USP18 promotes colon adenocarcinoma progression via targeting the ERK-MNK signaling pathway

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine Pub Date : 2024-07-01 DOI:10.1002/jgm.3709

Nan Tang, Xiaojian Liu

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引用次数: 0

Abstract

Background

Colorectal cancer is the third most common malignancy worldwide and is one of the leading causes of cancer-related mortality. Ubiquitin-specific peptidase 18 (USP18) protein has been reported to exert different tumor-related effects in distinct tumor types. Here, we initially investigated the expression and signaling pathways of USP18 in colon adenocarcinoma (COAD).

Methods

A quantitative real-time PCR was conducted to evaluate the mRNA level of USP18 in cultured cells. Immunohistochemical staining was used to explore the protein expression of USP18 in clinical COAD samples. Specific knockdown was achieved by transient transfection of small interfering RNAs into SW480 and HT29 cells using Lipo3000. Cell conting kit-8 assay, transwell assay and matrigel-transwell assays were conducted to evaluate proliferation, migration and invasion capacities, respectively. Western blotting was performed to analyze downstream signaling pathways. A chi-squared test and univariate and multivariate analyses were used to evaluate the clinical data. Xenografts from mice model were assessed to validate the in vitro findings.

Results

Higher USP18 level was identified in COAD tissues and was positively correlated with advanced tumor stage. High USP18 protein expression indicated poorer prognosis of COAD patients. Silencing USP18 suppressed COAD cell proliferation and invasion via destabilizing extracellular signal-regulated kinase (ERK) protein and suppressing ERK downstream pathways. Simultaneously silencing interferon-stimulated gene 15 (ISG15) with USP18 can partially rescue the tumor cell viability, indicating its involvement in USP18 signaling. The oncogenic effects of USP18 were also confirmed in mice models.

Conclusions

USP18 plays oncogenic effects in colon adenocarcinoma via ISG15-ERK pathways. High USP18 expression indicates poor clinical outcomes for colon adenocarcinoma patients.

Abstract Image

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USP18 通过靶向 ERK-MNK 信号通路促进结肠腺癌的进展。

背景：结直肠癌是全球第三大常见恶性肿瘤，也是导致癌症相关死亡的主要原因之一。据报道，泛素特异性肽酶 18（USP18）蛋白在不同的肿瘤类型中发挥不同的肿瘤相关作用。在此，我们初步研究了 USP18 在结肠腺癌（COAD）中的表达和信号通路：方法：采用实时定量 PCR 评估 USP18 在培养细胞中的 mRNA 水平。免疫组化染色法用于检测 USP18 在临床 COAD 样本中的蛋白表达。使用 Lipo3000 将小干扰 RNA 瞬时转染至 SW480 和 HT29 细胞，实现特异性基因敲除。细胞应急试剂盒-8检测、Transwell检测和matrigel-transwell检测分别用于评估细胞的增殖、迁移和侵袭能力。采用 Western 印迹法分析下游信号通路。采用卡方检验、单变量和多变量分析评估临床数据。对小鼠模型的异种移植进行了评估，以验证体外研究结果：结果：在 COAD 组织中发现 USP18 水平较高，且与肿瘤晚期呈正相关。高 USP18 蛋白表达表明 COAD 患者预后较差。通过破坏细胞外信号调节激酶（ERK）蛋白的稳定性和抑制ERK下游通路，沉默USP18可抑制COAD细胞的增殖和侵袭。与USP18同时沉默干扰素刺激基因15（ISG15）可部分挽救肿瘤细胞的活力，表明其参与了USP18信号转导。USP18 的致癌作用在小鼠模型中也得到了证实：结论：USP18 通过 ISG15-ERK 通路在结肠腺癌中发挥致癌作用。USP18的高表达预示着结肠腺癌患者的临床预后不佳。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.