Department of General Surgery, First People's Hospital of Hangzhou Lin'an District, NO.548 Yijin Street, Lin'an District, Hangzhou, Zhejiang, 311300, People's Republic of China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Feb;397(2):1025-1035. doi: 10.1007/s00210-023-02604-4. Epub 2023 Aug 11.
Primary hepatic carcinoma (PHC) is a leading threat to cancer patients with few effective treatment strategies. OPN is found to be an oncogene in hepatocellular carcinoma (HCC) with potential as a treating target for PHC. Fenofibrate is a lipid-lowering drug with potential anti-tumor properties, which is claimed with suppressive effects on OPN expression. Our study proposes to explore the molecular mechanism of fenofibrate in inhibiting HCC. OPN was found extremely upregulated in 6 HCC cell lines, especially Hep3B cells. Hep3B and Huh7 cells were treated with 75 and 100 μM fenofibrate, while OPN-overexpressed Hep3B cells were treated with 100 μM fenofibrate. Decreased clone number, elevated apoptotic rate, reduced number of migrated cells, and shortened migration distance were observed in fenofibrate-treated Hep3B and Huh7 cells, which were markedly abolished by the overexpression of OPN. Furthermore, the facilitating effect against apoptosis and the inhibitory effect against migration of fenofibrate in Hep3B cells were abolished by 740 Y-P, an agonist of PI3K. Hep3B xenograft model was established, followed by treated with 100 mg/kg and 200 mg/kg fenofibrate, while OPN-overexpressed Hep3B xenograft was treated with 200 mg/kg fenofibrate. The tumor growth was repressed by fenofibrate, which was notably abolished by OPN overexpression. Furthermore, the inhibitory effect of fenofibrate on the PI3K/AKT/Twist pathway in Hep3B cells and Hep3B xenograft model was abrogated by OPN overexpression. Collectively, fenofibrate suppressed progression of hepatoma downregulating OPN through inhibiting the PI3K/AKT/Twist pathway.
原发性肝癌（PHC）是癌症患者的主要威胁，目前治疗策略有限。OPN 被发现是肝癌（HCC）中的癌基因，具有作为 PHC 治疗靶点的潜力。非诺贝特是一种具有潜在抗肿瘤特性的降脂药物，据称可抑制 OPN 表达。我们的研究旨在探讨非诺贝特抑制 HCC 的分子机制。研究发现，OPN 在 6 种 HCC 细胞系中表达上调，尤其是 Hep3B 细胞。用 75 和 100μM 非诺贝特处理 Hep3B 和 Huh7 细胞，用 100μM 非诺贝特处理过表达 OPN 的 Hep3B 细胞。结果显示，非诺贝特处理的 Hep3B 和 Huh7 细胞克隆数减少，凋亡率升高，迁移细胞数减少，迁移距离缩短，而过表达 OPN 则明显抑制了这一作用。此外，PI3K 激动剂 740 Y-P 可消除非诺贝特对 Hep3B 细胞凋亡的促进作用和对迁移的抑制作用。建立 Hep3B 异种移植模型，用 100mg/kg 和 200mg/kg 非诺贝特处理，而过表达 OPN 的 Hep3B 异种移植则用 200mg/kg 非诺贝特处理。非诺贝特抑制肿瘤生长，而过表达 OPN 则明显抑制了这一作用。此外，过表达 OPN 可消除非诺贝特对 Hep3B 细胞和 Hep3B 异种移植模型中 PI3K/AKT/Twist 通路的抑制作用。综上所述，非诺贝特通过抑制 PI3K/AKT/Twist 通路下调 OPN 抑制肝癌进展。
