Involvement of SULF2 in γ-irradiation-induced invasion and resistance of cancer cells by inducing IL-6 expression

Jung, Chan-Hun; Ho, Jin‐Nyoung; Park, Jong Kuk; Kim, Eun Mi; Hwang, Sang‐Gu; Um, Hong‐Duck

doi:10.18632/oncotarget.7449

Cited by 16 publications

(23 citation statements)

References 44 publications

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“…Sulf2 and Ki67 double-positive type II AECs were also found in the injured alveoli after bleomycin challenge ( Figure E2). Sulf2 has been shown to be a direct transcription target of p53 (40,41), and Sulf2 induction by a number of stimuli, including chemotherapy, g irradiation, and hypoxia, is mediated by p53 (41)(42)(43). Our study suggests that bleomycin-induced Sulf2, likely mediated by p53 as well, in turn regulates p53 signaling.…”

Section: Discussionmentioning

confidence: 52%

Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality

Yue

2017

Am J Respir Cell Mol Biol

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Epithelial injury has been proposed to be the initiating factor in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have shown previously that heparan sulfate 6-O-endosulfatase (Sulf) 2 is overexpressed in the hyperplastic type II alveolar epithelial cells (AECs) in the IPF lungs. By removing 6-O-sulfates from specific heparan sulfate intrachain sites, Sulf2 modulates the functions of many growth factors and cytokines. In this study, we hypothesized that Sulf2 plays a regulatory role in alveolar epithelial injury and repair, using the murine bleomycin model. Consistent with our findings in human IPF lungs, bleomycin treatment in mice resulted in up-regulation of Sulf2 mRNA in whole-lung extracts and overexpression of Sulf2 protein in type II AECs on lung tissue sections. Sulf2 protein was detectable in bronchoalveolar lavage fluid at baseline, and its level was significantly increased after bleomycin exposure. To study the role of Sulf2 in alveolar injury and repair in vivo, we generated a doxycycline-inducible epithelial-specific Sulf2 conditional knockout (Sulf2 CKO) mouse line. After bleomycin exposure, Sulf2 CKO mice exhibited enhanced neutrophil infiltration in the lung, with elevated levels of total protein, lactate dehydrogenase, and cytokines (granulocyte colony-stimulating factor and interferon-γ-inducible protein 10) in bronchoalveolar lavage fluid compared with wild-type littermates. We further showed that both the p53-p21 DNA damage response and the transforming growth factor-β1 signaling pathway were up-regulated in Sulf2 CKO mice compared with wild-type. Finally, Sulf2 CKO mice suffered increased mortality after bleomycin exposure. In conclusion, Sulf2 expression in type II AECs plays a protective role in epithelial injury, inflammation and mortality.

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Section: Discussionmentioning

confidence: 52%

Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality

Yue

2017

Am J Respir Cell Mol Biol

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“…p53 mediates IR-induced cell invasion by stimulating cellular pathways sequentially involving SULF2, β-catenin, IL-6, and STAT3 7 . To investigate the relationship between this pathway and SOD2 induction, SULF2 was knocked down in H460 and A549 cells using a specific shRNA, which abolished or attenuated IR-induced SOD2 accumulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…STAT3 is a transcription factor that induces Bcl-X L expression 9 . Consistently, sublethal doses of IR increase the messenger RNA (mRNA) and protein levels of Bcl-X L in several cancer cell types, and Bcl-X L knockdown abolishes the pro-invasive activity of IR 7,10 , suggesting a role for Bcl-X L in IR-induced cell invasion. These results suggest the involvement of mitochondrial ROS in IR-induced cancer cell invasion.…”

Section: Introductionmentioning

confidence: 91%

“…We have previously shown that sublethal doses of IR increase sulfatase 2 (SULF2) expression via the p53 transcription factor 7 . SULF2 is an extracellular sulfatase that modulates the signaling activities of diverse cell surface receptors 8 , and IR-induced SULF2 mediates the pro-invasive activity of IR by stimulating the signaling pathway that sequentially involves β-catenin, interleukin-6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) 7 . STAT3 is a transcription factor that induces Bcl-X L expression 9 .…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial superoxide dismutase 2 mediates γ-irradiation-induced cancer cell invasion

et al. 2019

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Sublethal doses of γ-rays promote cancer cell invasion by stimulating a signaling pathway that sequentially involves p53, sulfatase 2 (SULF2), β-catenin, interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), and Bcl-XL. Given that Bcl-XL can increase O2•− production by stimulating respiratory complex I, the possible role of mitochondrial reactive oxygen species (ROS) in γ-irradiation-induced cell invasion was investigated. Indeed, γ-irradiation promoted cell invasion by increasing mitochondrial ROS levels, which was prevented by metformin, an inhibitor of complex I. γ-Irradiation-stimulated STAT3 increased the expression of superoxide dismutase 2 (SOD2), a mitochondrial enzyme that catalyzes the conversion of O2•− to hydrogen peroxide (H2O2). In contrast to O2•−, H2O2 functions as a signaling molecule. γ-Irradiation consistently stimulated the Src-dependent invasion pathway in a manner dependent on both complex I and SOD2. SOD2 was also essential for the invasion of un-irradiated cancer cells induced by upregulation of Bcl-XL, an intracellular oncogene, or extracellular factors, such as SULF2 and IL-6. Overall, these data suggested that SOD2 is critical for the malignant effects of radiotherapy and tumor progression through diverse endogenous factors.

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“…The Western Blot test was performed as described in previous reports [30]. Proteins were extracted from the HCC cell line SK-Hep1 and separated by SDS-PAGE.…”

Section: Methodsmentioning

confidence: 99%

Bi-directional roles of IRF-1 on autophagy diminish its prognostic value as compared with Ki67 in liver transplantation for hepatocellular carcinoma

Zhang

et al. 2016

Oncotarget

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The prognostic values of IRF-1 and Ki-67 for liver transplantation (LT) of hepatocellular carcinoma (HCC) were investigated, as well as the mechanisms of IRF-1 in tumor suppression. Adult orthotropic liver transplantation cases (N = 127) were involved in the analysis. A significant decreased recurrence free survival (RFS) was found in the Ki-67 positive groups. Ki-67, tumor microemboli, the Milan and UCSF criteria were found to be independent risk factors for RFS. In LT for HCC beyond the Milan criteria, a significant decrease in RFS was found in the IRF-1 negative groups. In SK-Hep1 cells, an increase in apoptosis and decrease in autophagy were observed after IFN-γ stimulation, which was accompanied with increasing IRF-1 levels. When IRF-1 siRNA or a caspase inhibitor were used, reductions in LC3-II were diminished or disappeared after IFN-γ stimulation, suggesting that IFN-γ inhibited autophagy via IRF-1 expression and caspase activation. However, after IRF-1 siRNA was introduced, a reduction in LC3-II was found. Thus basic expression of IRF-1 was also necessary for autophagy. IRF-1 may be used as a potential target for HCC treatment based on its capacity to affect apoptosis and autophagy. Ki-67 shows great promise for the prediction of HCC recurrence in LT and can be used as an aid in the selection of LT candidates.

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Involvement of SULF2 in γ-irradiation-induced invasion and resistance of cancer cells by inducing IL-6 expression

Cited by 16 publications

References 44 publications

Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality

Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality

Mitochondrial superoxide dismutase 2 mediates γ-irradiation-induced cancer cell invasion

Bi-directional roles of IRF-1 on autophagy diminish its prognostic value as compared with Ki67 in liver transplantation for hepatocellular carcinoma

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