Henan University School of Medicine, Kaifeng, 475004, Henan, China.
Sci Rep. 2017 Jul 11;7(1):5134. doi: 10.1038/s41598-017-05457-z.
Hydrogen sulfide (HS) is involved in cancer biological processes. However, there are several controversies concerning the role of HS in cancer development and progression. In this study, we found that the growth and migration of hepatocellular carcinoma (HCC) cells were enhanced by 10-100 μM NaHS and dose-dependently inhibited by 600-1000 μM NaHS. The apoptotic levels were reduced by 25-100 μM NaHS but increased by 400-1000 μM NaHS in HCC cells. After treatment with 25-50 μM NaHS, the protein levels of p-EGFR, p-ERK, MMP-2, and p-AKT were increased, whereas the levels of PTEN and the ratio of BAX/BCL-2 were down-regulated. Administration of 800-1000 μM NaHS showed opposite effects on these protein levels in HCC cells. However, HS showed no effects on the growth, migration, apoptosis, and the protein levels of the EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways in L02 cells. Furthermore, 25-100 μM NaHS promoted HCC tumor growth and blood vessel formation, while 800-1000 μM NaHS inhibited angiogenesis and tumor growth with no obvious systemic toxicity. These results indicate that HS acts as a double-edged sword in HCC cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Novel HS donors could be designed and applied for further antitumor research.
硫化氢 (HS) 参与癌症的生物学过程。然而，HS 在癌症发生和发展中的作用存在一些争议。在本研究中，我们发现 10-100μM 的 NaHS 增强了肝癌 (HCC) 细胞的生长和迁移，并呈剂量依赖性地被 600-1000μM 的 NaHS 抑制。凋亡水平在 25-100μM 的 NaHS 处理下降低，但在 400-1000μM 的 NaHS 处理下增加。用 25-50μM 的 NaHS 处理后，p-EGFR、p-ERK、MMP-2 和 p-AKT 的蛋白水平增加，而 PTEN 和 BAX/BCL-2 的比值下调。800-1000μM 的 NaHS 对 HCC 细胞中这些蛋白水平表现出相反的作用。然而，HS 对 L02 细胞的生长、迁移、凋亡以及 EGFR/ERK/MMP-2 和 PTEN/AKT 信号通路的蛋白水平没有影响。此外，25-100μM 的 NaHS 促进 HCC 肿瘤生长和血管形成，而 800-1000μM 的 NaHS 抑制血管生成和肿瘤生长，且无明显的全身毒性。这些结果表明，HS 通过 EGFR/ERK/MMP-2 和 PTEN/AKT 信号通路在 HCC 细胞中发挥双刃剑作用。可以设计和应用新型 HS 供体，以进一步开展抗肿瘤研究。
