Kaufmann Roland, Henklein Peter, Henklein Petra, Settmacher Utz
Department of General, Visceral and Vascular Surgery, Research Center Lobeda, Medical Faculty at the Friedrich Schiller University Jena, D-07747 Jena, Germany.
Oncol Rep. 2009 May;21(5):1261-7. doi: 10.3892/or_00000349.
Thrombin has been recently demonstrated to promote hepatocellular carcinoma (HCC) cell migration by activation of the proteinase-activated receptor (PAR) subtypes PAR1 and PAR4 suggesting a role of these proteinase-receptor systems in HCC progression. In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound of green tea on thrombin-PAR1/PAR4-mediated hepatocellular carcinoma cell invasion and p42/p44 MAPKinase activation. In this study we used the permanent liver carcinoma cell line HEP-3B and two primary cultures established from surgically resected HCCs. We found that stimulation of HCC cells with thrombin, the PAR1-selective activating peptide, TFLLRN-NH2, and the PAR4-selective activating peptide, AYPGKF-NH2, increased cell invasion across a Matrigel-coated membrane barrier and stimulated activation of p42/p44 MAPKinase phosphorylation. Both the effects on p42/p44 MAPKinases, and on cell invasiveness induced by thrombin and the PAR1/4 subtype-selective agonist peptides were effectively blocked by EGCG. The results clearly identify EGCG as a potent inhibitor of the thrombin-PAR1/PAR4-p42/p44 MAPKinase invasive signaling axis in hepatocellular carcinoma cells as a previously unrecognized mode of action for EGCG in cancer cells. Moreover, the results suggest that (-)-epigal-locatechin-3-gallate might have therapeutic potential for hepatocellular carcinoma.
最近有研究表明，凝血酶可通过激活蛋白酶激活受体（PAR）亚型PAR1和PAR4来促进肝细胞癌（HCC）细胞迁移，提示这些蛋白酶-受体系统在HCC进展中发挥作用。在本研究中，我们调查了绿茶中的主要多酚化合物（-）-表没食子儿茶素-3-没食子酸酯（EGCG）对凝血酶-PAR1/PAR4介导的肝癌细胞侵袭及p42/p44丝裂原活化蛋白激酶（MAPKinase）激活的影响。在本研究中，我们使用了永久性肝癌细胞系HEP-3B以及从手术切除的HCC中建立的两种原代培养细胞。我们发现，用凝血酶、PAR1选择性激活肽TFLLRN-NH2和PAR4选择性激活肽AYPGKF-NH2刺激HCC细胞，可增加细胞穿过基质胶包被的膜屏障的侵袭能力，并刺激p42/p44 MAPKinase磷酸化的激活。EGCG可有效阻断凝血酶及PAR1/4亚型选择性激动剂肽对p42/p44 MAPKinases的作用以及对细胞侵袭性的影响。这些结果明确表明，EGCG是肝癌细胞中凝血酶-PAR1/PAR4-p42/p44 MAPKinase侵袭信号轴的有效抑制剂，这是EGCG在癌细胞中一种此前未被认识的作用模式。此外，这些结果提示（-）-表没食子儿茶素-3-没食子酸酯可能对肝细胞癌具有治疗潜力。
