Occult hepatitis B virus (OBI) infection presents a significant global health challenge, notoriously flying under the radar of standard viral screening while relentlessly driving the pathogenesis of hepatocellular carcinoma (HCC). A critical but poorly understood factor in OBI-related tumorigenesis is the frequent emergence of mutations in the HBV pre-S genomic region. While these mutations are known to correlate with advanced liver disease, the precise molecular mechanisms by which they hijack host cellular machinery to fuel unregulated tumor growth have remained largely elusive.

This new research, published in Genes & Diseases by researchers from National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine and Peking Union Medical College, investigated the oncogenic capacity of specific OBI-associated pre-S mutations to uncover their role in aberrant cell proliferation.

Through rigorous in vitro molecular experiments utilizing constructed wild-type and mutated full-length HBV plasmids transfected into human hepatoma (Huh-7) cells, the researchers systematically evaluated cellular growth and cycle dynamics. The data revealed that specific OBI-associated pre-S mutations—namely E39K, D44N, N98T, H128R, and I161T—accelerate the G1/S phase transition of the cell cycle, leading to aggressive cellular proliferation.

Comprehensive protein analyses deciphered the underlying intracellular networks, demonstrating that these mutations aggressively up-regulate the expression of the large hepatitis B surface protein (LHBs). This excessive LHBs subsequently triggers a massive activation of the Akt/mTOR signaling cascade, which strongly up-regulates the cell cycle driver Cyclin D1 and its associated kinases CDK4 and CDK6. This targeted protein surge dismantles normal cellular checkpoints, unleashing uncontrolled cell division.

To directly counter these severe hyper-proliferative effects, the researchers explored the therapeutic potential of targeted kinase inhibitors. Remarkably, advanced cellular assays confirmed that administering the highly specific Akt inhibitor MK2206 or the mTOR inhibitor rapamycin successfully intercepted this malignant cascade, decisively suppressing the mutation-driven hyper-proliferation and arresting the cells back in the G0/G1 phase.

By chemically blocking the Akt/mTOR signaling axis, these targeted therapies stripped the mutated hepatoma cells of their oncogenic growth advantage, fundamentally shielding the liver cells from unchecked replication. While these comprehensive data robustly highlight the critical influence of OBI-associated pre-S mutations in regulating the cell cycle, additional clinical studies are necessary to translate these targeted interventions into human therapies.

In conclusion, elucidating the oncogenic role of the LHBs-Akt/mTOR/Cyclin D1 signaling network offers a powerful new strategy to combat OBI-related liver cancer. This significant finding directly positions specific Akt and mTOR inhibitors as highly compelling therapeutic candidates for the next generation of precision hepatocellular carcinoma treatments.

Reference

Title of Original Paper: Potential oncogenic role of occult hepatitis B virus pre-S mutations: Activation of Akt/mTOR/Cyclin D1 signaling drives cell cycle dysregulation and proliferation in hepatocellular carcinogenesis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101919

Funding Information:
The National Natural Science Foundation of China (No. 82202612)
The Beijing Natural Science Foundation (China) (No. 7232142)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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