Yang Haoran, Deng Qingmei, Ni Tun, Liu Yu, Lu Li, Dai Haiming, Wang Hongzhi, Yang Wulin
Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
University of Science and Technology of China, Hefei 230026, China.
Int J Biol Sci. 2021 Oct 11;17(15):4207-4222. doi: 10.7150/ijbs.64714. eCollection 2021.
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. 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 . Microsphere formation and clonal formation assays were applied to study if inhibition of the LPL/FABP4/CPT1 axis can reduce the viability of liver cancer stem cells (LCSCs). 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. 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.
非酒精性脂肪性肝炎（NASH）作为非酒精性脂肪性肝病（NAFLD）发展的关键阶段之一，可直接进展为肝癌（HCC），但其潜在机制尚未完全明确。通过一个源自Stelic动物模型（STAM）的基因表达综合数据库（GEO）数据集，研究疾病发展各阶段的差异表达基因（DEG），该模型可模拟人类NAFLD/NASH向HCC的演变过程。进行基因集变异分析（GSVA）以分析各阶段差异表达的致癌特征。利用来自GEO数据库的人类NAFLD相关数据集进行基因表达验证，并在STAM小鼠的蛋白质水平上进一步验证。将小分子抑制剂应用于STAM小鼠，以研究抑制脂蛋白脂肪酶（LPL）/脂肪酸结合蛋白4（FABP4）/肉碱棕榈酰转移酶1（CPT1）轴是否能预防NASH相关HCC的发生。应用微球形成和克隆形成试验研究抑制LPL/FABP4/CPT1轴是否能降低肝癌干细胞（LCSC）的活力。我们发现，作为脂肪酸代谢重编程过程，LPL/FABP4/CPT1分子轴的上调特异性发生在NASH阶段。GSVA分析显示大量致癌信号广泛激活，这可能有助于NASH期间的恶性转化。此外，抑制LPL/FABP4/CPT1轴可有效延缓STAM小鼠的肿瘤生长。细胞试验表明，靶向该轴的抑制剂可显著降低LCSC的成球、增殖和克隆能力。这些结果表明，LPL/FABP4/CPT1轴的激活对LCSC的维持至关重要，它与多种上调的致癌信号协同作用，在NASH向HCC进展过程中驱动肝细胞向LCSC的转分化。因此，靶向LPL/FABP4/CPT1轴可能为预防NASH相关HCC提供一个潜在方向。
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