Santos-Pereira José M, Carnero Amancio, Muñoz-Galván Sandra
Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n 41013, Seville, Spain.
Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, 41012 Sevilla, Spain.
NAR Genom Bioinform. 2025 Aug 27;7(3):lqaf113. doi: 10.1093/nargab/lqaf113. eCollection 2025 Sep.
The transcription factor PAX8 is expressed in most ovarian tumors, being associated with increased tumorigenesis. Although recent studies have addressed the gene regulatory functions of PAX8 in ovarian cancer, an integrative analysis of multi-omic and patient data is required to identify the core regulatory network of PAX8 and its prognostic and therapeutic value. Here, we integrate PAX8 chromatin binding and accessibility data in ovarian cancer cells with transcriptomic and patients' data to gain insight into the core gene regulatory network orchestrated by PAX8 in ovarian tumors. Integration of differential chromatin accessibility, transcription factor binding, and gene expression upon PAX8 knockout provides a core regulatory network that explains most of the genes regulated by PAX8. We combine these target genes with patient expression data and find a PAX8 gene signature associated with tumor stemness, a property related to therapy resistance. Indeed, we show that the PAX8 gene signature predicts disease outcome and response to therapy in ovarian cancer patients. Finally, we validated experimentally our results from bioinformatic analyses, thus reassuring their robustness. Our findings uncover a PAX8 core network that represents a promising strategy for targeted antitumor therapies and open new pathways to fight against ovarian cancer resistance.
转录因子PAX8在大多数卵巢肿瘤中表达，与肿瘤发生增加有关。尽管最近的研究探讨了PAX8在卵巢癌中的基因调控功能，但仍需要对多组学和患者数据进行综合分析，以确定PAX8的核心调控网络及其预后和治疗价值。在此，我们将卵巢癌细胞中PAX8的染色质结合和可及性数据与转录组学和患者数据相结合，以深入了解PAX8在卵巢肿瘤中精心编排的核心基因调控网络。PAX8基因敲除后差异染色质可及性转录因子结合和基因表达的整合提供了一个核心调控网络，该网络解释了大多数受PAX8调控的基因。我们将这些靶基因与患者表达数据相结合，发现了一个与肿瘤干性相关的PAX8基因特征，肿瘤干性是一种与治疗抗性相关的特性。事实上，我们表明PAX8基因特征可预测卵巢癌患者的疾病预后和对治疗的反应。最后，我们通过实验验证了生物信息学分析的结果，从而确保了其稳健性。我们的研究结果揭示了一个PAX8核心网络，它代表了一种有前景的靶向抗肿瘤治疗策略，并为对抗卵巢癌抗性开辟了新途径。
