TRAF6 作为晚期乳腺癌的潜在靶点：系统评价、荟萃分析和生物信息学验证。

TRAF6 as a potential target in advanced breast cancer: a systematic review, meta-analysis, and bioinformatics validation.

机构信息

Department of Oncology and Metabolism, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.

Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenes Street, 1516, Nicosia, Cyprus.

出版信息

Sci Rep. 2023 Mar 21;13(1):4646. doi: 10.1038/s41598-023-31557-0.

DOI:10.1038/s41598-023-31557-0

PMID:36944688

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10029787/

Abstract

TRAF6 has emerged as a key regulator of breast cancer (BCa). However, the TRAF family constitutes of seven members that exhibit distinct and overlapping functions. To explore which TRAF represents a potential druggable target for BCa treatment, we searched Medline, Web of Science and Scopus for relevant studies from inception to June 27, 2021. We identified 14 in vitro, 11 in vivo and 4 human articles. A meta-analysis of pharmacological studies showed that in vitro inhibition of TRAF2/4 (mean difference (MD): - 57.49, 95% CI: - 66.95, - 48.02, P < 0.00001) or TRAF6 (standard(Std.)MD: - 4.01, 95% CI: - 5.75, - 2.27, P < 0.00001) is associated with reduction in BCa cell migration. Consistently, inhibition of TRAF2/4 (MD: - 51.08, 95% CI: - 64.23, - 37.94, P < 0.00001) and TRAF6 (Std.MD: - 2.80, 95% CI: - 4.26, - 1.34, P = 0.0002) is associated with reduced BCa cell invasion, whereas TRAF2/4 inhibition (MD: - 40.54, 95% CI: - 52.83, - 28.26, P < 0.00001) is associated with reduced BCa cell adhesion. Interestingly, only inhibition of TRAF6 (MD: - 21.46, 95% CI: - 30.40, - 12.51, P < 0.00001) is associated with reduced cell growth. In animal models of BCa, administration of pharmacological inhibitors of TRAF2/4 (Std.MD: - 3.36, 95% CI: - 4.53, - 2.18, P < 0.00001) or TRAF6 (Std.MD: - 4.15, 95% CI: - 6.06, - 2.24, P < 0.0001) in mice is associated with reduction in tumour burden. In contrast, TRAF6 inhibitors (MD: - 2.42, 95% CI: - 3.70, - 1.14, P = 0.0002) reduced BCa metastasis. In BCa patients, high expression of TRAF6 (Hazard Ratio: 1.01, CI: 1.01, 1.01, P < 0.00001) is associated with poor survival rate. Bioinformatics validation of clinical and pathway and process enrichment analysis in BCa patients confirmed that gain/amplification of TRAF6 is associated with secondary BCa in bone (P = 0.0079), and poor survival rate (P < 0.05). Overall, TRAF6 inhibitors show promise in the treatment of metastatic BCa. However, low study number and scarcity of evidence from animal and human studies may limit the translation of present findings into clinical practice.

摘要

TRAF6 已成为乳腺癌 (BCa) 的关键调节因子。然而，TRAF 家族由七个成员组成，它们具有不同和重叠的功能。为了探索 TRAF 家族中哪一个代表了治疗 BCa 的潜在可药物靶点，我们在 Medline、Web of Science 和 Scopus 上搜索了从成立到 2021 年 6 月 27 日的相关研究。我们确定了 14 项体外研究、11 项体内研究和 4 项人类研究。药物研究的荟萃分析表明，体外抑制 TRAF2/4（平均差异 (MD)：-57.49，95%CI：-66.95，-48.02，P<0.00001）或 TRAF6（标准(Std.)MD：-4.01，95%CI：-5.75，-2.27，P<0.00001）与减少 BCa 细胞迁移有关。一致地，抑制 TRAF2/4（MD：-51.08，95%CI：-64.23，-37.94，P<0.00001）和 TRAF6（Std.MD：-2.80，95%CI：-4.26，-1.34，P=0.0002）与减少 BCa 细胞侵袭有关，而 TRAF2/4 抑制（MD：-40.54，95%CI：-52.83，-28.26，P<0.00001）与减少 BCa 细胞黏附有关。有趣的是，只有 TRAF6 抑制（MD：-21.46，95%CI：-30.40，-12.51，P<0.00001）与减少细胞生长有关。在 BCa 动物模型中，给予 TRAF2/4（Std.MD：-3.36，95%CI：-4.53，-2.18，P<0.00001）或 TRAF6（Std.MD：-4.15，95%CI：-6.06，-2.24，P<0.0001）的药理学抑制剂治疗与肿瘤负担的减少有关。相比之下，TRAF6 抑制剂（MD：-2.42，95%CI：-3.70，-1.14，P=0.0002）减少了 BCa 的转移。在 BCa 患者中，TRAF6 高表达（风险比：1.01，CI：1.01，1.01，P<0.00001）与生存率差有关。BCa 患者的临床和通路和过程富集分析的生物信息学验证证实，TRAF6 的增益/扩增与骨中的继发性 BCa（P=0.0079）和生存率差（P<0.05）有关。总的来说，TRAF6 抑制剂在治疗转移性 BCa 方面显示出了希望。然而，研究数量低和动物及人类研究证据稀缺可能限制了目前研究结果在临床实践中的转化。