Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Cell Death Dis. 2022 Jul 27;13(7):652. doi: 10.1038/s41419-022-05099-8.
Endoplasmic reticulum (ER) stress is widely involved in the drug resistance of hepatocellular carcinoma (HCC), but the mechanism of ER stress-induced drug resistance involves multiple signaling pathways that cannot be fully explained. Exploring genes associated with ER stress could yield a novel therapeutic target for ER stress-induced drug resistance. By analyzing RNA-sequencing, ATAC-sequencing, and Chip-sequencing data of Tunicamycin (TM)-treated or untreated HCC cells, we found that Rho guanine nucleotide exchange factor 2 (ARHGEF2) is upregulated in HCC cells with ER stress. ARHGEF2 plays an active role in tumor malignant progression. Notwithstanding, no research has been done on the link between ER stress and ARHGEF2. The function of ARHGEF2 as a novel downstream effector of ER stress in the angiogenesis and treatment resistance of HCC was revealed in this work. ARHGEF2 overexpression was linked to malignant development and a poor prognosis in HCC. ER stress stimulates the expression of ARHGEF2 through upregulation of ZNF263. Elevated ARHGEF2 accelerates HCC angiogenesis via the EDN1 pathway, enhances HCC cell proliferation and tumor growth both in vitro and in vivo, and contributes to ER stress-related treatment resistance. HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.
内质网应激广泛参与肝癌（HCC）的耐药性，但内质网应激诱导耐药性的机制涉及多个信号通路，无法完全解释。探索与内质网应激相关的基因可能为内质网应激诱导的耐药性提供新的治疗靶点。通过分析他莫昔芬（TM）处理或未处理的 HCC 细胞的 RNA-seq、ATAC-seq 和 Chip-seq 数据，我们发现内质网应激的 HCC 细胞中 Rho 鸟嘌呤核苷酸交换因子 2（ARHGEF2）上调。ARHGEF2 在肿瘤恶性进展中发挥积极作用。然而，目前尚无关于内质网应激与 ARHGEF2 之间联系的研究。本工作揭示了 ARHGEF2 作为内质网应激在 HCC 血管生成和治疗耐药性中的新型下游效应因子的功能。ARHGEF2 的过表达与 HCC 的恶性发展和不良预后相关。内质网应激通过上调 ZNF263 刺激 ARHGEF2 的表达。升高的 ARHGEF2 通过 EDN1 途径加速 HCC 血管生成，增强 HCC 细胞在体外和体内的增殖和肿瘤生长，并促进与内质网应激相关的治疗耐药性。当 ARHGEF2 敲低与靶向药物联合使用时，HCC 细胞生长受到更强烈的抑制。总之，我们揭示了一个以前隐藏的机制，即 ARHGEF2/EDN1 途径促进血管生成，并参与 HCC 中的内质网应激相关耐药性。
