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SP1 诱导的 HOXD-AS1 通过调节 miR-520c-3p/MYCN 促进胆管癌的恶性进展。

SP1-induced HOXD-AS1 promotes malignant progression of cholangiocarcinoma by regulating miR-520c-3p/MYCN.

机构信息

Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China.

出版信息

Aging (Albany NY). 2020 Aug 28;12(16):16304-16325. doi: 10.18632/aging.103660.

DOI:10.18632/aging.103660
PMID:32857725
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7485728/
Abstract

The purpose of this article is to explore the function and mechanism of HOXD-AS1 in cholangiocarcinoma. TCGA, StarBase and JASPAR were applied to predict the differential expression and molecular mechanism. The qRT-PCR was conducted to detect molecular expression. The effect of HOXD-AS1 on tumor proliferation, metastasis and stemness was measured through corresponding experiments. ChIP, luciferase reporter and RIP assays were implemented to explore the regulatory mechanism of HOXD-AS1 in CCA. In this study, HOXD-AS1 expression was significantly upregulated in CCA tissues and cells compared with control groups, respectively. Increased HOXD-AS1 was markedly correlated with lymph node invasion, advanced TNM stage and poor survival of CCA patients. Moreover, HOXD-AS1 was confirmed to be an unfavorable independent prognostic factor for CCA patients. Functionally, gain- and loss-of-function experiments demonstrated that HOXD-AS1 facilitated tumor proliferation, migration, invasion, EMT, stemness and drug resistance and . For the mechanism, transcription factor SP1-induced HOXD-AS1 upregulated oncogene MYCN through competitively binding to miR-520c-3p. Furthermore, HOXD-AS1-induced malignant phenotypes were rescued by interfering miR-520c-3p and MYCN, respectively. SP1/HOXD-AS1/miR-520c-3p/MYCN plays a vital role in initiation and progression of CCA, and HOXD-AS1 is expected to be an efficient biomarker and therapeutic target.

摘要

本文旨在探讨 HOXD-AS1 在胆管癌中的功能和作用机制。我们运用 TCGA、StarBase 和 JASPAR 预测差异表达和分子机制，采用 qRT-PCR 检测分子表达，通过相应的实验检测 HOXD-AS1 对肿瘤增殖、转移和干性的影响。我们实施 ChIP、荧光素酶报告和 RIP 实验以探究 HOXD-AS1 在 CCA 中的调控机制。在本研究中，与对照组相比，HOXD-AS1 在 CCA 组织和细胞中的表达显著上调。HOXD-AS1 的增加与 CCA 患者的淋巴结侵犯、晚期 TNM 分期和不良生存明显相关。此外，HOXD-AS1 被证实是 CCA 患者不良的独立预后因素。功能上，过表达和敲低实验表明 HOXD-AS1 促进肿瘤增殖、迁移、侵袭、EMT、干性和耐药性。对于机制，转录因子 SP1 诱导 HOXD-AS1 通过竞争性结合 miR-520c-3p 而上调癌基因 MYCN。此外，干扰 miR-520c-3p 和 MYCN 分别挽救了 HOXD-AS1 诱导的恶性表型。SP1/HOXD-AS1/miR-520c-3p/MYCN 在 CCA 的发生和进展中起着重要作用，HOXD-AS1 有望成为一种有效的生物标志物和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/1de515d43d57/aging-12-103660-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/1de515d43d57/aging-12-103660-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/4ea4921e9eb3/aging-12-103660-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/4218dabc8d3c/aging-12-103660-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/e91b4f580af3/aging-12-103660-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/2508612c8102/aging-12-103660-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/e7e5506e4315/aging-12-103660-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f0/7485728/1e388a8905ab/aging-12-103660-g006.jpg
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