ONECUT2 upregulation is associated with CpG hypomethylation at promoter‐proximal DNA in gastric cancer and triggers ACSL5

Seo, Eun‐Hye; Kim, Hee‐Jin; Kim, Jong‐Hwan; Lim, Byungho; Park, Jong‐Lyul; Kim, Seon‐Young; Lee, Sang Il; Kim, Jeong Il; Song, Kyu‐Sang; Kim, Yong‐Sung

doi:10.1002/ijc.32946

Cited by 24 publications

(15 citation statements)

References 42 publications

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“…Therefore, ONECUT2 may serve as a potential oncogene in GC. Using siRNA and CRISPR deletion system, we found that knockdown of ONECUT2 significantly inhibited GC cell proliferation, which is in agreement with another recent study by Seo et al 22 Our works firstly identified that ONECUT2 controlled the Wnt signaling pathway and regulated ROCK1 expression. ROCK1 gene encodes a serine/threonine kinase protein and is activated when bound to the GTP-bound form of RhoA protein.…”

Section: Discussionsupporting

confidence: 91%

ONECUT2 Accelerates Tumor Proliferation Through Activating ROCK1 Expression in Gastric Cancer

Chen¹,

Chen²,

Sun³

et al. 2020

CMAR

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Background Transcription factors (TFs) are key regulators which control gene expression during cancer initiation and progression. In the current study, we aimed to explore the proliferative function and clinical significance of TFs in gastric cancer (GC). Methods Differential analysis was used to investigate the overall expression difference between normal and tumor tissues of each TF in TCGA-STAD cohort. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to confirm the mRNA expression of one cut homeobox 2 ( ONECUT2 ) in GC tissues. Western blot analysis was conducted to confirm the protein knockdown efficiency. Cell counting, colony formation, and GC xenograft model assays were performed to confirm the proliferative function of ONECUT2 in GC cells. Gene set enrichment analysis (GESA) and qRT-PCR were conducted to confirm the affected signaling pathways and downstream targets of ONECUT2. Results Our data indicated that a TF named ONECUT2 was highly expressed in GC and correlated with patients’ poor prognosis. Importantly, knockdown of ONECUT2 dramatically decreased GC cells proliferation, whereas overexpression of ONECUT2 promoted carcinogenesis in GC. Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the upregulating ONECUT2 induced the activation of Wnt signaling pathway and cell cycle regulation pathway. We further identified that ONECUT2 boosted gastric cancer cell proliferation through enhancing ROCK1 (Rho associated coiled-coil containing protein kinase 1) mRNA expression. High level of ROCK1 expression rescued proliferative behavior of ONECUT2 -deficient GC cells. Conclusion Our findings demonstrated that ONECUT2 promoted GC cells proliferation through activating ROCK1 expression at the DNA level, suggesting that ONECUT2-ROCK1 axis might be a potential therapeutic target in GC.

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Section: Discussionsupporting

confidence: 91%

ONECUT2 Accelerates Tumor Proliferation Through Activating ROCK1 Expression in Gastric Cancer

Chen¹,

Chen²,

Sun³

et al. 2020

CMAR

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“…Furthermore, ACSL5 lower regulation predicted a worse prognosis in breast cancer [ 52 ]. However, opposing results were also reported in studies on glioma [ 55 ] and gastric cancer [ 56 ], where ACSL5 was upregulated. In addition, fibroblast growth factor receptor 2 (FGFR2) -ACSL5 chimera RNA caused clinical gastric cancer cells to be resistant to the treatment with FGFR inhibitors [ 57 ].…”

Section: Resultsmentioning

confidence: 83%

“…In addition, fibroblast growth factor receptor 2 (FGFR2) -ACSL5 chimera RNA caused clinical gastric cancer cells to be resistant to the treatment with FGFR inhibitors [ 57 ]. Evidences showed that high levels of ACSL5, as a potential downstream target of the transcription factor ONECUT2 (OC2), together with OC2, may cooperatively promote intestinal metaplasia and gastric cancer progression [ 56 ]. These contradicting results indicated that the roles of ACSL5 were different among the different cancer types.…”

