Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The Akt signaling pathway is frequently hyperactivated in human cancers, making it a key target for cancer therapy.
• The specific physiological consequences of inhibiting different Akt isoforms systemically remain incompletely understood.

Purpose of the Study:

• To investigate the physiological effects of systemic Akt isoform inhibition in adult mice.
• To determine the role of Akt isoforms in hepatocarcinogenesis and metastasis.

Main Methods:

• Generated and analyzed knockout mice lacking specific Akt isoforms (Akt1, Akt2, Akt3).
• Assessed survival rates, spontaneous tumor development (hepatocellular carcinoma - HCC), and response to chemical carcinogens (diethylnitrosamine).
• Analyzed gene expression profiles and investigated FoxO-dependent liver injury and inflammation.

Main Results:

• Combined deletion of Akt1 and Akt2 induced rapid mortality.
• Mice with deleted Akt1 survived hepatic Akt deletion but developed spontaneous HCC, linked to FoxO-dependent liver injury and inflammation.
• The gene expression signature of HCC-bearing livers resembled aggressive human HCC.
• Akt isoform deficiency did not confer resistance to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2 deficiency increased lung metastasis incidence.

Conclusions:

• Systemic Akt isoform inhibition, especially Akt2, has severe physiological consequences, including rapid mortality.
• Hepatic Akt inhibition can paradoxically induce liver injury and inflammation, promoting the development of hepatocellular carcinoma.
• These findings suggest that targeting hepatic Akt may not be a viable strategy for HCC treatment and could potentially exacerbate the disease.