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Dysregulation of RalA signaling through dual regulatory mechanisms exerts its oncogenic functions in hepatocellular

Lu Tian1,2, Luqing Zhao1,2, Karen Man-Fong Sze1,2

  • 1Department of Pathology, The University of Hong Kong, Hong Kong.

Hepatology (Baltimore, Md.)
|November 12, 2021
PubMed
Abstract

Insights

Dysregulation of Ras-like (Ral) signaling, specifically RalA, promotes hepatocellular carcinoma (HCC) progression and metastasis. Targeting RalA offers a potential therapeutic strategy for HCC, alone or with sorafenib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Ras-like (Ral) small guanosine triphosphatases (GTPases), RalA and RalB, are downstream effectors of Ras proto-oncogenes.
  • The role of Ral signaling up-regulation in cancer, particularly hepatocellular carcinoma (HCC), remains incompletely understood.
  • RalGTPase-activating protein (RalGAP) complex negatively regulates Ral GTPase activity.

Purpose of the Study:

  • To investigate the clinical significance, functional roles, and molecular mechanisms of RalA signaling in HCC.
  • To explore the potential of targeting RalA as a therapeutic strategy in HCC.

Main Methods:

  • Analysis of RNA sequencing and quantitative PCR data from HCC patients and cell lines.
  • In vitro and in vivo experiments involving RalA knockdown and RalGAPA2 knockdown in HCC cells.
  • Assessment of RalA copy number alterations and transcription factor involvement (SP1, ETS2).
  • Evaluation of a Ral-specific inhibitor (RBC8) in HCC cells, alone and in combination with sorafenib.

Main Results:

  • RalA was significantly up-regulated in HCC, correlating with aggressive tumor behavior and poor prognosis.
  • RalA knockdown reduced HCC cell proliferation, migration, tumorigenicity, and metastasis.
  • RalA up-regulation was driven by copy number gain and co-transcription by SP1 and ETS2.
  • RalGAPA2 down-regulation increased RalA activity and promoted metastasis; simultaneous RalGAPA2 down-regulation and RalA up-regulation were associated with aggressive HCC features.
  • Ral inhibition suppressed oncogenic functions and sensitized HCC cells to sorafenib by inhibiting mTOR signaling.

Conclusions:

  • Dysregulated RalA signaling, driven by dual mechanisms, contributes to oncogenic functions in HCC.
  • Targeting RalA presents a promising therapeutic avenue for HCC, potentially enhancing current treatments like sorafenib.
  • The findings provide critical biological insights into RalA's role in HCC progression and metastasis.

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