ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics
| Autor: | Qingfu Xu, Yugang Jiang, Li-Chao Li, Kimberly Wang, Shuli Xia, Chengchen Hu, Jun-Hai Tang, Guo-Hao Huang, Bachuchu Lal, Sheng-Qing Lv, John Laterra, Yan Zhu, Yunqing Li, Shuang Wei |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death DNA repair Biology Article Small hairpin RNA Mice 03 medical and health sciences 0302 clinical medicine SOX2 Cell Movement Cell Line Tumor Neurosphere Temozolomide Animals Humans RNA Small Interfering Cell Proliferation DNA Polymerase III Gene knockdown Radiotherapy Brain Neoplasms Cell growth DNA replication Drug Synergism Survival Analysis Xenograft Model Antitumor Assays Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Oncology 030220 oncology & carcinogenesis Neoplastic Stem Cells Cancer research Glioblastoma |
| Zdroj: | Cancer Lett |
| ISSN: | 0304-3835 |
| Popis: | 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 So×2 expression in clinical specimens. Its expression was induced by So×2 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. |
| Databáze: | OpenAIRE |
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