m(6)A Modification of Long Non-Coding RNA HNF1A-AS1 Facilitates Cell Cycle Progression in Colorectal Cancer via IGF2BP2-Mediated CCND1 mRNA Stabilization.
m(6)A Modification of Long Non-Coding RNA HNF1A-AS1 Facilitates Cell Cycle Progression in Colorectal Cancer via IGF2BP2-Mediated CCND1 mRNA Stabilization.
复制标题
m（6）长非编码RNA HNF 1A-AS 1的修饰通过IGF 2BP 2介导的CCND 1 mRNA稳定化促进结直肠癌细胞周期进展。
作者：
背景：长的非编码RNA通过不同的分子机制调控肿瘤的发生。有报道称，HNF1A-AS1(HNF1A反义RNA1)在多种肿瘤中有不同的表达。HNF1A-AS1在结直肠癌中的作用研究较少，其调控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。采用RT-qPCR方法检测结直肠癌临床标本和细胞株中HNF1A-AS1的表达。采用CCK8实验、集落形成实验、流式细胞仪、Transwell实验、试管形成实验和体内实验等方法研究HNF1A-AS1在结直肠癌发生发展中的作用。通过生物信息学分析、荧光素酶报告分析、RNA下拉分析和RIP分析，寻找与HNF1A-AS1结合的蛋白质和潜在的下游靶点。结果：HNF1A-AS1在结直肠癌中表达上调，且与预后不良相关。HNF1A-AS1促进结直肠癌细胞的增殖、迁移和血管生成，加快细胞周期，减少细胞凋亡。生物信息学预测和进一步的实验证明，HNF1A-AS1可以通过抑制PDCD4或竞争性地海绵化miR-93-5p来促进CCND1的表达。同时，METTL3介导HNF1A-AS1 m6A的修饰并影响其RNA的稳定性。HNF1A-AS1/IGF2BP2/CCND1可能是一个调节CCND1稳定性的复合体。结论：综上所述，我们的结果揭示了m6A介导的HNF1A-AS1/IGF2BP2/CCND1轴促进结直肠癌细胞周期进展的新机制，同时竞争性地海绵化miR-93-5p上调CCND1，显示其在细胞周期调控中的重要作用，并提示HNF1A-AS1可能成为未来结直肠癌潜在的预后标志物。
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 m6A 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 m6A-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.
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