Interleukin 6 trigged ataxia-telangiectasia mutated activation facilitates lung cancer metastasis via MMP-3/MMP-13 up-regulation

Jiang, Yi; Hong, Yan; Xiao, Hang; Wang, Yi Nan; Li, Qing; Gao, Feng

doi:10.18632/oncotarget.5825

Cited by 30 publications

(36 citation statements)

References 67 publications

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“…IL-6 reportedly prevents the initiation of lung cancer by activating the transcription factor STAT3 to regulate lung macrophages and to preserve lung homeostasis [73]. However, Jiang et al also demonstrated that IL-6 enhances the progression of lung cancer by inducing ATM phosphorylation and increasing the expression of MMP-3/MMP-13, thus enhancing cell migration and promoting the metastasis of lung tumor cells [74]. Liu et al demonstrated that IL-6 can also boost the proliferation of lung cancer stem cells by suppressing the expression of cell cycle regulators [75].…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

Cen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Since the function of microRNA (miR)-210 in non-small cell lung cancer (NSCLC) remains unclear, we aimed to explore the clinical significance of miR-210 in NSCLC. Methods: NSCLC-related data from 1673 samples on Gene Expression Omnibus and 1090 samples on The Cancer Genome Atlas were obtained and analyzed. The expression level of miR-210 was validated via real-time quantitative PCR analysis with 125 paired clinical samples. A meta-analysis was performed to generate a comprehensive understanding of miR-210 expression and its clinical significance in NSCLC. In addition, bioinformatics analysis was also conducted to reveal the potential underlying mechanism of miR-210 action in NSCLC. Results: miR-210 expression was consistently elevated in NSCLC solid tissue samples. However, its expression was controversial in easily obtained body fluids (i.e., blood, plasma, and serum). Moreover, an overall pooled meta-analysis implied a comparatively higher level of miR-210 expression in NSCLC cancerous tissue than in normal control tissue (P < 0.001). In addition, a meta-analysis of outcome revealed a significant diagnostic capacity of miR-210 in NSCLC by detecting its expression in serum and sputum (area under the summary receiver operating characteristic curve 0.82 and 0.81, respectively). miR-210 overexpression was associated with poor progression-free survival (PFS) in NSCLC and was negatively related to overall survival and disease-free survival. Bioinformatic gene enrichment and annotation analyses showed that the target genes of miR-210 were greatly enriched in cell adhesion and plasma membrane, and three pathways were considered to be the main functional circuits of miR-210: renin secretion, the cGMP-PKG signaling pathway, and cell adhesion molecules. Conclusion: In NSCLC, miR-210 expression was elevated and overexpression indicated poor PFS. Expression level of miR-210 in serum and sputum showed significant diagnostic value for NSCLC.

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Section: Discussionmentioning

confidence: 99%

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

Cen

et al. 2018

Cell Physiol Biochem

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“…IL‐6 is a multifunctional cytokine involving in inflammatory response, immune regulation, metabolism homeostasis and so on (Scheller, Chalaris, Schmidt‐Arras, & Rose‐John, ; Wolf, Rose‐John, & Garbers, ). It has been reported that IL‐6 is implicated in ovarian and lung cancer cell migration, which associates with the invasion and metastasis characteristics of cancer cells (Ferraresi et al, ; Jiang et al, ). Consistently, in our current study we found that IL‐6 treatment accelerates wound closure of podocytes, increases the numbers of migrated podocytes, and promotes the invasion of cell‐free areas in a time‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

IL‐6 increases podocyte motility via MLC‐mediated focal adhesion impairment and cytoskeleton disassembly

