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核长链非编码 RNA HOXD-AS1 通过抑制 HOXD3 诱导的整合素 β3 转录激活和 MAPK/AKT 信号通路抑制结直肠癌的生长和转移。

Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin β3 transcriptional activating and MAPK/AKT signalling.

机构信息

Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.

出版信息

Mol Cancer. 2019 Mar 1;18(1):31. doi: 10.1186/s12943-019-0955-9.

DOI:10.1186/s12943-019-0955-9
PMID:30823921
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6397497/
Abstract

BACKGROUND

Long noncoding RNAs (lncRNAs) have been indicated to play critical roles in cancer development and progression. LncRNA HOXD cluster antisense RNA1 (HOXD-AS1) has recently been found to be dysregulated in several cancers. However, the expression levels, cellular localization, precise function and mechanism of HOXD-AS1 in colorectal carcinoma (CRC) are largely unknown.

METHODS

Real-time PCR and in situ hybridization were used to detect the expression of HOXD-AS1 in CRC tissue samples and cell lines. Gain- and loss-of-function experiments were performed to investigate the biological roles of HOXD-AS1 in CRC cell line. RNA pull down, RNA immunoprecipitation and chromatin immunoprecipitation assays were conducted to investigate the mechanisms underlying the functions of HOXD-AS1 in CRC.

RESULTS

We observed that HOXD-AS1 was located in the nucleus of CRC cells and that nuclear HOXD-AS1 was downregulated in most CRC specimens and cell lines. Lower levels of nuclear HOXD-AS1 expression were associated with poor outcomes of CRC patients. HOXD-AS1 downregulation enhanced proliferation and migration of CRC cells in vitro and facilitated CRC tumourigenesis and metastasis in vivo. Mechanistic investigations revealed that HOXD-AS1 could suppress HOXD3 transcription by recruiting PRC2 to induce the accumulation of the repressive marker H3K27me3 at the HOXD3 promoter. Subsequently, HOXD3, as a transcriptional activator, promoted Integrin β3 transcription, thereby activating the MAPK/AKT signalling pathways.

CONCLUSION

Our results reveal a previously unrecognized HOXD-AS1-HOXD3-Integrin β3 regulatory axis involving in epigenetic and transcriptional regulation constitutes to CRC carcinogenesis and progression.

摘要

背景

长链非编码 RNA（lncRNA）在癌症的发生和发展中起着关键作用。最近发现 lncRNA HOXD 簇反义 RNA1（HOXD-AS1）在几种癌症中失调。然而，HOXD-AS1 在结直肠癌（CRC）中的表达水平、细胞定位、精确功能和机制在很大程度上仍是未知的。

方法

实时 PCR 和原位杂交用于检测 CRC 组织样本和细胞系中 HOXD-AS1 的表达。进行增益和缺失功能实验，以研究 HOXD-AS1 在 CRC 细胞系中的生物学作用。RNA 下拉、RNA 免疫沉淀和染色质免疫沉淀实验用于研究 HOXD-AS1 在 CRC 中的作用机制。

结果

我们观察到 HOXD-AS1 位于 CRC 细胞的核内，并且大多数 CRC 标本和细胞系中的核 HOXD-AS1 下调。核 HOXD-AS1 表达水平较低与 CRC 患者的不良预后相关。HOXD-AS1 下调增强了 CRC 细胞的体外增殖和迁移，并促进了 CRC 肿瘤发生和转移。机制研究表明，HOXD-AS1 通过募集 PRC2 抑制 HOXD3 的转录，从而诱导 HOXD3 启动子处抑制性标记 H3K27me3 的积累。随后，HOXD3 作为转录激活因子，促进整合素 β3 的转录，从而激活 MAPK/AKT 信号通路。

结论

我们的研究结果揭示了一个以前未被认识到的 HOXD-AS1-HOXD3-整合素 β3 调节轴，涉及表观遗传和转录调控，构成了 CRC 的发生和发展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/d3bb867bad5f/12943_2019_955_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/50b846a9f8d1/12943_2019_955_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/533b087616c0/12943_2019_955_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/758952229d20/12943_2019_955_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/0641d26d7e03/12943_2019_955_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/6e678bb388dd/12943_2019_955_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/d3bb867bad5f/12943_2019_955_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/50b846a9f8d1/12943_2019_955_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/533b087616c0/12943_2019_955_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/758952229d20/12943_2019_955_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/0641d26d7e03/12943_2019_955_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/6e678bb388dd/12943_2019_955_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bbd/6397497/d3bb867bad5f/12943_2019_955_Fig6_HTML.jpg

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