Section: Resultsmentioning

confidence: 99%

Identification of Latent Oncogenes with a Network Embedding Method and Random Forest

Zhao

Hu²,

Lei

et al. 2020

BioMed Research International

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Oncogene is a special type of genes, which can promote the tumor initiation. Good study on oncogenes is helpful for understanding the cause of cancers. Experimental techniques in early time are quite popular in detecting oncogenes. However, their defects become more and more evident in recent years, such as high cost and long time. The newly proposed computational methods provide an alternative way to study oncogenes, which can provide useful clues for further investigations on candidate genes. Considering the limitations of some previous computational methods, such as lack of learning procedures and terming genes as individual subjects, a novel computational method was proposed in this study. The method adopted the features derived from multiple protein networks, viewing proteins in a system level. A classic machine learning algorithm, random forest, was applied on these features to capture the essential characteristic of oncogenes, thereby building the prediction model. All genes except validated oncogenes were ranked with a measurement yielded by the prediction model. Top genes were quite different from potential oncogenes discovered by previous methods, and they can be confirmed to become novel oncogenes. It was indicated that the newly identified genes can be essential supplements for previous results.

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“…However, others have reported that ONECUT2 regulation occurs through epigenetic regulation and hypomethylation of that CpGs in the promoter of ONECUT2 occurs primarily in intestinal metaplasia and gastric cancers, and that hypomethylation was associated with ONECUT2 upregulation. It is therefore suggested that that ONECUT2 might promote intestinal differentiation or development of gastric cancer and could be used as a early detection biomarkers of gastric carcinogenesis, while its role in advanced disease is less defined (46).…”

Section: Resultsmentioning

confidence: 99%

Next generation sequencing analysis of gastric cancer identifies the leukemia inhibitory factor receptor (LIFR) as a driving factor in gastric cancer progression and as a predictor of poor prognosis

Giorgio

Marchianò

Marino

et al. 2022

Preprint

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Gastric cancer (GC) is the third cause of cancer-related-death worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited because the presence of diffuse disease. Peritoneal dissemination occurs in approximately one third of patients with GC and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the formation of peritoneal metastasis in GC remain poorly defined. To investigate this point, we conducted a high-throughput sequencing of transcriptome expression in paired samples of normal and neoplastic gastric mucosa in 31 GC patients with or without peritoneal carcinomatosis. The RNAseq analysis led to the discovery of a group of highly upregulated or downregulated genes that were differentially modulated in patients with peritoneal disease in comparison to GC patients without peritoneal involvement. Among these genes the leukemia inhibitory factor receptor (LIFR) and the one cut domain family member (ONECUT)2 were the only two genes that predicted survival at univariate statistical analysis. Because LIFR was the highest regulated gene we have further assessed whether this receptor plays a mechanistic role in GC dissemination. For this purpose, we have first assessed the expression of LIF, a member of IL-6 cytokine family, and LIFR in GC cell lines. Our results demonstrate that exposure of MKN45 cells to LIF, promoted a concentration-dependent proliferation and epithelial-mesenchymal transition (EMT) as shown by modulation of E-cadherin/vimentin gene expression along with JAK and STAT 3 phosphorylation and acquisition of a migratory phenotype. These features were reversed by in vitro treatment with a LIFR antagonist. Together, these data provide support to the notion that development of LIF/LIFR inhibitors might have a role in the treatment of GC.

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ONECUT2 upregulation is associated with CpG hypomethylation at promoter‐proximal DNA in gastric cancer and triggers ACSL5

Cited by 24 publications

References 42 publications

<p><em>ONECUT2</em> Accelerates Tumor Proliferation Through Activating <em>ROCK1</em> Expression in Gastric Cancer</p>

<p><em>ONECUT2</em> Accelerates Tumor Proliferation Through Activating <em>ROCK1</em> Expression in Gastric Cancer</p>

Identification of Latent Oncogenes with a Network Embedding Method and Random Forest

Next generation sequencing analysis of gastric cancer identifies the leukemia inhibitory factor receptor (LIFR) as a driving factor in gastric cancer progression and as a predictor of poor prognosis

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