EPHA2 antisense RNA modulates EPHA2 mRNA levels in basal-like/triple-negative breast cancer cells

Okuyama, Tetsuya; Sakamoto, Ryou; Kumagai, Kazuhiro; Nishizawa, Mikio; Kimura, Tomonori; Sugie, Tomoharu; Kimura, Tetsuya

doi:10.1016/j.biochi.2020.10.002

Cited by 14 publications

(18 citation statements)

References 45 publications

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“…Because the presence of natural antisense transcripts is essential for candidate mRNA degradation by sense oligonucleotides, this approach is termed natural antisense transcript-targeted regulation (NATRE) technology (5,36). Several genes reportedly transcribe AS transcripts, and sense oligonucleotides corresponding to their mRNAs can knock down the expression of candidate genes in mammalian cells (36,37).…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy With a Sense Oligonucleotide to Inducible Nitric Oxide Synthase Mrna and Human Soluble Thrombomodulin Improves Survival of Sepsis Model Rats After Partial Hepatectomy

Nakatake

Okuyama

Kotsuka

et al. 2023

Shock

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Sepsis after a major hepatectomy is a critical problem. In septic shock, the inflammatory mediator, nitric oxide (NO), is overproduced in hepatocytes and macrophages. The natural antisense (AS) transcripts, non-coding RNAs, are transcribed from a gene that encodes inducible nitric oxide synthase (iNOS). iNOS AS transcripts interact with and stabilize iNOS mRNAs. A single-stranded "sense oligonucleotide" (designated as SO1) corresponding to the iNOS mRNA sequence inhibits mRNA-AS transcript interactions and reduces iNOS mRNA levels in rat hepatocytes. In contrast, recombinant human soluble thrombomodulin (rTM) treats disseminated intravascular coagulopathy by suppressing coagulation, inflammation, and apoptosis. In this study, the combination therapy of SO1 and a low dose of rTM was evaluated for hepatoprotection in a rat septic shock model after partial hepatectomy. Rats underwent 70% hepatectomy, followed by intravenous (i.v.) injection of lipopolysaccharide (LPS) after 48 h. SO1 was injected (i.v.) simultaneously with LPS, whereas rTM was injected (i.v.) 1 h before LPS injection. Similarly to our previous report, SO1 increased survival after LPS injection. When rTM, which has different mechanisms of action, was combined with SO1, it did not interfere with the effect of SO1 and showed a significant increase in survival compared with LPS alone treatment. In serum, the combined treatment decreased NO levels. In the liver, the combined treatment inhibited iNOS mRNA and protein expression. A decreased iNOS AS transcript expression by the combined treatment was also observed. The combined treatment decreased mRNA expression of the inflammatory and pro-apoptotic genes while increasing that of the anti-apoptotic gene. Furthermore, the combined treatment reduced the number of myeloperoxidase-positive cells. These results suggested that the combination of SO1 and rTM has therapeutic potential for sepsis.

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Section: Discussionmentioning

confidence: 99%

Combination Therapy With a Sense Oligonucleotide to Inducible Nitric Oxide Synthase Mrna and Human Soluble Thrombomodulin Improves Survival of Sepsis Model Rats After Partial Hepatectomy

Nakatake

Okuyama

Kotsuka

et al. 2023

Shock

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“…Ephrin type-A receptor 2 (EPHA2) is a receptor tyrosine kinase (RTK), the overexpression of EPHA2 is associated with metastasis in a variety of cancers, including melanomas and ovarian, prostate, lung, and breast cancers. EphA2 receptor has a pro-oncogenic property which activates the tumor-suppressive signaling pathways of EphA2, and inhibits the PI3K/Akt and ERK pathways ( 108 , 109 ).…”

Section: Discussionmentioning

confidence: 99%

High-Throughput In Vitro Gene Expression Profile to Screen of Natural Herbals for Breast Cancer Treatment

