Department of Pharmacology, Gifu University Graduate School of Medicine, 501-1194, Gifu, Japan.
Department of Pharmacology, Gifu University Graduate School of Medicine, 501-1194, Gifu, Japan.
Arch Biochem Biophys. 2021 May 30;703:108851. doi: 10.1016/j.abb.2021.108851. Epub 2021 Mar 23.
Incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are hormones secreted from small intestine accompanied with oral intake. We previously showed that transforming growth factor (TGF)-α stimulates the migration of hepatocellular carcinoma (HCC) cells via mitogen-activated protein (MAP) kinases, AKT and Rho-kinase. However, it remains to be elucidated whether incretins affect HCC cell functions. In the present study, therefore, we investigated whether incretins affect the migration of HCC cells using human HCC-derived HuH7 cells. GLP-1, but not GIP, reduced both TGF-α- and hepatocyte growth factor (HGF)-induced cell migration. IBMX, an inhibitor of cyclic nucleotide phosphodiesterase, enhanced the suppressive effect of GLP-1. GLP-1 attenuated the phosphorylation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) by TGF-α and HGF. Our results strongly suggest that GLP-1 suppresses TGF-α- and HGF-induced migration of HCC cells through inhibiting the SAPK/JNK signaling pathway, and that the inhibition by GLP-1 is due to cAMP production.
肠促胰岛素，胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性胰岛素促分泌多肽（GIP），是伴随口服摄入从小肠分泌的激素。我们之前表明，转化生长因子（TGF）-α通过丝裂原活化蛋白（MAP）激酶、AKT 和 Rho 激酶刺激肝癌（HCC）细胞的迁移。然而，尚不清楚肠促胰岛素是否影响 HCC 细胞的功能。因此，在本研究中，我们使用人肝癌衍生的 HuH7 细胞研究了肠促胰岛素是否影响 HCC 细胞的迁移。GLP-1，但不是 GIP，减少了 TGF-α和肝细胞生长因子（HGF）诱导的细胞迁移。环核苷酸磷酸二酯酶抑制剂 IBMX 增强了 GLP-1 的抑制作用。GLP-1 减弱了 TGF-α和 HGF 对 SAPK/JNK 信号通路的磷酸化作用。我们的结果强烈表明，GLP-1 通过抑制 SAPK/JNK 信号通路抑制 TGF-α和 HGF 诱导的 HCC 细胞迁移，而 GLP-1 的抑制作用归因于 cAMP 的产生。
