Occult hepatitis B virus infection poses a significant challenge to global health, with its ability to evade standard viral screening and contribute to the development of hepatocellular carcinoma, according to research published on Jul. 22. Scientists from the National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, and Peking Union Medical College examined how specific mutations in the hepatitis B virus pre-S genomic region affect tumor growth.
The study involved molecular experiments using both wild-type and mutated full-length HBV plasmids introduced into human hepatoma cells. The researchers found that certain OBI-associated pre-S mutations—E39K, D44N, N98T, H128R, and I161T—accelerate the transition from G1 to S phase in the cell cycle, leading to increased cellular proliferation.
Further protein analysis revealed that these mutations cause an up-regulation of large hepatitis B surface protein expression. This increase activates the Akt/mTOR signaling pathway, which boosts levels of Cyclin D1 and its kinases CDK4 and CDK6. The resulting surge disrupts normal cellular checkpoints and promotes uncontrolled cell division.
To address these effects, the team tested targeted kinase inhibitors as potential therapies. Their assays showed that administering either an Akt inhibitor (MK2206) or an mTOR inhibitor (rapamycin) effectively blocked this malignant process by halting mutation-driven hyper-proliferation and arresting cells in the G0/G1 phase.
The findings suggest that chemically inhibiting Akt/mTOR signaling can protect liver cells from unchecked replication driven by these mutations. However, researchers say further clinical studies are needed before such interventions can be applied as human therapies.
"Elucidating the oncogenic role of the LHBs-Akt/mTOR/Cyclin D1 signaling network offers a powerful new strategy to combat OBI-related liver cancer," according to the study authors.
