KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer.
KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer.
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DOI：
10.1186/s13046-020-01775-9
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发表时间：
2020-11-30
期刊：
影响因子：
--
通讯作者：
Gallo D
中科院分区：
文献类型：
--
作者：
De Donato M;Babini G;Mozzetti S;Buttarelli M;Ciucci A;Arduini G;De Rosa MC;Scambia G;Gallo D
尽管在手术和临床管理方面取得了很大的进步，但到目前为止，高级别浆液性卵巢癌（HGSOC）患者的总生存率没有显著提高。疾病控制的重要方面仍未解决，包括不清楚的发病机制，高异质性和化疗后的复发抵抗。因此，需要进一步研究参与癌症进展的分子机制，以寻找疾病管理的新靶点。kr<s:1> ppel样因子（KLFs）是一个转录调控家族，控制几个基本的细胞过程，包括增殖、分化和迁移。它们已被证明在各种与癌症相关的过程中以一种依赖于环境的方式发挥作用。为了研究KLF家族成员作为预后生物标志物的可能作用，我们对不同队列的晚期HGSOC患者的卵巢转录组数据集进行了生物信息学荟萃分析。利用体外HGSOC细胞模型进行功能研究，探索KLF7在疾病发生和进展中的作用。最后，进行分子建模和虚拟筛选以确定假定的KLF7抑制剂。生物信息学分析显示，在17个家族成员中，KLF7是最重要的预后基因。单因素和多因素分析发现，在晚期TCGA-OV和GSE26712 HGSOC队列中，KLF7是一个不利的总生存预后标志物。体外功能研究表明，KLF7可以作为致癌基因发挥作用，驱动肿瘤生长和传播。KLF7的机制靶点包括参与上皮细胞向间充质细胞转化、维持癌症干细胞多能性和自我更新特征的基因。最后，计算机分析为药物-靶点相互作用预测提供了可靠的信息。本研究的结果首次证明了KLF7在HGSOC中的致癌作用，表明它是一个有希望的预后标志物和治疗靶点。本文附有补充信息10.1186/s13046-020-01775-9。
In spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way. To investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors. Bioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction. Results from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target. Supplementary information accompanies this paper at 10.1186/s13046-020-01775-9.
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