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NKX2-1-AS1 负调控 CD274/PD-L1、细胞间相互作用基因，并限制人肺癌细胞迁移。

NKX2-1-AS1 negatively regulates CD274/PD-L1, cell-cell interaction genes, and limits human lung carcinoma cell migration.

机构信息

The Pulmonary Center, Boston University School of Medicine, 72 E. Concord St, Boston, MA, 02118, USA.

Clinical and Translational Science Institute, Boston University School of Medicine, 72 E. Concord St, Boston, MA, 02118, USA.

出版信息

Sci Rep. 2018 Sep 26;8(1):14418. doi: 10.1038/s41598-018-32793-5.

DOI:10.1038/s41598-018-32793-5
PMID:30258080
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6158174/
Abstract

The function of most long noncoding RNAs (lncRNAs) is unknown. However, recent studies reveal important roles of lncRNAs in regulating cancer-related pathways. Human antisense lncRNA-NKX2-1-AS1 partially overlaps the NKX2-1/TTF1 gene within chromosomal region 14q13.3. Amplification of this region and/or differential expression of genes therein are associated with cancer progression. Herein we show higher levels of NKX2-AS1 and NKX2-1 in lung adenocarcinomas relative to non-tumor controls but no correlation between NKX2-1-AS1 and NKX2-1 levels across specimens, or with amplification of the 14q13.3 region, suggesting that NKX2-1-AS1 and NKX2-1 are independently regulated. Loss-and-gain of function experiments showed that NKX2-1-AS1 does not regulate NKX2-1 expression, or nearby genes, but controls genes in trans. Genes up-regulated by NKX2-1-AS1-knockdown belong to cell adhesion and PD-L1/PD-1 checkpoint pathways. NKX2-1-AS1 negatively regulates endogenous CD274/PD-L1, a known target of NKX2-1, and the transcriptional activity of -1kb-CD274 promoter-reporter construct. Furthermore, NKX2-1-AS1 interferes with NKX2-1 protein binding to the CD274-promoter, likely by NKX2-1 protein-NKX2-1-AS1 interactions. Finally, NKX2-1-AS1 negatively regulates cell migration and wound healing, but not proliferation or apoptosis. These findings support potential roles of NKX2-1-AS1 in limiting motility and immune system evasion of lung carcinoma cells, highlighting a novel mechanism that may influence tumorigenic capabilities of lung epithelial cells.

摘要

大多数长非编码 RNA（lncRNA）的功能尚不清楚。然而，最近的研究揭示了 lncRNA 在调节癌症相关途径中的重要作用。人类反义 lncRNA-NKX2-1-AS1 部分重叠染色体 14q13.3 区域内的 NKX2-1/TTF1 基因。该区域的扩增和/或其中基因的差异表达与癌症进展相关。本文显示，与非肿瘤对照相比，肺腺癌中 NKX2-AS1 和 NKX2-1 的水平较高，但 NKX2-1-AS1 水平在标本之间没有相关性，也与 14q13.3 区域的扩增无关，提示 NKX2-1-AS1 和 NKX2-1 是独立调控的。缺失和功能获得实验表明，NKX2-1-AS1 不调节 NKX2-1 的表达或附近基因，而是调控反式基因。NKX2-1-AS1 敲低上调的基因属于细胞黏附和 PD-L1/PD-1 检查点途径。NKX2-1-AS1 负调控内源性 CD274/PD-L1，这是 NKX2-1 的已知靶点，以及 -1kb-CD274 启动子报告构建体的转录活性。此外，NKX2-1-AS1 干扰 NKX2-1 蛋白与 CD274 启动子的结合，可能是通过 NKX2-1 蛋白-NKX2-1-AS1 相互作用。最后，NKX2-1-AS1 负调节细胞迁移和伤口愈合，但不调节增殖或凋亡。这些发现支持 NKX2-1-AS1 在限制肺癌细胞迁移和逃避免疫系统方面的潜在作用，突出了一种可能影响肺上皮细胞致瘤能力的新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/8d2ad8532ec0/41598_2018_32793_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/3f1768a38392/41598_2018_32793_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/ab85ecb5fa6d/41598_2018_32793_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/2d7ca57374b8/41598_2018_32793_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/a08c02fb23b4/41598_2018_32793_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/07a972a2fd91/41598_2018_32793_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/9ad235c68d96/41598_2018_32793_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/8d2ad8532ec0/41598_2018_32793_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/3f1768a38392/41598_2018_32793_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/ab85ecb5fa6d/41598_2018_32793_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/2d7ca57374b8/41598_2018_32793_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/a08c02fb23b4/41598_2018_32793_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/07a972a2fd91/41598_2018_32793_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/9ad235c68d96/41598_2018_32793_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0b/6158174/8d2ad8532ec0/41598_2018_32793_Fig7_HTML.jpg

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