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长链非编码 RNA HNF1A-AS1 提示结直肠癌预后不良,并通过激活 Wnt/β-连环蛋白信号通路促进肿瘤发生。

Long noncoding RNA HNF1A-AS1 indicates a poor prognosis of colorectal cancer and promotes carcinogenesis via activation of the Wnt/β-catenin signaling pathway.

机构信息

Department of Internal Medicine, Xi'an Central Hospital, Shaanxi Province, China.

General Surgery, Ankang Central Hospital, Shaanxi Province, China.

出版信息

Biomed Pharmacother. 2017 Dec;96:877-883. doi: 10.1016/j.biopha.2017.10.033. Epub 2017 Nov 6.

DOI:10.1016/j.biopha.2017.10.033
PMID:29145164
Abstract

Long non-coding RNAs (lncRNAs) have been identified to play critical roles in tumorigenesis. LncRNA HNF1A-AS1 has been suggested to act as an oncogene and serves as a novel prognostic biomarker for various cancer. However, the biological role and clinical significance of lncRNA HNF1A-AS1 in colorectal cancer (CRC) have yet to be fully elusive. Therefore, the present study was designed to determine the expression of lncRNA HNF1A-AS1 in patients with CRC, the role of lncRNA HNF1A-AS1 in CRC cells, as well as the underlying regulatory mechanisms. Our results indicated that the expression of lncRNA HNF1A-AS1 was significantly upregulated in both CRC tumor tissues and CRC cell lines in comparison with adjacent non-tumor tissues and the human normal colonic epithelial cell line (HcoEpiC). The Kaplan-Meier survival analysis further suggested that high expression of lncRNA HNF1A-AS1 might be an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in patients with CRC. Moreover, the area under the receiver operating characteristic (ROC) curve for HNF1A-AS1 was up to 0.8714, implying that HNF1A-AS1 had diagnostic significance as it could discriminate tumor tissues from nontumorous tissues. In addition, silencing of lncRNA HNF1A-AS1 abrogated the proliferation of CRC cells by MTS assay and clonogenic assay, arrested cell cycle at G0/G1 stage and reduced the migration and invasion in CRC cells. Finally, we found that decreased expression of lncRNA HNF1A-AS1 suppressed the Wnt/β-catenin signaling pathway activity by downregulating the expression of β-catenin,cyclinD1, and c-myc. In conclusion, these findings provide evidence that lncRNA HNF1A-AS1 may be considered as a new prognostic biomarker and therapeutic target in patients with CRC.

摘要

长链非编码 RNA(lncRNA)已被确定在肿瘤发生中发挥关键作用。lncRNA HNF1A-AS1 已被证明作为癌基因发挥作用,并作为各种癌症的新型预后生物标志物。然而,lncRNA HNF1A-AS1 在结直肠癌(CRC)中的生物学作用和临床意义尚未完全阐明。因此,本研究旨在确定 lncRNA HNF1A-AS1 在 CRC 患者中的表达,lncRNA HNF1A-AS1 在 CRC 细胞中的作用以及潜在的调节机制。

我们的结果表明,与相邻非肿瘤组织和人正常结肠上皮细胞系(HcoEpiC)相比,lncRNA HNF1A-AS1 在 CRC 肿瘤组织和 CRC 细胞系中的表达均显著上调。Kaplan-Meier 生存分析进一步表明,lncRNA HNF1A-AS1 的高表达可能是 CRC 患者无病生存(DFS)和总生存(OS)的独立预后因素。此外,HNF1A-AS1 的接收器操作特征(ROC)曲线下面积高达 0.8714,表明 HNF1A-AS1 具有诊断意义,因为它可以区分肿瘤组织与非肿瘤组织。

此外,沉默 lncRNA HNF1A-AS1 通过 MTS 测定和集落形成测定阻断 CRC 细胞的增殖,将细胞周期阻滞在 G0/G1 期,并降低 CRC 细胞的迁移和侵袭。最后,我们发现下调 lncRNA HNF1A-AS1 的表达通过下调β-catenin、cyclinD1 和 c-myc 的表达抑制了 Wnt/β-catenin 信号通路的活性。

总之,这些发现提供了证据表明,lncRNA HNF1A-AS1 可以被认为是 CRC 患者的新的预后生物标志物和治疗靶标。

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