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Updated: May 27, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Multi-pathway targeted therapy of MASH-HCC using miR-22
Ying Hu1, Tahereh Setayesh1, Dongguang Wei1
1Department of Pathology and Laboratory Medicine, Research Building III, University of California Davis Health, Room 3400B, 4645 2nd Ave, Sacramento, CA, 95817, USA.
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.
Insights
MicroRNA-22 (miR-22) shows significant potential in treating hepatocellular carcinoma (HCC) and metabolic dysfunction-associated steatohepatitis (MASH)-HCC. This novel approach prevents oncogenesis and improves survival by targeting key cancer pathways.
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.
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