Mohamed Nermin M, Mohamed Rania Hassan, Kennedy John F, Elhefnawi Mahmoud M, Hamdy Nadia M
Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
Department of Biochemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt.
Int J Biol Macromol. 2025 Jun;311(Pt 1):143616. doi: 10.1016/j.ijbiomac.2025.143616. Epub 2025 Apr 28.
Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.
肝细胞癌（HCC）是一种由多种细胞信号通路失调驱动的复杂恶性肿瘤。生存素是凋亡抑制蛋白（IAP）家族的关键成员，在HCC的肿瘤发生和进展中起核心作用。尽管进行了大量研究，但对生存素在癌症特征形成中的作用、其分子网络以及作为治疗靶点的潜力仍缺乏全面了解。在本综述中，我们将生物信息学分析与广泛的文献综述相结合，以更深入地了解生存素在HCC中的作用。我们使用人类蛋白质图谱、GEPIA、STRING、TIMER和Metascape等生物信息学工具，分析生存素的表达及其功能关联，并确定了HCC中前20个共表达基因。这些基因包括TK1、SPC25、SGO2、PTTG1、PRR11、PLK1、NCAPH、KPNA2、KIF2C、KIF11、HJURP、GTSE1、FOXM1、CEP55、CENPA、CDCA3、CDC45、CCNB2、CCNB1和CTD - 2510F5.4。我们的研究结果还揭示了这些基因之间存在显著的蛋白质 - 蛋白质相互作用，这些相互作用在与FOXM1致癌信号级联相关的通路以及细胞周期调控、有丝分裂检查点等生物学过程和肝脏肿瘤等疾病中富集。我们还讨论了生存素在关键致癌通路中的作用，包括PI3K/AKT、WNT/β - 连环蛋白、Hippo和JAK/STAT3通路，以及它在调节细胞周期检查点、凋亡和自噬中的作用。此外，我们探讨了它与肿瘤微环境的相互作用，特别是其通过髓源性抑制细胞（MDSC）、肿瘤相关巨噬细胞以及HCC中自然杀伤细胞功能对免疫调节的影响。此外，我们强调了它在烷基甘油磷酸合酶（AGPS）介导的脂质重编程中的作用，并确定了生存素网络中需要进一步研究的重要空白。本综述还研究了生存素在癌症干性、炎症和病毒介导的肝癌发生中的作用。我们评估了它作为HCC诊断、预后、预测和药效学生物标志物的潜力，强调了其在精准医学中的相关性。最后，我们总结了新兴的针对生存素的治疗方法和正在进行的临床试验，强调了需要新策略来有效靶向HCC中的生存素。
