Department of Biology, Changhua University of Education, 1 Jin-De Road, Changhua, Taiwan 50007.
Department of Uroloy, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei, Taiwan 11031.
Molecules. 2018 Dec 14;23(12):3327. doi: 10.3390/molecules23123327.
Metastasis of hepatocellular carcinoma (HCC) is usually unrecognized before any pathological examination, resulting in time-taking treatment and poor prognosis. As a consequence, HCC patients usually show symptoms of depression. In order to suppress such psychiatric disorders and to facilitate better treatment outcome, antidepressants are prescribed. Up to present, information about the effect of antidepressants on HCC is still lacking. Therefore, we chose fluoxetine (FXT), one of the top five psychiatric prescriptions in the United States, together with the HepG2 cell model to explore its effect on HCC. Our study found that FXT (5 µM) increased the migratory distance of HepG2 cells by a factor of nearly 1.7 compared to control. In addition, our study also investigated the effect of genipin (GNP), which is an active compound from Gardenia jasminoides Ellis fruit (family Rubiaceae), on the FXT-induced HepG2 cells. Our study found that 30 and 60 µM GNP reduced the migratory distance by 42% and 74% respectively, compared to FXT treatment alone. Furthermore, we also found that FXT upregulated matrix metalloproteinases (MMPs) genes, increased the protein expression of MMPs, urokinase-type plasminogen activator (uPA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activator protein 1 (AP-1), phosphorylated mitogen-activated protein kinase (P-p38), phosphorylated protein kinase B (P-Akt), downregulated tissue inhibitor metalloproteinases (TIMPs) genes and decreased the TIMPs proteins expression whereas, GNP fully counteracted the action of FXT. Conclusively, this study has provided valuable information regarding the possible molecular mechanisms through which FXT affects the metastatic invasiveness of HepG2 cells and evidences to support that GNP counteracts such effect via the same molecular mechanisms.
肝细胞癌（HCC）的转移通常在任何病理检查之前都无法被识别，这导致治疗时间延长，预后不良。因此，HCC 患者通常会出现抑郁症状。为了抑制这种精神障碍并促进更好的治疗效果，会开抗抑郁药。到目前为止，关于抗抑郁药对 HCC 的影响的信息仍然缺乏。因此，我们选择了氟西汀（FXT），它是美国处方量排名前五的精神科药物之一，与 HepG2 细胞模型一起，探索它对 HCC 的影响。我们的研究发现，与对照组相比，FXT（5µM）将 HepG2 细胞的迁移距离增加了近 1.7 倍。此外，我们的研究还研究了栀子苷（GNP）的作用，栀子苷是茜草科栀子属植物栀子（Gardenia jasminoides Ellis）果实中的一种活性化合物，对 FXT 诱导的 HepG2 细胞的影响。我们的研究发现，与单独使用 FXT 相比，30 和 60µM 的 GNP 分别使迁移距离减少了 42%和 74%。此外，我们还发现 FXT 上调了基质金属蛋白酶（MMPs）基因，增加了 MMPs、尿激酶型纤溶酶原激活物（uPA）、核因子κB 轻链增强子的活化 B 细胞（NF-kB）、激活蛋白 1（AP-1）、磷酸化丝裂原活化蛋白激酶（P-p38）、磷酸化蛋白激酶 B（P-Akt）的蛋白表达，下调了组织金属蛋白酶抑制剂（TIMP）基因，降低了 TIMPs 蛋白的表达，而 GNP 完全抵消了 FXT 的作用。总之，本研究提供了有关 FXT 影响 HepG2 细胞转移侵袭性的可能分子机制的有价值信息，并提供了证据支持 GNP 通过相同的分子机制对抗这种作用。
