Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis

Fedorova, Olga; Petukhov, Alexey; Daks, Alexandra; Shuvalov, Oleg; Leonova, Tatyana; Vasileva, Elena; Aksenov, N. D.; Melino, Gerry; Barlev, Nikolai A.

doi:10.1038/s41388-018-0566-8

Cited by 41 publications

(42 citation statements)

References 54 publications

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“…Among these genes, we noted NR4A3, which was up‐regulated after LINC00467 knockdown and inversely associated with LINC00467 in HCC tissues. NR4A3 is a member of nuclear receptors superfamily and frequently reported to act as a tumour suppressor in gastric, breast and lung cancer . Therefore, we further investigated whether LINC00467 regulates NR4A3 and whether the modulation of NR4A3 mediates the oncogenic roles of LINC00467 in HCC.…”

Section: Resultsmentioning

confidence: 99%

“…NR4A3 (orphan nuclear receptor 4A3) belongs to the nuclear receptor superfamily. NR4A3 has been shown to regulate cell proliferation, apoptosis and migration and have generally tumour‐suppressive roles in breast cancer, lung cancer, gastric cancer and leukaemia . Therefore, we hypothesized that the tumour suppressor NR4A3 may mediate the oncogenic roles of LINC00467 in HCC.…”

Section: Discussionmentioning

confidence: 99%

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Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Wang

Guo

Nampoukime

et al. 2020

J Cellular Molecular Medi

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Hepatocellular carcinoma (HCC) is a main cause of cancer‐related deaths globally. Long non‐coding RNAs (lncRNAs) play important roles in diverse cancers. Our previous microarray‐based lncRNA profiling showed that LINC00467 was highly expressed in HCC. Here, we further explored the expression, role and functional mechanism of lncRNA LINC00467 in HCC. Our findings revealed that LINC00467 was up‐regulated in HCC tissues and HCC cell lines. Increased expression of LINC00467 was positively associated with tumour size and vascular invasion. In vitro functional experiments revealed that LINC00467 accelerated HCC cell proliferation, cell cycle progression and migration and reduced HCC cell apoptosis. In vivo functional assays revealed that LINC00467 drove HCC xenograft growth and HCC cell proliferation and repressed HCC cell apoptosis in vivo. Moreover, LINC00467 inhibited NR4A3 post‐transcriptionally via interacting with NR4A3 mRNA to form double‐stranded RNA, which was further degraded by Dicer. The expression of NR4A3 was inversely associated with LINC00467 in HCC tissues. Functional rescue assays found that restore of NR4A3 expression blocked the oncogenic roles of LINC00467 in HCC. Taken together, our results demonstrated that lncRNA LINC00467 was a novel highly expressed and oncogenic lncRNA in HCC via inhibiting NR4A3. Targeting LINC00467 or enhancing NR4A3 may be potential therapeutic strategies against HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Wang

Guo

Nampoukime

et al. 2020

J Cellular Molecular Medi

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“…This interaction activates a death inducing signaling complex which catalyzes procaspase-8. Cleaved caspase-8 activates effector caspases which cause cell death by damaging the nucleus and other internal organelle [139,140,141].…”

Section: Apoptosismentioning

confidence: 99%

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Herring

Elison

Tessem

2019

Cells

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The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

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“…Being a transcriptional factor, p53 plays a key role in the maintenance of genome integrity by regulating such important processes as cell cycle progression, apoptosis, senescence, DNA repair, and cell metabolism in response to various forms of cell stress. Perhaps not surprisingly, the TP53 gene is the most commonly mutated gene in various tumors including breast cancer 50 – 53 . Importantly, about 30% of all breast cancer cases are characterized by mutations in the TP53 gene, while for HER2-positive subtypes, the proportion of TP53 mutations reaches 70% 54 , 55 .…”

Section: The P53 Family Of Tumor Suppressors In Breast Cancermentioning

confidence: 99%

Attenuation of p53 mutant as an approach for treatment Her2-positive cancer

et al. 2020

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Breast cancer is one of the world’s leading causes of oncological disease-related death. It is characterized by a high degree of heterogeneity on the clinical, morphological, and molecular levels. Based on molecular profiling breast carcinomas are divided into several subtypes depending on the expression of a number of cell surface receptors, e.g., ER, PR, and HER2. The Her2-positive subtype occurs in ~10–15% of all cases of breast cancer, and is characterized by a worse prognosis of patient survival. This is due to a high and early relapse rate, as well as an increased level of metastases. Several FDA-approved drugs for the treatment of Her2-positive tumors have been developed, although eventually cancer cells develop drug resistance. These drugs target either the homo- or heterodimerization of Her2 receptors or the receptors’ RTK activity, both of them being critical for the proliferation of cancer cells. Notably, Her2-positive cancers also frequently harbor mutations in the TP53 tumor suppressor gene, which exacerbates the unfavorable prognosis. In this review, we describe the molecular mechanisms of RTK-specific drugs and discuss new perspectives of combinatorial treatment of Her2-positive cancers through inhibition of the mutant form of p53.

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Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis

Cited by 41 publications

References 54 publications

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Attenuation of p53 mutant as an approach for treatment Her2-positive cancer

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