Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
Am J Pathol. 2024 Oct;194(10):1951-1966. doi: 10.1016/j.ajpath.2024.07.002. Epub 2024 Jul 26.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with high incidence and mortality worldwide. Despite diagnostic and therapeutic advancements, HCC remains poorly responsive to treatment, with a poor prognosis. Understanding the molecular mechanisms driving HCC is crucial for developing effective therapies. Emerging evidence indicates that dysregulated fatty acid metabolism contributes to HCC. Acyl-CoA medium-chain synthetase 5 (ACSM5), involved in fatty acid metabolism, is down-regulated in HCC; however, its role is not well understood. This study was used to analyze ACSM5 expression in HCC patient samples and cell lines. The newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6-ACSM5, were used to investigate the effects and regulatory mechanisms of ACSM5. The results showed that ACSM5 was significantly down-regulated in HCC tumor tissues compared with non-tumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNA methyltransferase 1 (DNMT1) inhibitor effectively increasing ACSM5 expression and reducing promoter region methylation. Overexpression of ACSM5 in Huh7 cells reduced fatty acid accumulation, decreased cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in mouse xenografts. Furthermore, ACSM5 overexpression also decreased STAT3 phosphorylation, subsequently affecting downstream cytokine TGFB and FGF12 mRNA levels. These findings suggest that ACSM5 down-regulation contributes to HCC progression, providing insights into its oncogenic role and highlighting its potential as a biomarker and therapeutic target for HCC.
肝细胞癌（HCC）是最常见的原发性肝癌，全球发病率和死亡率都很高。尽管在诊断和治疗方面取得了进展，但 HCC 对治疗的反应仍然很差，预后不良。了解驱动 HCC 的分子机制对于开发有效的治疗方法至关重要。新出现的证据表明，脂肪酸代谢失调与 HCC 有关。酰基辅酶 A 中链合成酶 5（ACSM5）参与脂肪酸代谢，在 HCC 中下调；然而，其作用尚不清楚。本研究用于分析 HCC 患者样本和细胞系中的 ACSM5 表达。新建立的 ACSM5 过表达 HCC 细胞系 Huh7-ACSM5 和 Hepa1-6-ACSM5 用于研究 ACSM5 的作用和调节机制。结果表明，与非肿瘤组织相比，ACSM5 在 HCC 肿瘤组织中显著下调。ACSM5 的表达受 DNA 甲基化调控，DNA 甲基转移酶 1（DNMT1）抑制剂可有效增加 ACSM5 的表达并减少启动子区域的甲基化。ACSM5 在 Huh7 细胞中的过表达减少了脂肪酸的积累，降低了细胞在体外的增殖、迁移和侵袭能力，并抑制了小鼠异种移植中的肿瘤生长。此外，ACSM5 的过表达还降低了 STAT3 的磷酸化，进而影响下游细胞因子 TGFB 和 FGF12 的 mRNA 水平。这些发现表明 ACSM5 的下调导致 HCC 的进展，深入了解其致癌作用，并突出其作为 HCC 的生物标志物和治疗靶点的潜力。
