Wang Ruonan, Li Xiaolin, Jiang Yapei, Zhang Haowei, Yang Shiyue, Xie Weidong, Xu Naihan
State Key Laboratory of Chemical Oncogenomics, Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
School of Food and Drug, Shenzhen Polytech University, Shenzhen, 518055, China.
Inflammation. 2024 Nov 6. doi: 10.1007/s10753-024-02170-8.
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and poses a significant threat to human health. Recent studies have underscored the crucial role of aberrant expression of long non-coding RNAs (lncRNAs) in the initiation and progression of CRC. In this study we identified that lncRNA USP30-AS1 is significantly downregulated in colorectal cancer tissues, particularly in the advanced stages of the disease. This downregulation correlates with reduced survival rates among patients. Enrichment analysis of genes associated with USP30-AS1 indicates a strong association with inflammatory responses. Notably, pro-inflammatory stimuli, including lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α), were found to upregulate the expression of USP30-AS1. Functional assays demonstrated that the knockdown of USP30-AS1 resulted in increased degradation of IκBα protein and enhanced NF-κB transcriptional activity, as well as elevated expression levels of NF-κB downstream inflammatory molecules, including NLRP3, IL-1β, and IL-18. Conversely, ectopic expression of USP30-AS1 inhibited NF-κB transactivation. Mechanistically, USP30-AS1 interacts with MYBBP1A, a known regulator of NF-κB signaling. Notably, overexpression of MYBBP1A alleviated the stimulatory effect of USP30-AS1 knockdown on NF-κB activation. Collectively, these findings suggest that USP30-AS1 acts as a suppressor of colorectal cancer cell growth by modulating the MYBBP1A/NF-κB signaling pathway, thereby highlighting USP30-AS1 as a potential novel therapeutic target for colorectal cancer treatment.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一，对人类健康构成重大威胁。最近的研究强调了长链非编码RNA（lncRNAs）异常表达在CRC发生和发展中的关键作用。在本研究中，我们发现lncRNA USP30-AS1在结直肠癌组织中显著下调，尤其是在疾病的晚期阶段。这种下调与患者生存率降低相关。对与USP30-AS1相关基因的富集分析表明其与炎症反应密切相关。值得注意的是，发现包括脂多糖（LPS）和肿瘤坏死因子-α（TNF-α）在内的促炎刺激可上调USP30-AS1的表达。功能分析表明，敲低USP30-AS1会导致IκBα蛋白降解增加、NF-κB转录活性增强，以及NF-κB下游炎症分子（包括NLRP3、IL-1β和IL-18）的表达水平升高。相反，USP30-AS1的异位表达抑制NF-κB反式激活。机制上，USP30-AS1与已知的NF-κB信号调节因子MYBBP1A相互作用。值得注意的是，MYBBP1A的过表达减轻了USP30-AS1敲低对NF-κB激活的刺激作用。总体而言，这些发现表明USP30-AS1通过调节MYBBP1A/NF-κB信号通路作为结直肠癌细胞生长的抑制剂，从而突出了USP30-AS1作为结直肠癌治疗潜在新靶点的地位。
