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14-3-3? Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2.

ABSTRACT: 14-3-3? has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3? contributes to these resistances via inhibiting apoptosis and arresting cells in G2-M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3? causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2-M phase following DNA-damaging treatments. We showed that 14-3-3? contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2-M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3?-mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2-M arrest following IR was due to 14-3-3?-induced Chk2 expression.Implications: These findings reveal an important molecular basis of 14-3-3? function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers. Mol Cancer Res; 15(4); 418-28. ©2017 AACR.

SUBMITTER: Chen Y

PROVIDER: S-EPMC5380477 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2.

Chen Yifan Y Li Zhaomin Z Dong Zizheng Z Beebe Jenny J Yang Ke K Fu Liwu L Zhang Jian-Ting JT

Molecular cancer research : MCR 20170113 4

14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G<sub>2</sub>-M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G< ...[more]

PMID: 28087741

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Project description:Long non?coding RNA (lncRNA) LINC00473 plays a carcinogenic role in a variety of different tumor types. Nevertheless, the mechanisms through which LINC00473 regulates the radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells remains elusive. In the present study, reverse transcription?quantitative PCR was used to quantify the expression of LINC00473, microRNA (miRNA/miR)?497?5p and cell division cycle 25A (CDC25A) in ESCC tissues. The association between LINC00473 expression and the clinicopathological characteristics of patients with ESCC was also assessed. Furthermore, Cell Counting kit?8 and colony formation assays were carried out to monitor the proliferation of ESCC cells exposed to X?ray radiation. A dual?luciferase reporter assay was also conducted to analyze the interaction between LINC00473 and miR?497?5p, as well as the interaction between CDC25A and miR?497?5p. The findings of the present study demonstrated that in ESCC tissues and cells, the expression levels of LINC00473 and CDC25A were significantly upregulated, while the expression of miR?497?5p was downregulated. The high expression level of LINC00473 was associated with a higher T stage, lymph node metastasis stage and a lower tumor differentiation grade in patients with ESCC. Following irradiation, transfection with miR?497?5p mimics reduced the promoting effect of LINC00473 overexpression on ESCC cell proliferation, and partially impeded the resistance of ESCC cells to X?ray radiation induced by LINC00473 overexpression. Moreover, transfection with miR?497?5p inhibitors partially alleviated the inhibitory effects of LINC00473 knockdown on cellular proliferation, and partly reversed the sensitivity of cells to X?ray irradiation induced by LINC00473 knockdown. Furthermore, it was confirmed that miR?497?5p was able to bind LINC00473 and the 3'?untranslated region of CDC25A. On the whole, the findings of the present study demonstrate that LINC00473 reduces the radiosensitivity of ESCC cells by modulating the miR?497?5p/CDC25A axis.

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14-3-3? Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2.

Publications

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2.

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