NEK9, a novel effector of IL-6/STAT3, regulates metastasis of gastric cancer by targeting ARHGEF2 phosphorylation

Lu, Guofang; Tian, Siyuan; Sun, Yi; Dong, Jiaqiang; Wang, Na; Zeng, Jiaoxia; Nie, Yongzhan; Wu, Kaichun; Han, Ying; Feng, Bin; Shang, Yulong

doi:10.7150/thno.53169

Cited by 28 publications

(22 citation statements)

References 27 publications

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“…Previous studies have substantiated that ARHGEF2 has unique RhoA exchange activity that facilitates the exchange of guanosine diphosphate (GDP) and GTP, thus promoting RhoA activation. As attested by the study, ARHGEF2 plays a key role in a variety of cancers by activating the RhoA signaling pathway, which may contribute to the proliferation and metastasis of cancer cells [ 18 – 21 ]. It is worth mentioning that ARHGEF2 was further studied as a RhoA-activating enzyme in already published literature.…”

Section: Discussionmentioning

confidence: 99%

“…ARHGEF2 has been proven to have specific RhoA exchange activity by increasing the guanosine triphosphate (GTP) -binding form of RhoA [ 15 ], thereby regulating the cytoskeleton, morphology, and promotion of cell proliferation [ 15 – 17 ]. Early studies identified ARHGEF2 as a RhoA-activating enzyme, despite the fact that ARHGEF2 has since been shown to play a crucial role in the invasion and metastasis of a variety of cancers [ 18 – 21 ]. However, the involvement of ARHGEF2 in tumor angiogenesis is uncertain up to now.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…Activation of IL-6/STAT3 inhibits the transcription of miR-520f-3p, which amplifies the excessive activation of STAT3 by targeting GP130. Therefore, targeting this pathway may have the potential to treat GC 62 . EGFR is associated with gastric mucosal hyperplasia and poor prognosis of GC 63 .…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and experimental verification based research into the effect and mechanism of Aucklandiae Radix–Amomi Fructus against gastric cancer

Song

Zhou

et al. 2022

Sci Rep

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To investigate the mechanism of the Aucklandiae Radix–Amomi Fructus (AR–AF) herb pair in treating gastric cancer (GC) by using network pharmacology and experimental verification. Using the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP), the major active components and their corresponding targets were estimated and screened out. Using Cytoscape 3.7.2 software, a visual network was established using the active components of AR–AF and the targets of GC. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways of the target enrichment were performed. AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The mRNA and protein expression levels of the hub targets were analyzed by the Oncomine, GEPIA, HPA databases and TIMER online tool, and the predicted targets were verified by qRT–PCR in vitro. Eremanthin, cynaropicrin, and aceteugenol were identified as vital active compounds, and AKT1, MAPK3, IL6, MAPK1, as well as EGFR were considered as the major targets. These targets exerted therapeutic effects on GC by regulating the cAMP signaling pathway, and PI3K-Akt signaling pathway. Molecular docking revealed that these active compounds and targets showed good binding interactions. The validation in different databases showed that most of the results were consistent with this paper. The experimental results confirmed that eremanthin could inhibit the proliferation of AGS by reducing the mRNA expression of hub targets. As predicted by network pharmacology and validated by the experimental results, AR–AF exerts antitumor effects through multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of GC.

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“…It is possible that the cellular context of Nek9 expression may dictate patient outcomes, with some promoting longer survival and others having the opposite effect. Recent work has also implicated Nek9 in metastasis of gastric cancer via phosphorylation of ARHGEF2, Rho/Rac Guanine Nucleotide Exchange Factor 2 [ 247 ]. In essence, these authors showed that Nek9 can influence RhoA activation and enhance cellular motility in gastric cancer via this phosphorylation event.…”

Section: Mammalian Nek9mentioning

confidence: 99%

In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals

Bachus

Graves

Fulham

et al. 2022

IJMS

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The Never in mitosis gene A (NIMA) family of serine/threonine kinases is a diverse group of protein kinases implicated in a wide variety of cellular processes, including cilia regulation, microtubule dynamics, mitotic processes, cell growth, and DNA damage response. The founding member of this family was initially identified in Aspergillus and was found to play important roles in mitosis and cell division. The yeast family has one member each, Fin1p in fission yeast and Kin3p in budding yeast, also with functions in mitotic processes, but, overall, these are poorly studied kinases. The mammalian family, the main focus of this review, consists of 11 members named Nek1 to Nek11. With the exception of a few members, the functions of the mammalian Neks are poorly understood but appear to be quite diverse. Like the prototypical NIMA, many members appear to play important roles in mitosis and meiosis, but their functions in the cell go well beyond these well-established activities. In this review, we explore the roles of fungal and mammalian NIMA kinases and highlight the most recent findings in the field.

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NEK9, a novel effector of IL-6/STAT3, regulates metastasis of gastric cancer by targeting ARHGEF2 phosphorylation

Cited by 28 publications

References 27 publications

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

Network pharmacology and experimental verification based research into the effect and mechanism of Aucklandiae Radix–Amomi Fructus against gastric cancer

In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals

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