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

Abstract

Background: The treatment options for hepatocellular carcinoma (HCC) are limited, and there is no effective drug that can improve long-term survival rates. Complicated cocktails consisting of multiple medications with toxicities are frequently used to treat cancer. The current study addresses these challenges.

Methods: The study uses metabolic dysfunction-associated steatohepatitis (MASH)-HCC and HCC mouse models established by transfecting the livers using myr-AKT1, NRasV12, and Sleeping Beauty transposase. AAV8-miR-22 was delivered to MASH-HCC and HCC to study its preventive and therapeutic effects. Spatial transcriptomic profiling revealed the signaling pathways affected by miR-22 according to histological locations.

Results: miR-22 treatment effectively treated MASH-HCC and HCC. Treating mice with miR-22 before tumor initiation prevented oncogenesis. The promising anti-cancer effects were revealed by reduced tumor load, fibrosis, and splenomegaly, extending the survival time. miR-22 treatment generated anti-tumor immunity. The favorable treatment outcomes were accompanied by a reduction in dendritic cells, T and B cells, and plasma cells, which were expanded inside the tumors of MASH-HCC. In all animal trials, miR-22 improved metabolism and reduced glycolysis inside the tumors. Moreover, miR-22 profoundly inhibited extracellular matrix (ECM) and targeted MET, PDGF, tyrosine kinase signaling, and IGF pathways inside the tumors. Furthermore, the roles of miR-22 in blocking collagen formation and cross-assembly of collagen fibrils could be due to miR-22's effects in inhibiting Rho GTPase pathways, revealed at the tumor margin.

Conclusion: miR-22 generates anti-HCC effects by targeting many critical pathways in liver carcinogenesis in cancer and tumorigenic niches, potentially revolutionizing HCC treatment.