Bao

et al. 2018

Journal Cellular Physiology

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The disturbance of podocyte motility is an essential pathogenic mechanisms of foot process effacement during proteinuric diseases, and myosin light chain (MLC) is a pivotal component in regulating the motility of podocytes. Inflammatory cytokine interleukin-6 (IL-6) has been reported to induce podocyte abnormalities by various mechanisms, however, whether aberrant cell motility contributes to the IL-6-induced podocyte injury remains unknown. Here, by wound healing, transwell, and cell migration assays, we confirmed that IL-6 accelerates the motility of podocyte. Simultaneously, the phosphorylation of MLC is elevated along with perturbed focal adhesion (FAs) and cytoskeleton. Next, via genetic and pharmacologic interruption of MLC or its phosphorylation we revealed that the activation of MLC is implicated in IL-6-mediated podocyte hypermotility as well as the disassembly of FAs and F-actin. By using stattic, an inhibitor for STAT3 phosphorylation, we uncovered that STAT3 activation is the upstream event for MLC phosphorylation and the following aberrant motility of podocytes. Additionally, we found that calcitriol markedly attenuates podocyte hypermotility via blocking STAT3-MLC. In conclusion, our study demonstrated that IL-6 interrupts FAs dynamic, cytoskeleton organization, and eventually leads to podocyte hypermotility via STAT3/MLC, whereas calcitriol exerts its protective role by inhibiting this pathway. These findings enrich the mechanisms accounting for IL-6-mediated podocyte injury from the standpoint of cell motility and provide a novel therapeutic target for podocyte disorders.

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“…For example, nuclear MMP2 cleaves PARP in nucleus for the degradation to promote cell invasion [27, 31]. Nuclear MMP3 activates CCN2 gene transcription for IL-6-mediated cell migration [28, 32]. As MMP7 is associated with the malignant features of cancers [33, 34], our findings offer novel and valuable insights into understanding the functions of MMP7 in PCa as following: 1) MMP7 shuttles to nucleus without being cleaved, and it certainly deserves further investigation to elucidate the mechanisms on shuttling and the biological actions of MMP7 in nucleus of PCa cells; 2) ARF binds pro-MMP7 (~30 kDa) not active-MMP7 (~19 kDa) in nucleus, and it will be interesting to know these binding domains of MMP7 and ARF proteins; 3) Nuclear factors associated with ARF-MMP7 in nuclear compartments promote cell migration of PCa cells.…”

Section: Discussionmentioning

confidence: 99%

MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo

Xie

Liu

et al. 2016

Oncotarget

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ARF couples with TP53 in a canonical signaling pathway to activate cellular senescence for tumor suppressive function under oncogenic insults. However, the mechanisms on aberrant elevation of ARF in cancers are still poorly understood. We previously showed that ARF (p14ARF in human and p19Arf in mouse) elevation correlates with PTEN loss and stabilizes SLUG to reduce cell adhesion in prostate cancer (PCa). Here we report that ARF is essential for MMP7 expression, E-Cadherin decrease and the anchorage loss to the extracellular matrix (ECM) in PCa in vitro and in vivo. We found that Mmp7 is aberrantly elevated in cytosol and nucleus of malignant prostate tumors of Pten/Trp53 mutant mice. Interestingly, p19Arf deficiency strikingly decreases Mmp7 levels but increases E-Cadherin in Pten/Trp53/p19Arf mice. ARF knockdown markedly reduces MMP7 in human PCa cells. Conversely, tetracycline-inducible expression of ARF increases MMP7 with a decrease of E-Cadherin in PCa cells. Importantly, MMP7 physically binds ARF to show the co-localization in nucleus. Co-expression of MMP7 and ARF promotes cell migration, and MMP7 knockdown decreases wound healing in PCa cells. Furthermore, MMP7 elevation correlates with ARF expression in advanced human PCa. Our findings reveal for the first time that the crosstalk between ARF and MMP7 in nucleus contributes to ECM network in tumor microenvironments in vivo, implicating a novel therapeutic target for advanced PCa treatment.

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Interleukin 6 trigged ataxia-telangiectasia mutated activation facilitates lung cancer metastasis via MMP-3/MMP-13 up-regulation

Cited by 30 publications

References 67 publications

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

IL‐6 increases podocyte motility via MLC‐mediated focal adhesion impairment and cytoskeleton disassembly

MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo

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