VPS35 controls hepatocellular proliferation through SRC signalling and promotes diethyl nitrosamine-induced tumor initiation

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Therapeutic options for HCC remain limited, and the mechanisms underlying HCC are not fully understood. Therefore, gaining a comprehensive understanding of the pathways that drive HCC is essential for improving treatments. Recent studies have identified VPS35, a component of the endosomal cargo sorting machinery called retromer, as a novel oncogene in various types of cancer, including HCC. However, its role in the initiation and progression of HCC is still unclear. METHODS: ). Hepatocellular proliferation was studied in young and middle-aged mice, as well as during liver regeneration after two-thirds partial hepatectomy (PH). Diethyl nitrosamine (DEN) was used to induce HCC. Livers were analyzed at histological, transcriptional, and proteomic levels. RESULTS: mice. In contrast, hepatic VPS35 deficiency did not alter hepatocellular proliferation after PH in adult mice. Although VPS35-deficient postnatal livers exhibited an increased proliferative phenotype, hepatic loss of VPS35 reduced the number of DEN-induced liver lesions without affecting tumor size. CONCLUSIONS: Our in vivo data identify murine VPS35 as a critical regulator of hepatocellular proliferation in postnatal livers, but not after PH. Although VPS35 deficiency mitigates DEN-induced liver lesion formation, it does not affect tumor progression, arguing against a role for VPS35 as a canonical oncogene.