MicroRNA-101 inhibits invasion and angiogenesis through targeting ITGA3 and its systemic delivery inhibits lung metastasis in nasopharyngeal carcinoma.
MicroRNA-101 inhibits invasion and angiogenesis through targeting ITGA3 and its systemic delivery inhibits lung metastasis in nasopharyngeal carcinoma.
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MicroRNA-101通过靶向ITGA3抑制侵袭和血管生成及其全身递送抑制鼻咽癌肺转移
DOI：
10.1038/cddis.2016.486
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发表时间：
2017-01-19
影响因子：
9
通讯作者：
Liu N
中科院分区：
文献类型：
--
作者：
Tang XR;Wen X;He QM;Li YQ;Ren XY;Yang XJ;Zhang J;Wang YQ;Ma J;Liu N
临床上，原发治疗后的远处转移仍是鼻咽癌（nasopharyngeal carcinoma，NPC）的主要问题，转移性NPC的治疗效果令人失望，因此迫切需要寻找新的治疗策略。根据我们先前的微阵列数据，我们发现miR-101在NPC临床标本和细胞系中下调。在鸡胚绒毛尿囊膜模型中，miR-101的异位表达可显著抑制NPC细胞的迁移、侵袭和血管生成，并抑制体内的血管生成和转移。此外，ITGA 3被鉴定并验证为miR-101的新靶点，ITGA 3表达的恢复有力地挽救了miR-101的抑制作用。此外，ITGA 3高表达的鼻咽癌患者的总生存率和无远处转移生存率均低于ITGA 3低表达的患者，ITGA 3过表达是影响鼻咽癌预后的独立因素。更重要的是，我们证明了慢病毒介导的miR-101的全身递送消除了NPC细胞的肺转移定植形成，而没有明显的毒性。我们的研究阐明了miR-101/ITGA 3通路调控NPC转移和血管生成的分子机制，miR-101的系统性递送为开发针对NPC患者的新型microRNA靶向抗癌策略提供了有力证据。
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.