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Abstract：
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Antisense RNAs (asRNAs) are closely associated with cancer malignancy. This study aimed to identify the action mechanism of asRNAs in controlling CRC malignancy. Analysis of the RNA sequencing data revealed that AFAP1-AS1 and MLK7-AS1 were upregulated in CRC patients and cell lines. High levels of both asRNAs were associated with poor prognosis in patients with CRC. Both in vitro and in vivo experiments revealed that the knockdown of the two asRNAs decreased the proliferative and metastatic abilities of CRC cells. Mechanistically, AFAP1-AS1 and MLK7-AS1 decreased the levels of miR-149-5p and miR-485-5p by functioning as ceRNAs. Overexpression of miRNAs by introducing miRNA mimics suppressed the expression of SHMT2 and IGFBP5 by directly binding to the 3\' UTR of their mRNA. Knockdown of both asRNAs decreased the expression of SHMT2 and IGFBP5, which was reversed by inhibition of both miRNAs by miRNA inhibitors. In vivo pharmacological targeting of both asRNAs by small interfering RNA-loaded nanoparticles showed that knockdown of asRNAs significantly reduced tumor growth and metastasis. Our findings demonstrate that AFAP1-AS1 and MLK7-AS1 promote CRC progression by sponging the tumor-suppressing miRNAs miR-149-5p and miR-485-5p, thus upregulating SHMT2 and IGFBP5.
摘要：
结直肠癌(CRC)是癌症相关死亡的主要原因之一。反义RNA(asRNA)与癌症恶性程度密切相关。本研究旨在确定asRNA在控制CRC恶性肿瘤中的作用机制。RNA测序数据的分析显示AFAP1-AS1和MLK7-AS1在CRC患者和细胞系中上调。两种asRNA的高水平与CRC患者的不良预后相关。体外和体内实验均表明，两种asRNA的敲除降低了CRC细胞的增殖和转移能力。机械上,AFAP1-AS1和MLK7-AS1通过充当ceRNA降低miR-149-5p和miR-485-5p的水平。通过引入miRNA模拟物的miRNA的过表达通过直接结合其mRNA的3'UTR来抑制SHMT2和IGFBP5的表达。两种asRNA的敲低降低了SHMT2和IGFBP5的表达,这通过miRNA抑制剂抑制两种miRNA而被逆转。通过小干扰RNA负载的纳米颗粒对两种asRNA的体内药理学靶向表明asRNA的敲低显著降低了肿瘤生长和转移。我们的研究结果表明，AFAP1-AS1和MLK7-AS1通过形成肿瘤抑制性miRNAmiR-149-5p和miR-485-5p促进CRC进展，从而上调SHMT2和IGFBP5。