et al. 2021

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Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in women worldwide. Some therapeutic drugs and approaches could cause side effects and weaken the immune system. The combination of conventional therapies and traditional Chinese medicine (TCM) significantly improves treatment efficacy in breast cancer. However, the chemical composition and underlying anti-tumor mechanisms of TCM still need to be investigated. The primary aim of this study is to provide unique insights to screen the natural components for breast cancer therapy using high-throughput transcriptome analysis. Differentially expressed genes were identified based on two conditions: single samples and groups were classified according to their pharmaceutical effect. Subsequently, the sample treated with E. cochinchinensis Lour. generated the most significant DEGs set, including 1,459 DEGs, 805 upregulated and 654 downregulated. Similarly, group 3 treatment contained the most DEGs (414 DEGs, 311 upregulated and 103 downregulated). KEGG pathway analyses showed five significant pathways associated with the inflammatory and metastasis processes in cancer, which include the TNF, IL−17, NF-kappa B, MAPK signaling pathways, and transcriptional misregulation in cancer. Samples were classified into 13 groups based on their pharmaceutical effects. The results of the KEGG pathway analyses remained consistent with signal samples; group 3 presents a high significance. A total of 21 genes were significantly regulated in these five pathways, interestingly, IL6, TNFAIP3, and BRIC3 were enriched on at least two pathways, seven genes (FOSL1, S100A9, CXCL12, ID2, PRS6KA3, AREG, and DUSP6) have been reported as the target biomarkers and even the diagnostic tools in cancer therapy. In addition, weighted correlation network analysis (WGCNA) was used to identify 18 modules. Among them, blue and thistle2 were the most relevant modules. A total of 26 hub genes in blue and thistle2 modules were identified as the hub genes. In conclusion, we screened out three new TCM (R. communis L., E. cochinchinensis Lour., and B. fruticosa) that have the potential to develop natural drugs for breast cancer therapy, and obtained the therapeutic targets.

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“…AS transcripts are transcribed from many genes that are involved in inflammation, such as mRNAs that encode alpha subunit (p19) of IL-23 (IL-23A), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C -X 3 -C) motif ligand 1 (CX3CL1), p65 and p50 subunits of nuclear factor kappaB (NF-kappaB) [14]. Additionally, AS transcript is transcribed from the human gene encoding ephrin type A receptor 2 (EPHA2), which is a receptor tyrosine kinase whose over-expression is observed in various cancers [25,26].…”

Section: Structures Of Natural Antisense Transcriptsmentioning

confidence: 99%

“…Decrease iNOS (iNOS/NOS2) NATRE [18,19] Il23A (IL-23, alpha subunit) NATRE [14] IFN-A1 (IFN-alpha1) NATRE [20] EPHA2 (EPHA2) NATRE [26] Increase Ccl2 (CCL2) NATRE [14] Ccl20 (CCL20) NATRE [14] Cx3xl1 (CX3CL1) NATRE [14] Cd69 (CD69) NATRE [14] RelA (NF-kappaB, p65 subunit) NATRE [14] Tnf (TNF-alpha) NATRE [24] Bdnf (BDNF) AntagoNAT [37] Gdnf (GDNF) AntagoNAT [37] * Genes were classified by the main effect of sense oligonucleotides on the mRNA levels.…”

Section: Technology Referencementioning

confidence: 99%

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The Natural Antisense Transcript-Targeted Regulation Technology Using Sense Oligonucleotides and Its Application

Nishizawa¹,

Okuyama²,

Nakatake³

2023

Oligonucleotides - Overview and Applications

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Natural antisense transcripts (NATs or AS transcripts) are frequently transcribed from many eukaryotic genes and post-transcriptionally regulate gene expression. The AS transcript is classified as noncoding RNA and acts as a regulatory RNA in concert with RNA-binding proteins that bind to cis-controlling elements on the mRNA, microRNAs, and drugs. The AS transcript that overlaps with mRNA regulates mRNA stability by interacting with mRNA, and the network of mRNAs, AS transcripts, microRNAs, and RNA-binding proteins finely tunes the output of gene regulation, i.e., mRNA levels. We found that single-stranded ‘sense’ oligonucleotides corresponding to an mRNA sequence decreased the mRNA levels by interfering with the mRNA-AS transcript interactions of several genes, such as inducible nitric oxide synthase (iNOS) and interferon-alpha1 (IFN-A1) genes. In contrast, AntagoNAT oligonucleotides, which are complementary to AS transcripts, are sense oligonucleotides when they overlap with mRNA, but they increase the levels of specific mRNAs. Collectively, the sense oligonucleotide is a powerful tool for decreasing or increasing mRNA levels. The natural antisense transcript-targeted regulation (NATRE) technology using sense oligonucleotides is a method with a unique modality for modulating cytosolic mRNA levels and may be used to treat human diseases in which AS transcripts are involved.

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EPHA2 antisense RNA modulates EPHA2 mRNA levels in basal-like/triple-negative breast cancer cells

Cited by 14 publications

References 45 publications

Combination Therapy With a Sense Oligonucleotide to Inducible Nitric Oxide Synthase Mrna and Human Soluble Thrombomodulin Improves Survival of Sepsis Model Rats After Partial Hepatectomy

Combination Therapy With a Sense Oligonucleotide to Inducible Nitric Oxide Synthase Mrna and Human Soluble Thrombomodulin Improves Survival of Sepsis Model Rats After Partial Hepatectomy

High-Throughput In Vitro Gene Expression Profile to Screen of Natural Herbals for Breast Cancer Treatment

The Natural Antisense Transcript-Targeted Regulation Technology Using Sense Oligonucleotides and Its Application

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