Department of Plastic Surgery, Lanzhou University Second Hospital, Lanzhou, China.
J Cancer Res Clin Oncol. 2023 Jul;149(7):3089-3107. doi: 10.1007/s00432-022-04164-1. Epub 2022 Jul 23.
BACKGROUND: AURKA, Aurora kinase A encoding gene, is an important signaling hub gene for mitosis. In recent years, AURKA has been implicated in the occurrence and development of several cancers. However, its relationship with the tumor microenvironment in skin cutaneous melanoma (SKCM) and the molecular mechanisms underlying its effects are still unclear. METHOD: We adopted a variety of bioinformatics methods to comprehensively analyze the potential carcinogenesis of AURKA in SKCM, and constructed a prognostic nomogram model. We also dentified an inhibitor targeting AURKA and verified its therapeutic effects against SKCM using the molecular docking technology. RESULTS: We found that abnormally high expression of AURKA was responsible for driving the occurrence and development of SKCM, and affected various pathological factors in SKCM. In addition, AURKA was established as an independent marker of poor SKCM prognosis. We also characterized the potential mechanisms by which AURKA manifests its effects in SKCM and found that AURKA inhibits the infiltration of CD8+ T cells and promotes hypoxia by activating the TGF-β signaling pathway. At the same time, the high AURKA expression group had higher tumor stemness index and promoted cell proliferation and metastasis. Finally, the small-molecule compound ZNC97018978 targeting AURKA screened by molecular docking technology can inhibit the proliferation, invasion and metastasis of SKCM. The possible mechanism is that ZNC97018978 induces apoptosis by arresting the cell cycle, thereby inhibiting cell proliferation. CONCLUSION: AURKA is the core hub gene driving the occurrence and development of SKCM, and its expression is regulated by epigenetic modifications. AURKA can regulate the infiltration level of various immune cells in the tumor microenvironment, reshape the immunosuppressive tumor microenvironment, and apoptosis, and hypoxia. Thus, it is a prognostic biomarker and potential therapeutic target in SKCM. ZNC97018978 is an effective and safe inhibitor of AURKA in vitro; its safety and effectiveness in vivo as a potential treatment for cutaneous melanoma should be further determined.
背景：AURKA 是 Aurora 激酶 A 的编码基因，是有丝分裂过程中的一个重要信号枢纽基因。近年来，AURKA 被认为与多种癌症的发生和发展有关。然而，其与皮肤黑色素瘤（SKCM）肿瘤微环境的关系及其作用的分子机制尚不清楚。
方法：我们采用多种生物信息学方法，全面分析 AURKA 在 SKCM 中的潜在致癌作用，并构建了一个预后列线图模型。我们还确定了一种针对 AURKA 的抑制剂，并使用分子对接技术验证了其对 SKCM 的治疗效果。
结果：我们发现 AURKA 的异常高表达是导致 SKCM 发生和发展的原因，并影响 SKCM 中的各种病理因素。此外，AURKA 被确立为 SKCM 预后不良的独立标志物。我们还描述了 AURKA 在 SKCM 中发挥作用的潜在机制，发现 AURKA 通过激活 TGF-β 信号通路抑制 CD8+T 细胞的浸润并促进缺氧。同时，高 AURKA 表达组具有更高的肿瘤干性指数，并促进细胞增殖和转移。最后，通过分子对接技术筛选出的靶向 AURKA 的小分子化合物 ZNC97018978 可抑制 SKCM 的增殖、侵袭和转移。其可能的机制是 ZNC97018978 通过细胞周期阻滞诱导细胞凋亡，从而抑制细胞增殖。
结论：AURKA 是驱动 SKCM 发生和发展的核心枢纽基因，其表达受表观遗传修饰调控。AURKA 可调节肿瘤微环境中各种免疫细胞的浸润水平，重塑免疫抑制性肿瘤微环境，并诱导细胞凋亡、缺氧。因此，它是 SKCM 的预后生物标志物和潜在治疗靶点。ZNC97018978 是体外有效且安全的 AURKA 抑制剂；作为一种潜在的皮肤黑色素瘤治疗方法，其在体内的安全性和有效性应进一步确定。
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