Wu Szu-Yuan, Yang Wan-Yu, Cheng Chun-Chia, Lin Kuan-Hao, Sampurna Bonifasius Putera, Chan Suat-Ming, Yuh Chiou-Hwa
Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, 41354, Taiwan.
Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, 26546, Taiwan.
Clin Transl Med. 2020 Dec;10(8):e252. doi: 10.1002/ctm2.252. Epub 2017 Jul 28.
Hepatocellular carcinoma ranks fourth in cancer-related mortality currently lacks effective therapeutics. Fucoidan is sulfated polysaccharide that is mainly found in brown seaweeds. In this study, we investigated the effects and mechanisms of low molecular weight fucoidan (i.e. oligo-fucoidan [OF]) preventing hepatocarcinogenesis.
We used [HBx,src], [HBx,src,p53 ], and [CD36] transgenic zebrafish liver cancer model treated with OF, and performed molecular and histopathological analysis. Transcriptomic and pathways analysis was performed.
Decreased expression of lipogenic enzymes, fibrosis markers, and cell cycle/proliferation markers by OF in [HBx,src] and [HBx,src,p53 ] transgenic fish. Liver fibrosis was decreased as revealed by Sirius Red staining, and the liver cancer formation was eventually reduced by feeding OF. OF was also found to be capable of reducing lipid accumulation and cancer formation in non-B non-C Hepatocellular carcinoma (HCC) model in CD36 transgenic zebrafish. Whole-genome expression analysis showed that 661 genes were up-regulated, and 451 genes were downregulated by feeding OF. Upregulated genes were mostly found in protein transporter activity, and downregulated genes were enriched with response to extracellular stimulus and metal binding in gene ontology analysis. The driver gene was HNF4A revealed by NetworkAnalyst from OF differential regulated genes at various insults. OF is able to bind the asialoglycoprotein receptor (ASGR) in hepatoma cells, and increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both hepatoma cells and [HBx,src,p53 ] transgenic fish liver cancer model. Using chromatin-immunoprecipitation, we found pSTAT3 could associate with the P1 promoter of HNF4A. Knockdown of either ASGR or HNF4A reversed OF mediated anti-cancer cell proliferation.
Taken together, we provide evidence that OF exhibits the anti-HCC, anti-steatosis, and anti-fibrosis effect for liver in zebrafish models, and the anti-cancer potential of OF attributed to the binding to ASGR and activation of STAT3/HNF4A signaling. OF might be potentially valuable for the management of HCC.
肝细胞癌在癌症相关死亡率中排名第四，目前缺乏有效的治疗方法。岩藻依聚糖是一种主要存在于褐藻中的硫酸化多糖。在本研究中，我们调查了低分子量岩藻依聚糖（即寡聚岩藻依聚糖[OF]）预防肝癌发生的作用及机制。
我们使用经OF处理的[HBx,src]、[HBx,src,p53]和[CD36]转基因斑马鱼肝癌模型，并进行分子和组织病理学分析。进行了转录组和通路分析。
在[HBx,src]和[HBx,src,p53]转基因鱼中，OF降低了脂肪生成酶、纤维化标志物以及细胞周期/增殖标志物的表达。天狼星红染色显示肝纤维化减轻，喂食OF最终减少了肝癌的形成。还发现OF能够减少CD36转基因斑马鱼非B非C型肝细胞癌（HCC）模型中的脂质积累和癌症形成。全基因组表达分析表明，喂食OF后，661个基因上调，451个基因下调。在基因本体分析中，上调基因大多存在于蛋白质转运活性中，下调基因则富集于对细胞外刺激的反应和金属结合。通过NetworkAnalyst从OF在各种损伤下差异调节的基因中发现驱动基因是HNF4A。OF能够结合肝癌细胞中的去唾液酸糖蛋白受体（ASGR），并增加肝癌细胞和[HBx,src,p53]转基因鱼肝癌模型中信号转导和转录激活因子3（STAT3）的磷酸化。使用染色质免疫沉淀法，我们发现pSTAT3可与HNF4A的P1启动子结合。敲低ASGR或HNF4A可逆转OF介导的抗癌细胞增殖。
综上所述，我们提供的证据表明，在斑马鱼模型中，OF对肝脏具有抗HCC、抗脂肪变性和抗纤维化作用，OF的抗癌潜力归因于其与ASGR的结合以及STAT3/HNF4A信号通路的激活。OF可能对HCC的治疗具有潜在价值。
