Dataset Information

Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases.

ABSTRACT: Exosomes are nano-vesicles secreted by tumor cells. Exosomes can transfer complex biological information and induce a diverse signaling response in a wide array of pathological conditions, such as hypoxia. Hypoxia is associated with aggressive phenotypes and poor outcomes in nasopharyngeal carcinoma (NPC) patients. Here, we analyzed the role of exosomes from hypoxic NPC cells in enhancing the metastases of normoxic cells in a hypoxia-induced factor-1? (HIF-1?)-dependent manner. HIF-1? rapidly accumulates and trans-activates hundreds of genes, such as matrix metalloproteinases (MMPs). We found that MMP-13 was over-expressed in exosomes and cells under hypoxic conditions. HIF-1? depletion in hypoxic CNE2 cells led to decreased MMP-13 levels in exosomes and significantly reduced cell migration and invasion. Moreover, exosomal MMP-13 significantly up-regulated Vimentin expression while decreasing E-cadherin levels in CNE2 cells in vitro and in vivo. Furthermore, MMP-13 levels were closely associated with HIF-1? expression (r?=?0.679, P?

SUBMITTER: Shan Y

PROVIDER: S-EPMC5841433 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases.

Shan Ying Y You Bo B Shi Si S Shi Wei W Zhang Zhenxin Z Zhang Qicheng Q Gu Miao M Chen Jing J Bao Lili L Liu Dong D You Yiwen Y

Cell death & disease 20180307 3

Exosomes are nano-vesicles secreted by tumor cells. Exosomes can transfer complex biological information and induce a diverse signaling response in a wide array of pathological conditions, such as hypoxia. Hypoxia is associated with aggressive phenotypes and poor outcomes in nasopharyngeal carcinoma (NPC) patients. Here, we analyzed the role of exosomes from hypoxic NPC cells in enhancing the metastases of normoxic cells in a hypoxia-induced factor-1α (HIF-1α)-dependent manner. HIF-1α rapidly ac ...[more]

PMID: 29515112

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Project description:BackgroundOverexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a DNA/RNA binding protein, is associated with metastasis in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying hnRNP K-mediated metastasis is unclear. The aim of the present study was to determine the role of matrix metalloproteinase (MMP) in hnRNP K-mediated metastasis in NPC.MethodsWe studied hnRNP K-regulated MMPs by analyzing the expression profiles of MMP family genes in NPC tissues and hnRNP K-knockdown NPC cells using Affymetrix microarray analysis and quantitative RT-PCR. The association of hnRNP K and MMP12 expression in 82 clinically proven NPC cases was determined by immunohistochemical analysis. The hnRNP K-mediated MMP12 regulation was determined by zymography and Western blot, as well as by promoter, DNA pull-down and chromatin immunoprecipitation (ChIP) assays. The functional role of MMP12 in cell migration and invasion was demonstrated by MMP12-knockdown and the treatment of MMP12-specific inhibitor, PF-356231.ResultsMMP12 was overexpressed in NPC tissues, and this high level of expression was significantly correlated with high-level expression of hnRNP K (P?=?0.026). The levels of mRNA, protein and enzyme activity of MMP12 were reduced in hnRNP K-knockdown NPC cells. HnRNP K interacting with the region spanning -42 to -33 bp of the transcription start site triggered transcriptional activation of the MMP12 promoter. Furthermore, inhibiting MMP12 by MMP12 knockdown and MMP12-specific inhibitor, PF-356231, significantly reduced the migration and invasion of NPC cells.ConclusionsOverexpression of MMP12 was significantly correlated with hnRNP K in NPC tissues. HnRNP K can induce MMP12 expression and enzyme activity through activating MMP12 promoter, which promotes cell migration and invasion in NPC cells. In vitro experiments suggest that NPC metastasis with high MMP12 expression may be treated with PF-356231. HnRNP K and MMP12 may be potential therapeutic markers for NPC, but additional validation studies are warranted.

Project description:Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal-derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13-null mice. In independent in vivo studies, MMP13-null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed. Ex vivo stromal coculture assays showed reduced formation and activity in MMP13-null osteoclasts. Analysis of soluble factors from wild-type and MMP13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. SIGNIFICANCE: Genetic and pharmacologic approaches show that bone stromal-derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2415/F1.large.jpg.

Dataset Information

Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases.

Publications

Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases.

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