Multi-pathway targeted therapy of MASH-HCC using miR-22

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Hepatocellular carcinoma (HCC) treatment options are limited, with current therapies often involving toxic drug combinations.
• There is a critical need for effective drugs to improve long-term survival rates in HCC patients.

Purpose of the Study:

• To investigate the preventive and therapeutic effects of microRNA-22 (miR-22) in mouse models of HCC and MASH-HCC.
• To elucidate the molecular mechanisms underlying miR-22's anti-cancer activity.

Main Methods:

• Established MASH-HCC and HCC mouse models using genetic manipulation (myr-AKT1, NRasV12, Sleeping Beauty transposase).
• Administered AAV8-miR-22 to assess its impact on oncogenesis, tumor progression, and survival.
• Utilized spatial transcriptomic profiling to identify pathways affected by miR-22.

Main Results:

• miR-22 treatment effectively reduced tumor load, fibrosis, and splenomegaly, extending survival in HCC and MASH-HCC models.
• miR-22 demonstrated preventive effects against oncogenesis when administered before tumor initiation.
• miR-22 modulated anti-tumor immunity, improved metabolism, reduced tumor glycolysis, and inhibited key signaling pathways including ECM, MET, PDGF, tyrosine kinase, and IGF.

Conclusions:

• miR-22 exhibits potent anti-HCC effects by targeting critical pathways involved in liver carcinogenesis.
• miR-22 has the potential to revolutionize HCC treatment by acting within both the tumor and its microenvironment.