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mA 修饰长链非编码 RNA HNF1A-AS1 通过 IGF2BP2 介导的 CCND1 mRNA 稳定促进结直肠癌细胞周期进程。

mA Modification of Long Non-Coding RNA HNF1A-AS1 Facilitates Cell Cycle Progression in Colorectal Cancer via IGF2BP2-Mediated CCND1 mRNA Stabilization.

机构信息

Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

出版信息

Cells. 2022 Sep 27;11(19):3008. doi: 10.3390/cells11193008.

DOI:10.3390/cells11193008
PMID:36230970
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9562639/
Abstract

BACKGROUND

Long non-coding RNAs modulate tumor occurrence through different molecular mechanisms. It had been reported that HNF1A-AS1 (HNF1A Antisense RNA 1) was differently expressed in multiple tumors. The role of HNF1A-AS1 in colorectal cancer was less analyzed, and the mechanism of regulating the cell cycle has not been completely elucidated.

METHODS

Differentially expressed lncRNAs were screened out from the TCGA database. HNF1A-AS1 was examined in CRC clinical samples and cell lines by RT-qPCR. CCK8 assay, colony formation assay, flow cytometry, transwell assays, tube forming assay and vivo experiments were performed to study the function of HNF1A-AS1 in CRC tumor progression. Bioinformatic analysis, luciferase report assay, RNA pull-down and RIP assays were carried out to explore proteins binding HNF1A-AS1 and the potential downstream targets.

RESULTS

Our results showed that HNF1A-AS1 was upregulated in CRC and associated with unfavorable prognosis. HNF1A-AS1 promoted proliferation, migration and angiogenesis, accelerated cell cycle and reduced cell apoptosis in CRC. Bioinformatics prediction and further experiments proved that HNF1A-AS1 could promote CCND1 expression by suppressing PDCD4 or competitively sponging miR-93-5p. Meanwhile, METTL3 mediated HNF1A-AS1 mA modification and affected its RNA stability. HNF1A-AS1/IGF2BP2/CCND1 may act as a complex to regulate the stability of CCND1.

CONCLUSION

In summary, our result reveals the novel mechanism in which mA-mediated HNF1A-AS1/IGF2BP2/CCND1 axis promotes CRC cell cycle progression, along with competitively sponging miR-93-5p to upregulate CCND1, demonstrating its significant role in cell cycle regulation and suggesting that HNF1A-AS1 may act as a potential prognostic marker of colorectal cancer in the future.

摘要

背景

长链非编码 RNA 通过不同的分子机制调节肿瘤的发生。据报道，HNF1A-AS1（HNF1A 反义 RNA1）在多种肿瘤中表达不同。HNF1A-AS1 在结直肠癌中的作用分析较少，其调节细胞周期的机制尚未完全阐明。

方法

从 TCGA 数据库中筛选出差异表达的 lncRNA。通过 RT-qPCR 检测 CRC 临床样本和细胞系中的 HNF1A-AS1。通过 CCK8 assay、集落形成 assay、流式细胞术、transwell assay、管形成 assay 和 vivo 实验研究 HNF1A-AS1 在 CRC 肿瘤进展中的作用。通过生物信息学分析、荧光素酶报告 assay、RNA 下拉和 RIP assay 探索与 HNF1A-AS1 结合的蛋白及其潜在的下游靶标。

结果

我们的结果表明，HNF1A-AS1 在 CRC 中上调，并与不良预后相关。HNF1A-AS1 促进 CRC 增殖、迁移和血管生成，加速细胞周期，减少细胞凋亡。生物信息学预测和进一步的实验证明，HNF1A-AS1 通过抑制 PDCD4 或竞争性海绵 miR-93-5p 促进 CCND1 的表达。同时，METTL3 介导 HNF1A-AS1 mA 修饰并影响其 RNA 稳定性。HNF1A-AS1/IGF2BP2/CCND1 可能作为一个复合物调节 CCND1 的稳定性。

结论

综上所述，我们的结果揭示了 mA 介导的 HNF1A-AS1/IGF2BP2/CCND1 轴促进 CRC 细胞周期进程的新机制，同时竞争性海绵 miR-93-5p 上调 CCND1，表明其在细胞周期调控中具有重要作用，并提示 HNF1A-AS1 可能成为结直肠癌未来有潜力的预后标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/66c6b91f94da/cells-11-03008-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/5318e6e8d668/cells-11-03008-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/ebea593477d1/cells-11-03008-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/05eff4aff7f5/cells-11-03008-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/93c76d59b457/cells-11-03008-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/49494a92da3e/cells-11-03008-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/a71618dfcad1/cells-11-03008-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/66c6b91f94da/cells-11-03008-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/5318e6e8d668/cells-11-03008-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/ebea593477d1/cells-11-03008-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/05eff4aff7f5/cells-11-03008-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/93c76d59b457/cells-11-03008-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/49494a92da3e/cells-11-03008-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/a71618dfcad1/cells-11-03008-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4c8/9562639/66c6b91f94da/cells-11-03008-g007.jpg

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