RESUMEN
Rationale: Nonalcoholic steatohepatitis (NASH), as one of the key stages in the development of nonalcoholic fatty liver disease (NAFLD), can directly progress to HCC, but the underlying mechanism is not fully understood. Methods: Differentially expressed genes (DEGs) in each stage of disease development were studied through a GEO dataset deriving from a Stelic Animal Model (STAM), which can simulate the evolution of NAFLD/NASH to HCC in humans. GSVA analysis was performed to analyze the differentially expressed oncogenic signatures in each stage. A human NAFLD-related dataset from GEO database was utilized for gene expression verification and further validated in the protein level in STAM mice. Small molecule inhibitors were applied to STAM mice for investigating whether inhibition of the LPL/FABP4/CPT1 axis could prevent the occurrence of NASH-related HCC in vivo. Microsphere formation and clonal formation assays in vitro were applied to study if inhibition of the LPL/FABP4/CPT1 axis can reduce the viability of liver cancer stem cells (LCSCs). Results: We found that upregulation of the LPL/FABP4/CPT1 molecular axis, as a fatty acid metabolic reprogramming process, occurred specifically during the NASH phase. GSVA analysis showed widespread activation of a large number of oncogenic signals, which may contribute to malignant transformation during NASH. Furthermore, inhibition of the LPL/FABP4/CPT1 axis could effectively delay the tumor growth in STAM mice. Cell assays revealed inhibitors targeting this axis can significantly reduce the sphere-forming, proliferation, and clonality of LCSCs. Conclusion: These results suggest that activation of the LPL/FABP4/CPT1 axis is essential for LCSCs maintenance, which acts synergistically with a variety of up-regulated oncogenic signals that drive the hepatocyte-LCSCs transdifferentiation during NASH to HCC progression. Thus, targeting the LPL/FABP4/CPT1 axis may provide a potential direction for NASH-related HCC prevention.
Asunto(s)
Carnitina O-Palmitoiltransferasa/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Lipoproteína Lipasa/metabolismo , Neoplasias Hepáticas/etiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Animales , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Línea Celular Tumoral , Biología Computacional , Bases de Datos Genéticas , Proteínas de Unión a Ácidos Grasos/genética , Regulación de la Expresión Génica , Humanos , Lipoproteína Lipasa/genética , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Regulación hacia ArribaRESUMEN
The hydrophobicity of vertically aligned multiwalled carbon nanotubes (MWCNTs) was improved through the creation of a parallel array of microwalls via a laser pruning technique. Changes to the hydrophobic nature of the patterned MWCNTs due to artificially induced roughness through variations in both the widths of the walls and the distance between adjacent walls, channel width, were investigated. The sample became more hydrophobic whenever water droplets landed on one microwall 7 or 13 microm in width. However, when a droplet bridged two microwalls, the surface became less hydrophobic. The optimal superhydrophobic MWCNT surface corresponded to a parallel array of microwalls with a width of 13 microm and a channel width of approximately 50 microm. Such findings could possibly serve as value-add for further developments in the creation of water-repelling CNT surfaces via micropatterning.
