Glioblastoma (GBM) has limited therapeutic options. DNA repair mechanisms contribute GBM cells to escape therapies and re-establish tumor growth. Multiple studies have shown that POLD2 plays a critical role in DNA replication, DNA repair and genomic stability. We demonstrate for the first time that POLD2 is highly expressed in human glioma specimens and that expression correlates with poor patient survival. siRNA or shRNA POLD2 inhibited GBM cell proliferation, cell cycle progression, invasiveness, sensitized GBM cells to chemo/radiation-induced cell death and reversed the cytoprotective effects of EGFR signaling. Conversely, forced POLD2 expression was found to induce GBM cell proliferation, colony formation, invasiveness and chemo/radiation resistance. POLD2 expression associated with stem-like cell subsets (CD133+ and SSEA-1+ cells) and positively correlated with Sox2 expression in clinical specimens. Its expression was induced by Sox2 and inhibited by the forced differentiation of GBM neurospheres. shRNA-POLD2 modestly inhibited GBM neurosphere-derived orthotopic xenografts growth, when combined with radiation, dramatically inhibited xenograft growth in a cooperative fashion. These novel findings identify POLD2 as a new potential therapeutic target for enhancing GBM response to current standard of care therapeutics.

中文翻译：

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基于ShRNA的POLD2表达敲低可使胶质母细胞瘤对DNA损伤治疗剂敏感。

胶质母细胞瘤（GBM）的治疗选择有限。DNA修复机制有助于GBM细胞逃脱疗法并重新建立肿瘤生长。多项研究表明，POLD2在DNA复制，DNA修复和基因组稳定性中起关键作用。我们首次证明了POLD2在人类神经胶质瘤标本中高表达，并且该表达与患者生存不良有关。siRNA或shRNA POLD2抑制GBM细胞增殖，细胞周期进程，侵袭性，使GBM细胞对化学/放射诱导的细胞死亡敏感，并逆转EGFR信号传导的细胞保护作用。相反，发现强迫的POLD2表达诱导GBM细胞增殖，集落形成，侵袭性和化学/放射抗性。POLD2表达与干样细胞亚群（CD133 +和SSEA-1 +细胞）相关，并且与临床标本中的Sox2表达呈正相关。它的表达被Sox2诱导，并被GBM神经球的强制分化抑制。当与放射线结合使用时，shRNA-POLD2适度抑制GBM神经球来源的原位异种移植物的生长，以协同方式显着抑制异种移植物的生长。这些新颖的发现将POLD2鉴定为增强GBM对当前护理治疗标准反应的新潜在治疗靶标。以合作方式显着抑制异种移植物的生长。这些新颖的发现将POLD2鉴定为增强GBM对当前护理治疗标准反应的新潜在治疗靶标。以合作方式显着抑制异种移植物的生长。这些新颖的发现将POLD2鉴定为增强GBM对当前护理治疗标准反应的新潜在治疗靶标。