ARHGEF39

Last update 08 May 2025

Basic Info

Synonyms

ARHGEF39, C9orf100, FLJ14642

+ [1]

Introduction

Promotes cell proliferation.

100 Clinical Results associated with ARHGEF39

100 Translational Medicine associated with ARHGEF39

0 Patents (Medical) associated with ARHGEF39

Literatures (Medical) associated with ARHGEF39

01 Oct 2024·Clinics and Research in Hepatology and Gastroenterology

ARHGEF39 targeted by E2F1 fosters hepatocellular carcinoma metastasis by mediating fatty acid metabolism

Article

Author: Zeng, Jianxing ; Huang, Yao ; Zeng, Jinhua ; Song, Xianglin ; Liu, Teng ; Xu, Qingyi

BACKGROUNDHepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer. Previous studies have implicated ARHGEF39 in various cancer progression processes, but its impact on HCC metastasis remains unclear.METHODSBioinformatics analysis and qRT-PCR were employed to test ARHGEF39 expression in HCC tissues and cells, identified enriched pathways associated with ARHGEF39, and investigated its regulatory relationship with E2F1. The impact of ARHGEF39 overexpression or knockdown on cellular phenotypes in HCC was assessed through the implementation of CCK-8 and Transwell assays. Accumulation of neutral lipids was determined by BODIPY 493/503 staining, while levels of triglycerides and phospholipids were measured using specific assay kits. Expression of E-cadherin, Vimentin, MMP-2, MMP-9, and FASN were analyzed by Western blot. The interaction between ARHGEF39 and E2F1 was validated through ChIP and dual-luciferase reporter assays.RESULTSOur study demonstrated upregulated expression of both ARHGEF39 and E2F1 in HCC, with ARHGEF39 being associated with fatty acid metabolism (FAM) pathways. Additionally, ARHGEF39 was identified as a downstream target gene of E2F1. Cell-based experiments unmasked that high expression of ARHGEF39 mediated the promotion of HCC cell viability, migration, and invasion via enhanced FAM. Moreover, rescue assays demonstrated that the promotion of HCC cell metastasis by high ARHGEF39 expression was attenuated upon treatment with Orlistat. Conversely, the knockdown of E2F1 suppressed HCC cell metastasis and FAM, while the upregulation of ARHGEF39 counteracted the repressive effects of E2F1 downregulation on the metastatic potential of HCC cells.CONCLUSIONOur findings confirmed the critical role of ARHGEF39 in HCC metastasis and unmasked potential molecular mechanisms through which ARHGEF39 fostered HCC metastasis via FAM, providing a theoretical basis for exploring novel molecular markers and preventive strategies for HCC metastasis.

01 May 2023·Journal of Allergy and Clinical Immunology

Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans

Article

Author: Leung, John ; Mersha, Tesfaye B. ; Rothenberg, Marc E. ; Falk, Gary ; Furuta, Glenn ; Peterson, Kathryn ; Davis, Carla ; Chehade, Mirna ; Khoury, Paneez ; Kottyan, Leah ; Gautam, Yadu ; Aceves, Seema ; Caldwell, Julie ; Menard-Katcher, Paul ; Spergel, Jonathan ; Wechsler, Joshua ; Gonsalves, Nirmala Prabu ; Hirano, Ikuo ; Dellon, Evan S. ; Gupta, Sandeep K.

