期刊
THERANOSTICS
卷 10, 期 6, 页码 2553-2570出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.41120
关键词
MiR-1275; LUAD; Stemness; Wnt/beta-catenin; Notch
资金
- National Natural Science Foundation of China [30900650, 81372501, 81572260, 81172232, 31430030]
- Guangdong Natural Science Foundation [2011B031800025, S2012010008378, S2012010008270, S2013010015327, 2013B021800126, 20090171120070, 9451008901002146, 2014A030313052, 2014J4100132, 2015A020214010, 2016A020215055, 20180506, 2013B021800259]
- Science and Technology Foundation of Shenzhen [JCYJ20170412155231633, 20180225112449943, JCYJ20180305164128430]
Rationale: Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated. Methods: miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo. Results: MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1 alpha was identified as the transcription mediator of miR-1275. Activation of Wnt/beta-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/beta-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/beta-catenin and Notch pathways, including DKK3, SFRP1, GSK3 beta, RUNX3, and NUMB, respectively, which resulted in signaling activation. Conclusions: Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/beta-catenin and Notch signaling pathways. Thus, HIF-1 alpha-regulated miR-1275 might be a potential therapeutic target for LUAD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据