Abstract
Clinically, distant metastasis after primary treatment remains a key problem in nasopharyngeal carcinoma (NPC), and the treatment outcome of metastatic NPC remains disappointing, so there is a pressing need to identify novel therapeutic strategies. In accordance with our previous microarray data, we found that miR-101 was downregulated in NPC clinical specimens and cell lines. Ectopic expression of miR-101 significantly suppressed NPC cell migration, invasion and angiogenesis in vitro and inhibited angiogenesis and metastasis in vivo using the chicken chorioallantoic membrane model. Furthermore, ITGA3 was identified and validated as a novel target of miR-101, and the restoration of ITGA3 expression potently rescued the suppressive effects of miR-101. In addition, NPC patients with high ITGA3 expression had poorer overall survival and distant metastasis-free survival than patients with low ITGA3 expression, and ITGA3 overexpression was an independent poor prognostic factor in NPC. More importantly, we demonstrated that the systemic delivery of lentivirus-mediated miR-101 abrogated the lung metastatic colonization formation of NPC cells without obvious toxicity. Our study elucidates the molecular mechanisms of miR-101/ITGA3 pathway in regulating NPC metastasis and angiogenesis, and the systemic delivery of miR-101 provides a potent evidence for the development of a novel microRNA-targeting anticancer strategy for NPC patients.
Highlights
Nasopharyngeal carcinoma (NPC) is a cancer arising from the nasopharynx epithelium
Cell Death and Disease downregulated in NPC and there is a possible link between reduced miR-101 expression and NPC metastasis
These results suggest that miR-101 can suppress the migratory, invasive and angiogenic ability of NPC cells in vitro
Summary
Nasopharyngeal carcinoma (NPC) is a cancer arising from the nasopharynx epithelium. It is notable for its unique pattern of geographical distribution, with a high prevalence in South China, Southeast Asia, North Africa, the Middle East and Alaska.[1,2,3] The majority of NPC patients are diagnosed with advanced stages at their first visit. Increasing evidence indicates that they potently influence cellular behaviour through the regulation of extensive gene expression networks.[7,8] High throughput techniques such as microarrays or next-generation sequencing show that miRNAs are dysregulated in almost all types of human cancer, including NPC. We aim to further evaluate the biological function and molecular mechanism of miR-101 in NPC metastasis, as well as the therapeutic efficacy of miR-101 restoration therapy in NPC mouse model
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