BACKGROUNDEosinophilic esophagitis (EoE), a chronic allergic inflammatory disease, is linked to multiple genetic risk factors, but studies have focused on populations of European ancestry. Few studies have assessed Black or African American (AA) populations for loci involved in EoE susceptibility.OBJECTIVEWe performed admixture mapping (AM) and genome-wide association study (GWAS) of EoE using participants from AA populations.METHODSWe conducted AM and GWAS of EoE using 137 EoE cases and 1465 healthy controls from the AA population. Samples were genotyped using molecular evolutionary genetics analysis (MEGA). Genotype imputation was carried out with the Consortium on Asthma Among African-Ancestry Populations in the Americas (CAAPA) reference panel using the Michigan Imputation Server. Global and local ancestry inference was carried out, followed by fine mapping and RNA sequencing. After quality control filtering, over 6,000,000 variants were tested by logistic regression adjusted for sex, age, and global ancestry.RESULTSThe global African ancestry proportion was found to be significantly lower among cases than controls (0.751 vs 0.786, P = .012). Case-only AM identified 3 significant loci (9p13.3, 12q24.22-23, and 15q11.2) associated with EoE, of which 12q24.22-23 and 9p13.3 were further replicated in the case-control analysis, with associations observed with African ancestry. Fine mapping and multiomic functional annotations prioritized the variants rs11068264 (FBXW8) and rs7307331 (VSIG10) at 12q24.23 and rs2297879 (ARHGEF39) at 9p13.3. GWAS identified 1 genome-wide significant locus at chromosome 1p22.3 (rs17131726, DDAH1) and 10 other suggestive loci. Most GWAS variants were low-frequency African ancestry-specific variants. RNA sequencing revealed that esophageal DDAH1 and VSIG10 were downregulated and ARHGEF39 upregulated among EoE cases.CONCLUSIONSGWAS and AM for EoE in AA revealed that African ancestry-specific genetic susceptibility loci exist at 1p22.3, 9p13.3, and 12q24.23, providing evidence of ancestry-specific inheritance of EoE. More independent genetic studies of different ancestries for EoE are needed.

01 Dec 2021·Breast Cancer ResearchQ1 · MEDICINE

NRG1 fusions in breast cancer

Q1 · MEDICINE

ArticleOA

Author: Cooke, Susanna L ; Turro, Ernest ; Boursnell, Chris ; Mirza, Tashfina ; Edwards, Paul A W ; Howarth, Karen D ; Abraham, Jean E ; Pole, Jessica C ; Caldas, Carlos ; Garcia, Raquel Manzano ; Chin, Suet-Feung ; Rueda, Oscar M ; Eldridge, Matthew D

AbstractBackgroundNRG1gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. TheNRG1gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocrine stimulation of the receptor. TheNRG1fusion expressed in the breast cancer cell line MDA-MB-175 serves as a model example of such fusions, showing the proposed autocrine loop and exceptional drug sensitivity. However, its structure has not been properly characterised, its oncogenic activity has not been fully explained, and there is limited data on such fusions in breast cancer.MethodsWe analysed genomic rearrangements and transcripts ofNRG1in MDA-MB-175 and a panel of 571 breast cancers.ResultsWe found that the MDA-MB-175 fusion—originally reported as aDOC4(TENM4)-NRG1fusion, lacking the cytoplasmic tail ofNRG1—is in reality a double fusion,PPP6R3-TENM4-NRG1, producing multiple transcripts, some of which include the cytoplasmic tail. We hypothesise that manyNRG1fusions may be oncogenic not for lacking the cytoplasmic domain but because they do not encode NRG1’s nuclear-localised form. The fusion in MDA-MB-175 is the result of a very complex genomic rearrangement, which we partially characterised, that creates additional expressed gene fusions,RSF1-TENM4,TPCN2-RSF1, andMRPL48-GAB2.We searched forNRG1rearrangements in 571 breast cancers subjected to genome sequencing and transcriptome sequencing and found four cases (0.7%) with fusions,WRN-NRG1,FAM91A1-NRG1,ARHGEF39-NRG1, andZNF704-NRG1, all splicing intoNRG1at the same exon as in MDA-MB-175. However, theWRN-NRG1andARHGEF39-NRG1fusions were out of frame. We identified rearrangements ofNRG1in many more (8% of) cases that seemed more likely to inactivate than to create activating fusions, or whose outcome could not be predicted because they were complex, or both. This is not surprising becauseNRG1can be pro-apoptotic and isinactivated in some breast cancers.ConclusionsOur results highlight the complexity of rearrangements ofNRG1in breast cancers and confirm that some do not activate but inactivate. Careful interpretation ofNRG1rearrangements will therefore be necessary for appropriate patient management.

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ARHGEF39

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