Zou Juan, Li Hong, Huang Qianling, Liu Xiaomin, Qi Xiaoxiao, Wang Ying, Lu Linlin, Liu Zhongqiu
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
Tumour Biol. 2017 Oct;39(10):1010428317719272. doi: 10.1177/1010428317719272.
Hepatocellular carcinoma has the second highest incidence rate among malignant cancers in China. Hepatocellular carcinoma development is complex because of the metabolism disequilibrium involving SULT1A3/4, a predominant sulfotransferase that metabolizes sulfonic xenobiotics and endogenous catecholamines. However, the correlation between SULT1A3/4 and hepatocellular carcinoma progression is unclear. By utilizing immunofluorescence and immunohistochemical analysis, we found that in nine hepatocellular carcinoma clinical specimens, SULT1A3/4 was abundantly expressed in tumor tissues compared to that in the adjacent tissues. Moreover, liver cancer cells (HepG2, MHCC97-L, and MHCC97-H) had higher basal expression of SULT1A3/4 than immortalized liver cells (L02 and Chang liver). Ultra-high-pressure liquid chromatography-tandem mass spectrometry assay results further revealed that the concentration of dopamine (a substrate of SULT1A3/4) was negatively correlated with SULT1A3/4 protein expression. As a transcriptional regulator of SULT1A3/4 in turn, dopamine was used to induce SULT1A3/4 in vitro. Interestingly, dopamine significantly induced SULT1A3/4 expression in liver cancer HepG2 cells, while decreased that in L02 cells. More importantly, the expression levels of epithelial-mesenchymal transition biomarkers (N-cadherin and vimentin) and cell stemness biomarkers (nanog, sox2, and oct3/4) considerably increased in HepG2 with dopamine-induced SULT1A3/4, whereas in L02, epithelial-mesenchymal transition and cancer stem cell-associated proteins were contrarily decreased. Furthermore, invasion and migration assays further revealed that dopamine-induced SULT1A3/4 dramatically stimulated the metastatic capacity of HepG2 cells. Our results implied that SULT1A3/4 exhibited bidirectional effect on tumor and normal hepatocytes and may thus provide a novel strategy for hepatocellular carcinoma clinical targeting. In addition, SULT1A3/4 re-expression could serve as a biomarker for hepatocellular carcinoma prognosis.
肝细胞癌在中国恶性肿瘤中发病率位居第二。由于涉及SULT1A3/4的代谢失衡，肝细胞癌的发展较为复杂，SULT1A3/4是一种主要的磺基转移酶，可代谢磺酸类外源性物质和内源性儿茶酚胺。然而，SULT1A3/4与肝细胞癌进展之间的相关性尚不清楚。通过免疫荧光和免疫组化分析，我们发现，在9例肝细胞癌临床标本中，与相邻组织相比，肿瘤组织中SULT1A3/4表达丰富。此外，肝癌细胞（HepG2、MHCC97-L和MHCC97-H）中SULT1A3/4的基础表达高于永生化肝细胞（L02和Chang liver）。超高压液相色谱-串联质谱分析结果进一步显示，多巴胺（SULT1A3/4的一种底物）的浓度与SULT1A3/4蛋白表达呈负相关。作为SULT1A3/4的转录调节因子，多巴胺在体外被用于诱导SULT1A3/4。有趣的是，多巴胺显著诱导肝癌HepG2细胞中SULT1A3/4的表达，而降低L02细胞中的表达。更重要的是，在多巴胺诱导SULT1A3/4的HepG2细胞中，上皮-间质转化生物标志物（N-钙黏蛋白和波形蛋白）和细胞干性生物标志物（nanog、sox2和oct3/4）的表达水平显著增加，而在L02细胞中，上皮-间质转化和癌症干细胞相关蛋白则相反地减少。此外，侵袭和迁移试验进一步显示，多巴胺诱导的SULT1A3/4显著刺激了HepG2细胞的转移能力。我们的结果表明，SULT1A3/4对肿瘤和正常肝细胞具有双向作用，因此可能为肝细胞癌临床靶向治疗提供一种新策略。此外，SULT1A3/4的重新表达可作为肝细胞癌预后的生物标志物。
