Vacuolar Protein Sorting 35 Controls Hepatocellular Proliferation Through SRC Signaling and Promotes Diethyl...

Area of Science:

• Hepatobiliary Science
• Oncology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with limited treatment options.
• Understanding HCC mechanisms is crucial for developing effective therapies.
• VPS35, a retromer component, is implicated as an oncogene, but its role in HCC is unclear.

Purpose of the Study:

• To investigate the role of VPS35 in hepatocellular proliferation and HCC development.
• To determine if VPS35 acts as an oncogene in HCC initiation and progression.

Main Methods:

• Generated a liver-specific Vps35 knockout mouse model (Vps35^HepKO).
• Assessed hepatocellular proliferation in postnatal and regenerating livers post-partial hepatectomy (PH).
• Induced HCC using diethyl nitrosamine (DEN) and analyzed liver tissues at multiple levels.

Main Results:

• VPS35 loss enhanced postnatal hepatocellular proliferation via SRC/STAT3 signaling; Saracatinib normalized this.
• VPS35 deficiency did not affect proliferation during liver regeneration after PH.
• VPS35-deficient livers showed fewer DEN-induced lesions but similar tumor size.

Conclusions:

• Murine VPS35 is a key regulator of postnatal hepatocellular proliferation, not liver regeneration.
• VPS35 deficiency reduces HCC initiation but does not influence tumor progression.
• VPS35 is not a canonical oncogene in HCC development.