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NRF1-Induced lncRNA DDX11-AS1 Contributes to the Progression of Hepatocellular Carcinoma via Activating CA9

Yingnan Li1,2, Mengjiao Shi1,3, Beibei Bie4

  • 1Department of General Surgery, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China.

Journal of Hepatocellular Carcinoma
|May 13, 2025
PubMed
Abstract

Insights

DDX11-AS1 promotes hepatocellular carcinoma (HCC) by upregulating carbonic anhydrase IX (CA9) and activating the MEK/ERK pathway. This NRF1-induced lncRNA is a poor prognostic factor in HCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hepatocellular carcinoma (HCC) is a major global health concern.
  • The role of long non-coding RNAs (lncRNAs) like DDX11-AS1 in HCC pathogenesis is increasingly recognized but not fully understood.

Purpose of the Study:

  • To investigate the biological functions and molecular mechanisms of DDX11-AS1 in hepatocellular carcinoma.
  • To explore the clinical implications of DDX11-AS1 expression in HCC patients.

Main Methods:

  • Bioinformatic analysis of TCGA data for DDX11-AS1 expression and clinical correlation.
  • qRT-PCR and RNA-FISH for expression and localization studies.
  • In vitro and in vivo loss-of-function experiments.
  • RNA-sequencing to identify regulated genes and pathways.
  • Rescue experiments to confirm CA9 mediation.
  • Dual-luciferase reporter assays and ChIP-qPCR to investigate NRF1 regulation.

Main Results:

  • DDX11-AS1 expression is elevated in HCC and correlates with aggressive clinical features and poor survival.
  • DDX11-AS1 is primarily nuclear and its knockdown inhibits HCC cell growth, migration, and invasion.
  • Silencing DDX11-AS1 downregulates CA9 expression and inhibits the MEK/ERK signaling pathway.
  • CA9 acts as a downstream mediator of DDX11-AS1's oncogenic functions.
  • NRF1 transcriptionally regulates DDX11-AS1.

Conclusions:

  • DDX11-AS1 acts as an oncogenic lncRNA in HCC, promoting tumor progression.
  • DDX11-AS1 facilitates HCC development by upregulating CA9 and activating the MEK/ERK pathway.
  • DDX11-AS1 is a NRF1-induced molecule and a potential therapeutic target in HCC.
Keywords:
CA9DDX11-AS1MEK/ERK signalingNRF1hepatocellular carcinoma

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