Beyond ribosomal function: RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Cholangiocarcinoma (CCA) is a highly aggressive bile duct cancer with limited treatment options and poor patient outcomes.
• The molecular mechanisms driving CCA progression remain incompletely understood, necessitating the identification of novel therapeutic targets.

Purpose of the Study:

• To investigate the functional role of ribosomal protein S6 (RPS6) in cholangiocarcinoma (CCA) pathogenesis.
• To explore RPS6 as a potential therapeutic target for CCA treatment.

Main Methods:

• Correlation analysis of RPS6 expression with clinical outcomes in CCA patient tissues.
• In vitro functional assays (proliferation, gain/loss-of-function) and in vivo xenograft models to assess RPS6's impact on tumorigenicity.
• RNA sequencing, proteomics, immunoprecipitation-mass spectrometry, and RNA immunoprecipitation sequencing to elucidate RPS6 downstream pathways and interactions.
• In vivo efficacy studies using a phosphorodiamidate morpholino oligomer (V-PMO) targeting RPS6.

Main Results:

• RPS6 upregulation in CCA tissues significantly correlates with poor prognosis.
• RPS6 modulates CCA cell proliferation and enhances tumorigenicity in vivo.
• RPS6 influences cell cycle progression, DNA replication, and alternative splicing, notably interacting with MCM7.
• RPS6-V-PMO treatment demonstrated significant inhibition of CCA growth in vitro and in vivo.

Conclusions:

• RPS6 acts as an oncogenic driver in cholangiocarcinoma, influencing key cellular processes including proliferation and splicing.
• Targeting RPS6 with V-PMO represents a promising therapeutic strategy for cholangiocarcinoma, warranting further clinical investigation.