Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College London, London, United Kingdom.
Elife. 2020 Oct 26;9:e55865. doi: 10.7554/eLife.55865.
Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line-specific direct effects of inhibiting IRE1α in tumor cells.
肝细胞癌（HCC）是一种肝脏肿瘤，通常发生在肝硬化患者中。肝星状细胞是 HCC 进展的关键参与者，因为它们创造了一个纤维化的微环境，并产生生长因子和细胞因子，增强肿瘤细胞的增殖和迁移。我们评估了内质网（ER）应激在星状细胞和 HCC 细胞之间相互作用中的作用。用 IRE1α 抑制剂 4μ8C 治疗患有纤维化 HCC 的小鼠，可减少肿瘤负担和胶原沉积。通过将 HCC 细胞与星状细胞共培养，我们发现 HCC 细胞激活星状细胞中的 IREα，从而促进其激活。抑制 IRE1α 阻断了星状细胞的激活，进而减少了不同体外 2D 和 3D 共培养物中肿瘤细胞的增殖和迁移。此外，我们还观察到抑制 IRE1α 在肿瘤细胞中具有细胞系特异性的直接作用。
