Disturbance of DKK1 level is partly involved in survival of lung cancer cells via regulation of ROMO1 and γ-radiation sensitivity

Kim, In Gyu; Kim, Seo Yoen; Kim, Hyun A; Kim, Jeong Yul; Lee, Jaeha; Choi, Soo Im; Han, Jeong Ran; Kim, Kug Chan; Cho, Eun Wie

doi:10.1016/j.bbrc.2013.11.038

Cited by 20 publications

(15 citation statements)

References 27 publications

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“…Dkk1 also suppressed ROS generation and HSC senescence in irradiated mice, concordant with inhibitory effects on Wnt signaling. These findings are consistent with recent studies suggesting that Dkk1 treatment suppresses ROS generation in nonhematopoietic tissues, as well as a report demonstrating that Wnt pathway activation promotes mitochondrial ROS generation and senescence in myoblasts and fibroblasts 44,45 . However, in the hematopoietic system, several studies have suggested that activation of canonical Wnt signaling promotes HSC self-renewal 46–48 .…”

Section: Discussionsupporting

confidence: 93%

Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms

Himburg

Doan

Quarmyne

et al. 2016

Nat Med

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The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.

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Section: Discussionsupporting

confidence: 93%

Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms

Himburg

Doan

Quarmyne

et al. 2016

Nat Med

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“…When 38 regulated genes were analysed using GO (gene ontology), we found that some of the genes participated in GO including response to hypoxia and oxygen level (Table ). Interestingly, some of the down‐regulated genes such as MT1X , MT2A , ADM , ANGPTL4 , CTSS , CYP1A1 , PFKFB4 , FABP3 and DKK1 are involved in regulation of ROS scavenging and production . We confirmed the result from RNA‐seq by real‐time PCR (Fig.…”

Section: Resultssupporting

confidence: 79%

“…Furthermore, depletion of Fatty acid binding protein 3 (FABP3) enhanced ROS production in P19 embryonic carcinoma cells . Depletion of Dickkopf WNT signaling pathway inhibitor 1 (DKK1), an antagonist of Wnt/β‐catenin signalling, induced intracellular ROS because of up‐regulation of ROMO1 ( ROS modulator 1) expression in A549 cells . Although decrease in some genes such as CYP1A1, ANGPTL4 and CCN1 resulted in the reduction of ROS production in specific situations , we have suggested that 1 mM cFP treatment may increase intracellular ROS production by dysregulation of genes related to ROS scavenging and production.…”

Section: Discussionmentioning

confidence: 99%

Cyclo(phenylalanine‐proline) induces DNA damage in mammalian cells via reactive oxygen species

Lee

Jeong

Kim

et al. 2015

J Cellular Molecular Medi

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Cyclo(phenylalanine‐proline) is produced by various organisms such as animals, plants, bacteria and fungi. It has diverse biological functions including anti‐fungal activity, anti‐bacterial activity and molecular signalling. However, a few studies have demonstrated the effect of cyclo(phenylalanine‐proline) on the mammalian cellular processes, such as cell growth and apoptosis. In this study, we investigated whether cyclo(phenylalanine‐proline) affects cellular responses associated with DNA damage in mammalian cells. We found that treatment of 1 mM cyclo(phenylalanine‐proline) induces phosphorylation of H2AX (S139) through ATM‐CHK2 activation as well as DNA double strand breaks. Gene expression analysis revealed that a subset of genes related to regulation of reactive oxygen species (ROS) scavenging and production is suppressed by the cyclo(phenylalanine‐proline) treatment. We also found that cyclo(phenylalanine‐proline) treatment induces perturbation of the mitochondrial membrane, resulting in increased ROS, especially superoxide, production. Collectively, our study suggests that cyclo(phenylalanine‐proline) treatment induces DNA damage via elevation of ROS in mammalian cells. Our findings may help explain the mechanism underlying the bacterial infection‐induced activation of DNA damage response in host mammalian cells.

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“…8,9 In addition, it has been reported that Romo1induced ROS production is associated with chemotherapy (5-fluorouracil) resistance and γ-radiation sensitivity in lung cancer cell lines. 10,11 Based on these preclinical studies, clinical studies have been conducted to evaluate the clinical usefulness of Romo1 protein and it was reported that Romo1 overexpression is associated with poor survival in patients with hepatocellular carcinoma and colorectal cancer. 12,13 In addition, Romo1 overexpression was significantly associated with poor survival outcomes in patients with nonsmall cell lung cancer who received surgical resection, 14 chemotherapy, 15 and definitive radiotherapy, 16 in our previous studies.…”

Section: Introductionmentioning

confidence: 99%

<p>Reactive Oxygen Species Modulator 1 is Associated with Poor Survival in Patients with Non-Small Cell Lung Cancer After Stereotactic Fractionated Radiosurgery: A Retrospective Pilot Study</p>

Kong

Sung

Lee

2020

OTT

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Purpose: It has been reported that the overexpression of reactive oxygen species modulator 1 (Romo1) is significantly associated with poor survival outcomes in patients with lung cancer who received surgical resection, conventional fractionated radiotherapy, and chemotherapy. In this study, we investigated whether Romo1 expression is associated with survival outcomes in patients with early-stage lung cancer who were treated with radiosurgery. Methods: Romo1 protein expression was evaluated and scored in the tumor tissue specimens of 40 patients with non-small cell lung cancer by immunohistochemistry. An optimal cutoff for Romo1 expression was determined and used to allocate patients to low or high Romo1 expression groups. Survival outcomes were compared between the two groups. Results: Romo1 expression was significantly associated with distant metastasis-free survival. The 1-and 2-year distant metastasis-free survival rates were 96.4% and 92.6% in the low Romo1 expression group and 87.5% and 46.7% in the high Romo1 expression group (P=0.041), respectively. The overall, local recurrence-free, regional recurrence-free, and disease progression-free survival rates were higher in the low Romo1 expression group than the high Romo1 expression group. However, the differences were not statistically significant. Conclusion: Romo1 overexpression is associated with poor distant metastasis-free survival in patients with non-small cell lung cancer treated with radiosurgery. Further, large-scale prospective studies are required to identify the clinical efficacy of Romo1 as a potential adverse prognostic factor in lung cancer.

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Disturbance of DKK1 level is partly involved in survival of lung cancer cells via regulation of ROMO1 and γ-radiation sensitivity

Cited by 20 publications

References 27 publications

Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms

Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms

Cyclo(phenylalanine‐proline) induces DNA damage in mammalian cells via reactive oxygen species

<p>Reactive Oxygen Species Modulator 1 is Associated with Poor Survival in Patients with Non-Small Cell Lung Cancer After Stereotactic Fractionated Radiosurgery: A Retrospective Pilot Study</p>

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