHX9 axis provides a novel molecular mechanism that could be exploited for targeted therapy, potentially improving the efficacy of sorafenib and other treatments.
How was the study conducted?
The study utilized TCGA data and clinical samples from 116 HCC patients, followed by in vitro and in vivo experiments to assess the functional impact of RP11-439C15.4 and its interaction with DHX9.
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