ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation.
ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation.
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ARHGEF2/EDN1通路通过促进血管生成和恶性增殖参与内质网应激相关的肝细胞癌耐药
DOI：
10.1038/s41419-022-05099-8
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发表时间：
2022-07-27
影响因子：
9
通讯作者：
Sun, Guoping
中科院分区：
文献类型：
--
作者：
Zhu, Yue;Liu, Weiwei;Wang, Zishu;Wang, Yanfei;Tan, Chaisheng;Pan, Zhipeng;Wang, Anqi;Liu, Jiatao;Sun, Guoping
内质网应激广泛参与肝细胞癌的耐药过程，但内质网应激诱导耐药的机制涉及多条信号通路，目前尚不完全清楚。探索与内质网应激相关的基因可以为内质网应激诱导的耐药提供新的治疗靶点。通过分析衣霉素(TM)处理和未处理的肝癌细胞的RNA测序、ATAC测序和芯片测序数据，我们发现Rho鸟嘌呤核苷酸交换因子2(ARHGEF2)在内质网应激的肝癌细胞中上调。ARHGEF2在肿瘤恶性进展中发挥积极作用。尽管如此，还没有关于内质网应激和ARHGEF2之间的联系的研究。本研究揭示了ARHGEF2作为一种新的内质网应激下游效应因子在肝细胞癌血管生成和治疗耐药中的作用。ARHGEF2过表达与肝细胞癌的恶性发展和预后不良有关。内质网应激通过上调ZNF263的表达刺激ARHGEF2的表达。上调的ARHGEF2通过EDN1途径促进肝癌血管生成，促进肝癌细胞增殖和体内肿瘤生长，并参与内质网应激相关的治疗耐药。当ARHGEF2基因敲除与靶向药物配对时，肝癌细胞的生长受到更多的抑制。总而言之，我们揭示了一个先前隐藏的机制，即ARHGEF2/EDN1通路促进肝癌血管生成并参与内质网应激相关的耐药。
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.
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影响因子：
50.3
作者：
Cullis, Jane;Meiri, David;Rottapel, Robert
通讯作者：
Rottapel, Robert
影响因子：
12.4
作者：
Cianfrocca R;Rosanò L;Tocci P;Sestito R;Caprara V;Di Castro V;De Maria R;Bagnato A
通讯作者：
Bagnato A
NEK9是IL-6/STAT3的新型效应子，通过靶向ARHGEF2磷酸化调节胃癌转移
影响因子：
12.4
作者：
Lu G;Tian S;Sun Y;Dong J;Wang N;Zeng J;Nie Y;Wu K;Han Y;Feng B;Shang Y
通讯作者：
Shang Y
影响因子：
5.4
作者：
Shangguan WJ;Zhang YH;Li ZC;Tang LM;Shao J;Li H
通讯作者：
Li H
影响因子：
25.7
作者：
Arechederra, Maria;Bazai, Sehrish K.;Maina, Flavio
通讯作者：
Maina, Flavio