Kobayashi Kaido, Matsushima-Nishiwaki Rie, Yamada Noriko, Migita Saori, Hioki Tomoyuki, Mizutani Daisuke, Kozawa Osamu
Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
Department of Dermatology, Kizawa Memorial Hospital, Minokamo, Gifu, Japan.
Heliyon. 2020 Sep 23;6(9):e05002. doi: 10.1016/j.heliyon.2020.e05002. eCollection 2020 Sep.
Heat shock proteins (HSPs) are induced in response to extracellular stress and manage the quality of proteins as molecular chaperones. HSP70, a highly conserved HSP, has been reported to correlate with the proliferation and migration of human cancer cells, such as oral, prostate, lung and liver cancer. Regarding hepatocellular carcinoma (HCC), the HSP70 levels in the tumor tissues from patients are significantly higher than those in the normal liver tissues. HSP70 reportedly upregulates the migration and invasion of HCC. The AKT, p38 mitogen-activated protein kinase (MAPK), c- N-terminal kinase (JNK) and Rho-kinase signaling pathways regulate the transforming growth factor (TGF)-α-induced migration of human HCC-derived HuH7 cells. However, the exact mechanism underlying the role of HSP70 in growth factor-induced HCC migration remains unclear. Therefore, in the present study, the mechanism underlying the involvement of HSP70 in TGF-α-induced HCC cell migration was investigated. Treatment with the HSP70 inhibitors VER155008 and YM-08 and the downregulation of HSP70 protein were confirmed to significantly suppress the TGF-α-induced cell migration of HuH7 cells. Both VER155008 and YM-08 reduced the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK, JNK or Rho-kinase. These results strongly suggest that HSP70 positively regulates the TGF-α-induced migration of HCC cells via the AKT signaling pathway.
热休克蛋白(HSPs)是在细胞外应激反应中被诱导产生的,并作为分子伴侣来管理蛋白质质量。HSP70是一种高度保守的热休克蛋白,据报道它与人类癌细胞(如口腔癌、前列腺癌、肺癌和肝癌)的增殖和迁移相关。对于肝细胞癌(HCC),患者肿瘤组织中的HSP70水平显著高于正常肝组织。据报道,HSP70上调HCC的迁移和侵袭。AKT、p38丝裂原活化蛋白激酶(MAPK)、c-Jun氨基末端激酶(JNK)和Rho激酶信号通路调节转化生长因子(TGF)-α诱导的人肝癌来源的HuH7细胞迁移。然而,HSP70在生长因子诱导的HCC迁移中作用的确切机制仍不清楚。因此,在本研究中,研究了HSP70参与TGF-α诱导的HCC细胞迁移的机制。用HSP70抑制剂VER155008和YM-08处理以及HSP70蛋白的下调被证实可显著抑制TGF-α诱导的HuH7细胞迁移。VER155008和YM-08均降低了TGF-α诱导的AKT磷酸化,而不影响p38 MAPK、JNK或Rho激酶的磷酸化。这些结果强烈表明,HSP70通过AKT信号通路正向调节TGF-α诱导的HCC细胞迁移。