Co-expressed functional module-related genes in ovarian cancer stem cells represent novel prognostic biomarkers in ovarian cancer

Ovarian cancer is the leading cause of death from gynecologic malignancies. Cancer stem cells (CSC) seem to play a crucial role in tumor metastasis, recurrence, and chemoresistance. Therefore, CSCs offer significant potential for developing therapeutic targets and to understand tumor recurrence and chemoresistance mechanisms. In the present study, our aim was the identification of the gene group in ovarian CSCs (O-CSCs) and the potential of the resultant gene group in ovarian cancer prognosis. Two different microarray data sets were analyzed by comparing gene expression levels between O-CSCs and cancer samples. The O-CSC co-expression network was reconstructed and its modules were identified. According to the analysis results, 74 mutual DEGs were identified. The O-CSC-specific co-expression network included 32 nodes and 95 edges (network density: 19%), while the co-expression network in cancer samples was reconstructed with 74 nodes and 1066 edges (network density: 39%). Understanding of the molecular mechanism and signatures of O-CSCs should provide valuable insight into chemotherapy resistance and recurrence of ovarian tumors. A highly connected 12 gene module in O-CSC samples of BAMB1, NFKB12, EZR, TNFAIP3, C1orf86, PMAIP1, GEM, KHDRBS3, FILIP1, FGFR2, TGFBR3 and PEG10, (network density: 67%) was identified. Prognostic performance of these genes was evaluated independently using six ovarian cancer datasets (n = 1933 patient samples) via survival analysis. These co-expressed genes were determined as prognostic targets in ovarian cancer. Through literature search validation, five genes (C1orf86, PMAIP1, FILIP1, NFKB12 and PEG10) suggested as novel molecular targets in ovarian cancer. The presented prognostic biomarkers here provide a resource for the understanding of tumor recurrence and chemoresistance and may facilitate critical research directions and development of new prognostic and therapeutic strategies for ovarian cancer. CSCs: cancer stem cells; O-CSCs: ovarian CSCs; FACS: fluorescence-activated cell sorting; SP: side population; MP: main population; TFs: transcription factors.卵巢癌是妇科恶性肿瘤致死的首要病因。癌干细胞（cancer stem cells, CSC）似乎在肿瘤转移、复发及化疗耐药过程中发挥关键作用，因此其为治疗靶点开发以及解析肿瘤复发与化疗耐药机制提供了重要潜力。本研究旨在鉴定卵巢癌干细胞（ovarian CSCs, O-CSCs）相关基因集，并探究该基因集在卵巢癌预后中的应用价值。研究通过比较卵巢癌干细胞与癌组织样本的基因表达水平，分析了两套独立的微阵列（microarray）数据集。随后重构了卵巢癌干细胞的共表达网络并对其模块进行鉴定，分析结果显示共鉴定出74个共有差异表达基因（mutual DEGs）。卵巢癌干细胞特异性共表达网络包含32个节点与95条边（网络密度：19%），而癌组织样本中的共表达网络则包含74个节点与1066条边（网络密度：39%）。深入解析卵巢癌干细胞的分子机制与特征，可为卵巢肿瘤的化疗耐药与复发研究提供宝贵见解。研究在卵巢癌干细胞样本中鉴定出一个高度连通的12基因模块，其包含BAMB1、NFKB12、EZR、TNFAIP3、C1orf86、PMAIP1、GEM、KHDRBS3、FILIP1、FGFR2、TGFBR3及PEG10（网络密度：67%）。研究人员通过6套卵巢癌数据集（共1933例患者样本）开展生存分析，独立评估了上述基因的预后性能。这些共表达基因被确定为卵巢癌的预后靶点。经文献检索验证，其中5个基因（C1orf86、PMAIP1、FILIP1、NFKB12及PEG10）被提示为卵巢癌潜在新型分子靶点。本研究提出的预后生物标志物，可为理解肿瘤复发与化疗耐药机制提供研究资源，并有望为卵巢癌的新型预后策略与治疗方案开发指明关键研究方向。缩写说明：CSCs：癌干细胞（cancer stem cells）；O-CSCs：卵巢癌干细胞（ovarian CSCs）；FACS：荧光激活细胞分选术（fluorescence-activated cell sorting）；SP：侧群细胞（side population）；MP：主群细胞（main population）；TFs：转录因子（transcription factors）。