Aims: Hepatocellular carcinoma (HCC) exhibits aberrant lipid metabolism, notably increased de novo fatty acid synthesis and reduced fatty acid oxidation. PDAP1, a cancer-associated RNA-binding protein, is overexpressed in multiple malignancies, yet its specific contribution to fatty acid metabolic reprogramming and HCC progression remains undefined.
Methods: The expression pattern and prognostic relevance of PDAP1 were investigated using public datasets and validated in clinical specimens. To evaluate the functional role of PDAP1, a series of in vitro assays, including CCK-8, colony formation, EdU, wound healing, transwell invasion, and flow cytometry experiments were conducted. In vivo studies were performed using multiple mouse models, including subcutaneous tumor, orthotopic liver tumor, as well as lung and liver metastasis models. The underlying mechanisms of PDAP1 were elucidated through bulk and single-cell RNA sequencing and further validated by RNA immunoprecipitation, RNA pull-down assays, and lipid metabolism-related assays.
Results: PDAP1 was markedly upregulated in HCC and correlated with poor overall and progression-free survival. Functional assays demonstrated that PDAP1 knockdown inhibited HCC cell proliferation, migration, and invasion, while promoting apoptosis. Conversely, PDAP1 overexpression exerted the opposite effects. In vivo, PDAP1 also showed promoting effect on HCC growth and metastasis. Mechanistically, PDAP1 stabilized HSPA8 mRNA, activating the ERK/MAPK pathway, which enhanced SREBP1-mediated fatty acid synthesis and suppressed PPARα-driven fatty acid oxidation, thereby driving fatty acid metabolic reprogramming and malignant transformation of HCC.
Conclusions: PDAP1 stabilizes HSPA8 mRNA as an RNA-binding protein to activate ERK/MAPK signaling, which further modulates the expressions of the SREBP1 and PPARα, ultimately driving HCC progression and metastasis through fatty acid metabolism reprogramming. Targeting PDAP1 may provide a promising therapeutic strategy for HCC.
Keywords: HSPA8; Hepatocellular carcinoma; Lipid metabolism; PDAP1; Single-cell RNA sequencing.
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