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一种新型长非编码 RNA SP100-AS1 通过海绵吸附 miR-622 和稳定 ATG3 诱导结直肠癌的放射抵抗。

A novel long noncoding RNA SP100-AS1 induces radioresistance of colorectal cancer via sponging miR-622 and stabilizing ATG3.

机构信息

Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.

Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, China.

出版信息

Cell Death Differ. 2023 Jan;30(1):111-124. doi: 10.1038/s41418-022-01049-1. Epub 2022 Aug 17.

DOI:10.1038/s41418-022-01049-1
PMID:35978049
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9883267/
Abstract

Although radiotherapy is an essential modality in the treatment of colorectal cancer (CRC), the incidence of radioresistance remains high clinically. Long noncoding RNAs (lncRNAs) reportedly play critical roles in CRC radioresistance by regulating genes or proteins at the transcriptional or post-translational levels. This study aimed to identify novel lncRNAs involved in radioresistance. We found that SP100-AS1 (lncRNA targeting antisense sequence of SP100 gene) was upregulated in radioresistant CRC patient tissues using RNA-seq analysis. Importantly, knockdown of SP100-AS1 significantly reduced radioresistance, cell proliferation, and tumor formation in vitro and in vivo. Mechanistically, mass spectrometry and bioinformatics analyses were used to identify the interacting proteins and microRNAs of SP100-AS1, respectively. Moreover, SP100-AS1 was found to interact with and stabilize ATG3 protein through the ubiquitination-dependent proteasome pathway. In addition, it could serve as a sponge for miR-622, which targeted ATG3 mRNA and affected autophagic activity. Thus, lncRNA SP100-AS1 could act as a radioresistance factor in CRC patients via RNA sponging and protein stabilizing mechanisms. In conclusion, the present study indicates that SP100-AS1/miR-622/ATG3 axis contributes to radioresistance and autophagic activity in CRC patients, suggesting it has huge prospects as a therapeutic target for improving CRC response to radiation therapy.

摘要

虽然放射治疗是治疗结直肠癌(CRC)的重要手段,但临床上仍然存在放射抵抗的发生率较高的问题。长链非编码 RNA(lncRNA)据报道通过在转录或翻译后水平调节基因或蛋白质在 CRC 放射抵抗中发挥关键作用。本研究旨在鉴定参与放射抵抗的新的 lncRNA。我们通过 RNA-seq 分析发现,SP100-AS1(靶向 SP100 基因反义序列的 lncRNA)在放射抵抗的 CRC 患者组织中上调。重要的是,SP100-AS1 的敲低显著降低了体外和体内的放射抵抗、细胞增殖和肿瘤形成。机制上,分别使用质谱分析和生物信息学分析来鉴定 SP100-AS1 的相互作用蛋白和 microRNA。此外,发现 SP100-AS1 通过泛素化依赖的蛋白酶体途径与 ATG3 蛋白相互作用并稳定其蛋白水平。此外,它可以作为 miR-622 的海绵,miR-622 靶向 ATG3 mRNA 并影响自噬活性。因此,lncRNA SP100-AS1 可通过 RNA 海绵和蛋白稳定机制在 CRC 患者中作为放射抵抗因子发挥作用。总之,本研究表明 SP100-AS1/miR-622/ATG3 轴参与 CRC 患者的放射抵抗和自噬活性,表明其作为提高 CRC 对放射治疗反应的治疗靶点具有巨大的前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9f1/9883267/3edd76389abb/41418_2022_1049_Fig8_HTML.jpg
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