ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation

Abstract

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.

DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma

“…A transcription factor, ZNF3 85A , showed DNA hypomethylation in U III ‐N samples, and may be upregulated during U III ‐T development, which is consistent with a previous report that overexpression of ZNF3 85A in HCCs is associated with poorer prognosis 40 . ARHGEF2 , a Rho/Rac guanine nucleotide exchange factor, again shows DNA hypomethylation in U III ‐N samples, which is consistent with a previous report that ARHGEF2 overexpression is associated with malignant progression of HCCs 41 . In contrast, HADH involved in fatty acid β‐oxidation showed DNA hypermethylation in U III ‐N samples.…”

“…Among the eight genes other than ADCY5 in overexpression is associated with malignant progression of HCCs. 41 In contrast, HADH involved in fatty acid β-oxidation showed DNA hypermethylation in U III -N samples. This is consistent with a previous study indicating that HADH expression is decreased in cultured HCC cells.…”

Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells

“…Moreover, by alleviating ER stress, astragaloside IV sensitizes NSCLC cells to cisplatin ( 117 ). Furthermore, ER stress upregulates the expression of the ZNF263–ARHGEF2 pathway, which contributes to ER stress-related treatment resistance ( 118 ). When exposed to ER stress, nasopharyngeal carcinoma cells secrete endoplasmic reticulum resident protein 44(ERp44)-containing exosomes, which boost the chemoresistance of neighboring cells ( 119 ).…”