Department of Biochemistry, Faculty of Pharmacy, Suleyman Demirel University, 32260 Isparta, Turkey.
Department of Bioengineering, Institute of Science, Suleyman Demirel University, 32260 Isparta, Turkey.
Steroids. 2023 Jul;195:109238. doi: 10.1016/j.steroids.2023.109238. Epub 2023 Apr 11.
Hepatocellular carcinoma is one of the most common types of primary liver cancer in adults and also it is the third leading cause of cancer-related deaths worldwide. Although there are various treatment options such as surgery, radiation, targeted drug therapy, immunotherapy and chemotherapy, most hepatocellular carcinomas are highly resistant to systemic treatments. Today, the molecular pathogenesis of hepatocellular carcinoma remains largely obscure. Therefore, there is a need for detailed research for the characterization of molecular signaling networks related to the development of hepatocellular carcinoma. Recent studies have attention to the hormonal regulation of hepatocellular carcinoma cells mediated by systemic hormones such as glucocorticoids. However, glucocorticoid-mediated regulation of endoplasmic reticulum-associated degradation (ERAD) and unfolded protein response (UPR), which are known to be important survival mechanisms for cancer cells remains unknown in hepatocellular carcinoma. In the present study, we showed that dexamethasone-induced glucocorticoid receptor signaling mediated advanced regulation of ERAD and UPR signaling in hepatocellular carcinoma cells. Our findings indicated that glucocorticoid signaling positively regulated mRNA and protein levels of ERAD components and also protein kinase RNA-like ER Kinase (PERK) and inositol-requiring enzyme 1⍺ (IRE1⍺) branches of UPR signaling are accompanied by the glucocorticoid signaling. In addition, putative glucocorticoid response elements (GREs) were determined in the promoter regions of ERAD members in in-silico analyses. Additionally, silencing of ERAD components significantly reduced the tumorigenic features of hepatocellular carcinoma cells, including cell proliferation, metastasis, invasion and 3D tumor formation. Collectively, these results reveal a novel pattern of regulation of ERAD components by glucocorticoid-mediated in human hepatocellular carcinoma cells.
肝细胞癌是成人原发性肝癌中最常见的类型之一，也是全球癌症相关死亡的第三大主要原因。尽管有各种治疗选择，如手术、放疗、靶向药物治疗、免疫治疗和化疗，但大多数肝细胞癌对全身治疗具有高度耐药性。目前，肝细胞癌的分子发病机制在很大程度上仍不清楚。因此，需要对与肝细胞癌发展相关的分子信号网络进行详细研究。最近的研究引起了人们对全身性激素如糖皮质激素调节肝细胞癌细胞的关注。然而，糖皮质激素介导的内质网相关降解（ERAD）和未折叠蛋白反应（UPR）的调节，已知这是癌细胞的重要生存机制，在肝细胞癌中仍然未知。在本研究中，我们表明，地塞米松诱导的糖皮质激素受体信号通过调节肝细胞癌细胞中的 ERAD 和 UPR 信号转导来介导先进的调节。我们的研究结果表明，糖皮质激素信号正向调节 ERAD 成分的 mRNA 和蛋白水平，同时蛋白激酶 RNA 样内质网激酶（PERK）和内质网应激诱导的 1α（IRE1α）分支的 UPR 信号也伴随着糖皮质激素信号。此外，在计算机分析中确定了 ERAD 成员启动子区域中的推定糖皮质激素反应元件（GREs）。此外，沉默 ERAD 成分可显著降低肝细胞癌细胞的致瘤特征，包括细胞增殖、转移、侵袭和 3D 肿瘤形成。总之，这些结果揭示了糖皮质激素介导的人类肝细胞癌细胞中 ERAD 成分的新调节模式。
