Hepatocellular carcinoma (HCC) presents challenges in early detection, therapy development, and survival improvement. Patients with advanced HCC receive systemic treatments like sorafenib, lenvatinib, or immune checkpoint inhibitors. Despite targeting key pathways, treatment resistance remains, necessitating innovative approaches. Our study focused on identifying tumor-suppressor miRNAs for HCC therapy. A miRNA lethal screen using 2600 human miRNA mimics identified candidates inhibiting cell proliferation, metastasis, and restoring TKI sensitivity in HCC cell lines. The study integrated a miRNA library overexpression approach and advanced imaging.
Several lethal miRNAs, including miR-N1 and miR-N2, were identified, showing tumor-suppressive effects like proliferation inhibition, cell cycle arrest, and apoptosis induction across tested cell lines. MiR-N1 and miR-N2 reduced tumor growth, colony formation, migration, and invasion in 3D and 2D models, potentially acting as potent HCC tumor suppressors. Combination therapy with miR-N1, miR-N2, and lenvatinib synergistically reduced HCC proliferation and overcame lenvatinib resistance.
In conclusion, miR-N1 and miR-N2 exhibit promise in inhibiting HCC progression by regulating key cellular processes. Their synergistic effects with lenvatinib offer a novel strategy to combat HCC and drug resistance. These findings contribute to innovative therapeutic approaches for HCC management, with implications for further research and clinical application in cancer treatment.
Key words: Hepatocellular carcinoma, miRNA screen, drug resistance