The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling

Chen, Hang-zi; Li, Qingfeng; Li, Li; Wang, Weijia; Yao, Luming; Yang, Meng; Liu, Bo; Chen, Wei; Zhan, Yan-yan; Zhang, Mingqing; Cai, Jun; Zheng, Zhuo; Lin, Sheng-Cai; Li, Boan; Wu, Qiao

doi:10.1136/gutjnl-2011-300783

Cited by 66 publications

(54 citation statements)

References 48 publications

(58 reference statements)

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“…This result was consistent with the results of previous studies with regard to the interplay between Nur77 and the Wnt/β-catenin signaling pathway in colon cancer cells and in osteoblasts. 20,21,31 This signaling crosstalk may help to identify potential therapeutic targets for vascular remodeling associated with RAS hyperactivation during hypertension, atherosclerosis, vascular injury, restenosis, and aneurysm formation.…”

Section: Discussionmentioning

confidence: 99%

“…The interplay between Nur77 and the Wnt/β-catenin signaling pathway in cancer cells has been well reported in in vitro and in vivo settings. 20,21 Nur77 significantly suppresses Wnt/β-catenin activity via distinct mechanisms. 20,21 However, no direct information is available about the role of β-catenin in Ang II-induced vascular remodeling, and the mechanism by which β-catenin is regulated.…”

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confidence: 99%

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Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

et al. 2016

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Angiotensin II (Ang II) is the predominant effector peptide of the renin–angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II–induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II–induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77 −/− mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77 −/− mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II–induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II–induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II–induced vascular remodeling involved in many cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

et al. 2016

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“…In colon cancer cell lines, a bile acid carcinogen (deoxycholic acid) has been shown to stimulate b-catenin-dependent increased expression of NR4A1 (10). Conversely, NR4A1 has been shown to promote degradation of cytoplasmic b-catenin in a transcription-independent mechanism, whereas in murine models, NR4A1 has been shown to reduce tumor cell proliferation by transcriptional inhibition of Wnt signaling (11,12).…”

Section: Apoptosismentioning

confidence: 99%

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Mohan

Aherne

Rogers

et al. 2012

Clinical Cancer Research

155

142

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Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kB, phosphoinositide 3-kinase/AKT, c-jun-NH 2 -kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-¡). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

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“…The role of Ser-9 phosphorylation of GSK-3␤ in Wnt/␤-catenin signaling is still controversial (16 -19). For example, Ser-9 phosphorylation of GSK-3␤ is not correlated with Wnt-mediated GSK-3␤ activity in certain cell types (20,21). However, other studies demonstrated that many growth factors, such as insulin growth factor, transforming growth factor-␤, and epidermal growth factor, could increase ␤-catenin accumulation through Ser-9 phosphorylation of GSK-3␤ (21,22).…”

Section: Tumormentioning

confidence: 96%

“…For example, Ser-9 phosphorylation of GSK-3␤ is not correlated with Wnt-mediated GSK-3␤ activity in certain cell types (20,21). However, other studies demonstrated that many growth factors, such as insulin growth factor, transforming growth factor-␤, and epidermal growth factor, could increase ␤-catenin accumulation through Ser-9 phosphorylation of GSK-3␤ (21,22). Inactivation of GSK-3␤ through Ser-9 phosphorylation is involved in hepatitis B virus-x protein-mediated ␤-catenin stabilization in hepatocellular carcinoma cells (23).…”

Section: Tumormentioning

confidence: 99%

Succinate Dehydrogenase 5 (SDH5) Regulates Glycogen Synthase Kinase 3β-β-Catenin-mediated Lung Cancer Metastasis

Gao

Zhang

et al. 2013

Journal of Biological Chemistry

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The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling

Abstract: TR3 is a negative regulator of Wnt signalling and thus significantly suppresses intestinal tumorigenesis in Apc(min/+) mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3β in clinical colorectal cancers.

Cited by 66 publications

References 48 publications

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Succinate Dehydrogenase 5 (SDH5) Regulates Glycogen Synthase Kinase 3β-β-Catenin-mediated Lung Cancer Metastasis

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