Department of General Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China.
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
Clin Transl Oncol. 2022 May;24(5):864-874. doi: 10.1007/s12094-021-02733-3. Epub 2022 Jan 10.
Very-long-chain acyl-CoA dehydrogenase (VLCAD) is an essential mediator in fatty acid metabolism. The progression of human hepatocellular carcinoma (HCC) is closely associated with the disorder of energy supply. Here, we aimed to investigate the role and underlying molecule mechanism of VLCAD in pathological process of HCC.
In this study, VLCAD was induced silencing and overexpression using small hairpin RNA (shRNA) and lentiviral-mediated vector in HCC cell lines. The proliferation of HCC cells was determined using CCK-8 assay. Transwell assay and lung metastasis were performed to analysis cell metastasis in vitro and in vivo. ECAR and OCR were used to evaluate the activity of glycolysis and mitochondrial oxidative phosphorylation.
Our data indicated that VLCAD was downregulated in human HCC tissues and cells. VLCAD overexpression strongly suppressed the proliferation and metastasis of HCC cells associating with the decrease of ATP accumulation and glycolysis activity. Importantly, the PI3K/AKT inhibitor LY294002 strongly abolished the role of shVLCAD in HCC cells. Our results suggested that VLCAD suppressed the growth and metastasis in HCC cells by inhibiting the activities of glycolysis and mitochondrial oxidative phosphorylation metabolism via PI3K/AKT pathway.
Together, present findings not only demonstrated the protective role of and molecular network of VLCAD in HCC cells but also indicated its and potential use as a target in the therapy of HCC.
长链酰基辅酶 A 脱氢酶（VLCAD）是脂肪酸代谢中的重要介质。人类肝细胞癌（HCC）的进展与能量供应紊乱密切相关。在这里，我们旨在研究 VLCAD 在 HCC 病理过程中的作用及其潜在的分子机制。
在这项研究中，使用小发夹 RNA（shRNA）和慢病毒介导的载体在 HCC 细胞系中诱导 VLCAD 沉默和过表达。使用 CCK-8 测定法测定 HCC 细胞的增殖。Transwell 测定法和肺转移用于分析体外和体内细胞转移。ECAR 和 OCR 用于评估糖酵解和线粒体氧化磷酸化的活性。
我们的数据表明，VLCAD 在人 HCC 组织和细胞中下调。VLCAD 过表达强烈抑制 HCC 细胞的增殖和转移，与 ATP 积累和糖酵解活性的降低有关。重要的是，PI3K/AKT 抑制剂 LY294002 强烈消除了 shVLCAD 在 HCC 细胞中的作用。我们的结果表明，VLCAD 通过抑制 PI3K/AKT 通路抑制糖酵解和线粒体氧化磷酸化代谢的活性来抑制 HCC 细胞的生长和转移。
总之，本研究不仅证明了 VLCAD 在 HCC 细胞中的保护作用及其分子网络，还表明其可能作为 HCC 治疗的靶点。
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