Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.
Sheila Sherlock Liver Centre, Royal Free Hospital, London, United Kingdom.
Am J Physiol Gastrointest Liver Physiol. 2021 Apr 1;320(4):G543-G556. doi: 10.1152/ajpgi.00262.2020. Epub 2021 Jan 6.
Tumor stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known or mutations on primary human HSC activation, proliferation, and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hepatic stellate cell (hHSC) proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms () and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Data mining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 () and AMPKα2 () expression differed depending on the mutation ( or ), tumor grading, and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumor-promoting interactions between hHSC and HCC. HCC is marked by genetic heterogeneity and activated hepatic stellate cells (HSC) are considered key players during HCC development. The paracrine effect of different HCC cell lines on the activation of primary hHSC was accompanied by differential AMPK activation depending on the HCC line used. Pharmacological treatment inhibited the HCC-induced hHSC activation through AMPK-dependent and AMPK-independent mechanisms. This heterogenic effect on HCC-induced AMPK activation was confirmed by data mining TCGA and LICA-FR databases.
肿瘤基质和微环境已被证明会影响肝细胞癌（HCC）的生长，其中活化的肝星状细胞（HSC）是这一过程的主要贡献者。最近的证据表明，能量传感器腺苷单磷酸激活的蛋白激酶（AMPK）可能在致癌作用和 HCC 进展过程中介导一系列重要过程。在这里，我们研究了具有已知 或 突变的不同 HCC 细胞系对原代人 HSC 激活、增殖和 AMPK 激活的影响。我们表明，从多种 HCC 细胞系获得的条件培养基以旁分泌方式不同地调节人肝星状细胞（hHSC）的增殖和 hHSC 的 AMPK 活性。用 AICAR 和化合物 C 对 hHSC 进行药理学处理，通过 AMPK 依赖性和 AMPK 非依赖性机制抑制 HCC 诱导的 hHSC 增殖/激活，这在缺乏两种催化 AMPKα 同工型（）和野生型（wt）MEF 的小鼠胚胎成纤维细胞（MEF）中得到了进一步证实。这两种化合物均诱导 S 期细胞周期停滞，此外，AICAR 通过抑制 hHSC 和 wt MEF 中 4E-BP1 和 S6 的磷酸化来抑制 mTORC1 途径。对癌症基因组图谱（TCGA）和肝癌（LICA-FR）的数据挖掘表明，AMPKα1（）和 AMPKα2（）的表达根据突变（或）、肿瘤分级和 G1-G6 分类而不同，反映了人类 HCC 的异质性。总体而言，我们提供的证据表明，AMPK 调节药理学药物可负调节 HCC 诱导的 hHSC 激活，因此可能为靶向 hHSC 和 HCC 之间的相互促进的相互作用提供新的方法。HCC 的特征是遗传异质性，活化的肝星状细胞（HSC）被认为是 HCC 发展过程中的关键参与者。不同 HCC 细胞系对原代 hHSC 激活的旁分泌作用伴随着 AMPK 的不同激活，这取决于所用的 HCC 系。药理学治疗通过 AMPK 依赖性和 AMPK 非依赖性机制抑制 HCC 诱导的 hHSC 激活。通过对 TCGA 和 LICA-FR 数据库的数据挖掘，证实了这种对 HCC 诱导的 AMPK 激活的异质性影响。
