Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) remains a significant global health challenge.
• The molecular mechanisms driving HCC progression require further elucidation.
• Peroxiredoxin II (Prx II) is an antioxidant enzyme with potential roles in cancer.

Purpose of the Study:

• To investigate the role of Peroxiredoxin II (Prx II) in hepatocellular carcinoma (HCC) development.
• To elucidate the molecular mechanisms underlying Prx II's involvement in HCC progression.
• To explore the relationship between Prx II, FoxM1, and the ERK pathway in hepatic tumorigenesis.

Main Methods:

• Utilized H-ras(G12V)-transformed HCC cells and H-ras(G12V)-transgenic mice models.
• Assessed Prx II and FoxM1 expression levels via Western blotting and immunohistochemistry.
• Employed gene knockdown, site-directed mutagenesis, and overexpression techniques to study protein function.
• Analyzed cell proliferation, anchorage-independent growth, and tumor formation in vivo.

Main Results:

• Prx II and FoxM1 were significantly upregulated in HCC models and patient samples.
• FoxM1 was identified as a direct transcription factor for Prx II in HCC.
• Prx II deficiency reduced tumor number and size, while its overexpression promoted tumor phenotypes.
• Prx II knockdown decreased cyclin D1 expression, proliferation, and tumor formation.
• Prx II activated the ERK pathway, leading to increased FoxM1 and cyclin D1 expression.

Conclusions:

• Prx II acts as a FoxM1-dependent antioxidant that enhances Ras(G12V) oncogenic potential in HCC.
• The Prx II/ERK/FoxM1/cyclin D1 cascade is crucial for hepatic tumorigenesis.
• Prx II represents a potential therapeutic target for hepatocellular carcinoma.