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-1α (HIF-1α)-dependent manner. HIF-1α 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-1α 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-1α expression (r = 0.679, P < 0.001), lymph node metastasis, clinical stage (all P < 0.05) and poor prognosis in NPC patients (P < 0.01). In conclusion, our findings suggest that the hypoxic exosomes were loaded with MMP-13, which could enhance migration and invasiveness and induce microenvironment changes to promote NPC aggressiveness.

Elevated EGFL6 modulates cell metastasis and growth via AKT pathway in nasopharyngeal carcinoma

“…Zebrafish metastatic model was used to evaluate the metastatic of NPC . In our study, CNE2 cells were firstly stained with 2 g/mL of DiI (Fluka, Germany) for 30 minutes.…”

Pattern and prognosis of distant metastases in nasopharyngeal carcinoma: A large‐population retrospective analysis

“…Our report showed that the incidence of dual-site metastasis was higher than that of single-site metastasis, which may be related to the change in the tumor microenvironment after metastasis to one organ. 25,26 Regarding the tendency to develop metastases in two organs, bone metastasis was more likely to be combined with liver or brain metastasis, and lung metastasis was more likely to be combined with liver or DL metastasis. Although the sequence of combined organ metastases was not available in the SEER database, understanding the trends in metastatic combinations would be important for risk assessment and diagnostic screening in NPC patients with advanced-stage disease.…”

How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment?

“…A significant increase in the matrix metalloproteinase (MMP)‐13 contents was observed in exosomes derived from hypoxia‐induced NPC cells in an HIF‐1α‐dependent manner. MMP‐13 was associated with increased vimentin expression and decreased E‐cadherin levels in CNE2 cells both in vitro and in vivo and, subsequently, increased lymph node metastasis, and poor prognosis in patients with NPC …”