The essential role of PBX1, a stem cell reprogramming factor, in ovarian cancer chemoresistance. Homo sapiens

Elucidating the pathogenesis of chemoresistance is fundamental for developing more effective interventions that will improve the clinical outcome of neoplastic diseases such as ovarian cancer. Here, we report the upregulation of PBX1, a stem cell reprogramming factor, in recurrent ovarian carcinomas. Moreover, high levels of PBX1 expression are correlated with a shorter survival rate among post-chemotherapy ovarian cancer patients. Ectopic expression of PBX1 promotes cancer stem cell-like phenotypes, including increased side population and ALDH activity, enhanced tumorigenicity at a low cell density, and increased resistance to platinum-based therapy. Silencing PBX1 in platinum-resistant cell lines that overexpress PBX1 sensitizes cells to platinum treatment and reduces their “stemness”. Analysis of previously reported genome-wide chromatin immunoprecipitation data shows that PBX1 binds directly to promoters of genes involved in stem cell maintenance and tissue injury response. We confirmed direct regulation of STAT3 by PBX1, and demonstrated that the PBX1 binding motif located on the STAT3 promoter participates in positive transcriptional regulation of STAT3. Furthermore, a STAT3/JAK2 inhibitor potently sensitizes platinum-resistant cells to carboplatin and suppresses their growth in vivo. These findings establish PBX1 as an upstream regulator of key pathways in stem cell and tissue damage response and highlight the potential of targeting the PBX1/STAT3 axis to overcome chemoresistance in human cancers. Overall design: Determine gene expression changes after knockdown of PBX1 protein in an ovarian cancer cell line (OVCAR3)

阐明化疗耐药的发病机制，是开发更有效干预手段、改善卵巢癌等肿瘤性疾病临床结局的核心基础。本研究报道了干细胞重编程因子PBX1在复发性卵巢癌中的表达上调现象。进一步研究发现，化疗后卵巢癌患者体内PBX1高表达与较短的生存期显著相关。异位表达PBX1可促进癌症干细胞样表型的形成，具体包括侧群细胞比例升高、乙醛脱氢酶（ALDH）活性增强、低细胞密度下致瘤能力提升，以及对铂类疗法的耐药性增加。在过表达PBX1的铂耐药细胞系中敲低PBX1，可使细胞对铂类治疗增敏，并降低其干细胞特性。对已发表的全基因组染色质免疫沉淀数据进行分析后发现，PBX1可直接结合参与干细胞维持与组织损伤应答的基因启动子区域。本研究证实了PBX1可直接调控信号转导与转录激活因子3 (STAT3)，并证明位于STAT3启动子上的PBX1结合基序可对STAT3进行正向转录调控。此外，STAT3/JAK2（Janus激酶2）抑制剂可有效增敏铂耐药细胞对卡铂的敏感性，并在体内抑制其增殖。上述研究结果确立了PBX1作为干细胞与组织损伤应答关键通路的上游调控因子的地位，并凸显了靶向PBX1/STAT3轴以克服人类癌症化疗耐药的潜在应用价值。整体实验设计：在卵巢癌细胞系OVCAR3中敲低PBX1蛋白后，检测基因表达水平的变化。