A single extra copy of Dscr1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis

Shin, Jaehyun; Lee, Jang Choon; Baek, Kwan-Hyuck

doi:10.1016/j.canlet.2013.08.047

Cited by 23 publications

(15 citation statements)

References 48 publications

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“…To determine CDO expression during lung cancer progression, we took advantage of a NSCLC mouse model, LSL-K-ras G12D mice [46], [47]. After intranasal inhalation of Ad-Cre to induce spontaneous lung tumorigenesis in LSL-K-ras G12D mice, we assessed CDO expression in the lung tumor tissue showing four individual grades of tumor progression by fluorescent immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

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CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

Leem

Bae

et al. 2014

PLoS ONE

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Hedgehog (Hh) signaling plays essential roles in various developmental processes, and its aberrant regulation results in genetic disorders or malignancies in various tissues. Hyperactivation of Hh signaling is associated with lung cancer development, and there have been extensive efforts to investigate how to control Hh signaling pathway and regulate cancer cell proliferation. In this study we investigated a role of CDO, an Hh co-receptor, in non-small cell lung cancer (NSCLC). Inhibition of Hh signaling by SANT-1 or siCDO in lung cancer cells reduced proliferation and tumorigenicity, along with the decrease in the expression of the Hh components. Histological analysis with NSCLC mouse tissue demonstrated that CDO was expressed in advanced grade of the cancer, and precisely co-localized with GLI1. These data suggest that CDO is required for proliferation and survival of lung cancer cells via Hh signaling.

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Section: Resultsmentioning

confidence: 99%

“…LSL-K-ras G12D mice were provided by Dr. Tyler Jacks (MIT Cancer Center) [46], [47]. The paraffin sections from LSL-K-ras G12D mice were immunoreacted with 2B3 (mouse ascites against CDO) and anti-GLI1 antibody (1∶100; ab49314, Abcam), and detected using immunofluorescence.…”

Section: Methodsmentioning

confidence: 99%

CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

Leem

Bae

et al. 2014

PLoS ONE

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“…Studies from our lab and others have shown that inhibition of calcineurin by overexpression of its endogenous inhibitor DSCR1, or by deletion of calcineurin, negatively regulates endothelial cell activation (10,14,45). The calcineurin pathway in endothelial cells lies downstream of VEGFR2 activation and transmits angiogenic signals through one of its effectors, the NFAT family of transcription factors (10,11,27).…”

Section: Discussionmentioning

confidence: 97%

“…The calcineurin pathway in endothelial cells lies downstream of VEGFR2 activation and transmits angiogenic signals through one of its effectors, the NFAT family of transcription factors (10,11,27). We have previously shown that calcineurin inhibition in endothelial cells by DSCR1 blocks tumor angiogenesis (10,14). Given CsA is a potent calcineurin inhibitor, we would predict that CsA treatment would also block tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A Promotes Tumor Angiogenesis in a Calcineurin-Independent Manner by Increasing Mitochondrial Reactive Oxygen Species

Zhou

Ryeom

2014

Molecular Cancer Research

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The widely used immunosuppressant cyclosporin A (CsA), a potent calcineurin inhibitor, significantly increases the incidence of cancer in organ transplant patients. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis, in contrast to the effect observed after long-term CsA treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on tumor angiogenesis has not been investigated. Using an in vivo model of skin carcinogenesis, prolonged treatment with CsA promoted tumor growth and angiogenesis. The addition of CsA to endothelial cells in vitro increased proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species (ROS). Co-treatment with antioxidants significantly abrogated CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings suggest that CsA affects endothelial cells in a calcineurin-independent manner to potentiate tumor growth by promoting tumor angiogenesis through increasing mitochondrial ROS production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of CsA and suggests that co-treatment with antioxidants would inhibit the tumor promoting effects of CsA.

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“…RCAN1 gives rise to abroad cancer suppression via inhibiting the calcineurin pathway in the vascular endothelium in the transgenic mouse model of xenografted tumors [4]. A single extra copy of RCAN1 is sufficient to suppress tumor angiogenesis in mice [5]. Our recent reports showed that NF-κB signaling regulated RCAN1 isoform 4 gene transcription through a NF-κB responsive element [6] and RCAN1 as a novel inhibitor of NF-κB signaling pathway can suppress lymphoma growth in mice [7].…”

Section: Introductionmentioning

confidence: 99%

The regulator of calcineurin 1 (RCAN1) inhibits nuclear factor kappaB signaling pathway and suppresses human malignant glioma cells growth

Chen

Wang

et al. 2017

Oncotarget

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Nuclear factor-kappaB (NF-κB) has a vital role in cell survival and inhibition of NF-κB had proven to be an efficient therapeutic pathway for various cancers though little is known about the underlying mechanism. Previously we identified regulator of calcineurin 1 (RCAN1) as an endogenous inhibitor of NF-κB signaling pathway in lymphoma. In the present study, we have solid data to show that RCAN1 can inhibit the nuclear translocation of NF-κB protein then affect the activity of NF-κB signaling pathway in glioma cells. Overexpression of RCAN1 markedly reduced glioma cells viability. We further found that the suppressing glioma cell growth was closely related to the pro-apoptosis effect, not by inhibiting proliferation by the arrest of cell cycle. Our study implicated a novel therapeutic approach for glioma by RCAN1 through inhibition of NF-κB signaling.

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A single extra copy of Dscr1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis

Cited by 23 publications

References 48 publications

CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

Cyclosporin A Promotes Tumor Angiogenesis in a Calcineurin-Independent Manner by Increasing Mitochondrial Reactive Oxygen Species

The regulator of calcineurin 1 (RCAN1) inhibits nuclear factor kappaB signaling pathway and suppresses human malignant glioma cells growth

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