shRNA-Mediated XRCC2 Gene Knockdown Efficiently Sensitizes Colon Tumor Cells to X-ray Irradiation in Vitro and in Vivo

Wang, Qin; Wang, Yan; Du, Liqing; Xu, Chi; Sun, Yang; Yang, Bing; Sun, Zhao; Fu, Yue; Cai, Lu; Fan, Songqing; Fan, Feiyue; Liu, Qiang

doi:10.3390/ijms15022157

Cited by 10 publications

(9 citation statements)

References 22 publications

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“…Low levels of XRCC2 have been detected in breast cancer [42], whereas greater XRCC2 expression is present in rectal cancer and gastric cancer [30, 43]. It has been hypothesized that XRCC2 expression is related to the initiation or progression of carcinogenesis [44]. In the presents study, we found that XRCC2-deficient cells exhibit a high sensitivity to 5-FU, and a higher XRCC2 level indicated poor prognoses in patients with CRC.…”

Section: Discussionsupporting

confidence: 51%

XRCC2-Deficient Cells are Highly Sensitive to 5-Fluorouracil in Colorectal Cancer

Zhang¹,

An²,

Liu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Inhibition of the repair of 5-fluorouracil (5-FU)-induced DNA lesions may improve the responses of tumors to anticancer agents. XRCC2 is a key factor in DNA repair. However, the role of XRCC2 in the chemoresistance of colorectal cancer (CRC) treated with 5-FU remains unclear. The aim of this study is to investigate whether XRCC2 expression affects the chemosensitivity of colorectal cancer. Methods: XRCC2 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of XRCC2 expression. Following treatment with 5-FU, the effect of XRCC2 on proliferation was evaluated via a CCK-8 assay, the effects on cell cycle distribution and apoptosis were analyzed using flow cytometry, and γH2AX foci formation assays were performed to examine the influence of 5-FU on DNA Double-strand breaks(DSBs) repair in CRC cells. Results: XRCC2 expression in CRC tissues was significantly higher than that in normal tissues, and this increased XRCC2 expression was associated with advanced T staging, M staging, TNM staging, Duke’s staging, and greater liver and lymph node metastases. XRCC2 expression might be an independent prognostic indicator for CRC patients. Patients with negative XRCC2 expression exhibit greater sensitivity to treatment with 5-FU-based chemotherapy than those with positive XRCC2 expression. Moreover, our observations revealed that the knockdown of XRCC2 in CRC cells increased the sensitivities to 5-FU in terms of cell proliferation, apoptosis and cell cycle arrest. DNA DSBs repair was slower in the XRCC2-deficient cells than in the XRCC2-wild type cells. Conclusion: Our study demonstrated that XRCC2 might play an important role in CRC and function as a novel prognostic indicator and that the down-regulation of XRCC2 may be useful for sensitizing CRC cells during 5-FU chemotherapy.

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Section: Discussionsupporting

confidence: 51%

XRCC2-Deficient Cells are Highly Sensitive to 5-Fluorouracil in Colorectal Cancer

Zhang¹,

An²,

Liu³

et al. 2017

Cell Physiol Biochem

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“…XRCC2 gene product is a paralogue of RAD51 protein, involved in DNA DSB repair via HR [59]. Knockdown of XRCC2 in colon carcinoma cells decreased cell proliferation, increased apoptosis and lead to cell cycle arrest induced by irradiation [60]. XRCC2 is also involved in the regulation of replication fork progression to prevent DNA damage and genomic instability [61].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of different response to ionizing irradiation in isogenic head and neck cancer cell lines

et al. 2019

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Background: Treatment options for recurrent head and neck tumours in the previously irradiated area are limited, including re-irradiation due to radioresistance of the recurrent tumour and previous dose received by surrounding normal tissues. As an in vitro model to study radioresistance mechanisms, isogenic cells with different radiosensitivity can be used. However, they are not readily available. Therefore, our objective was to establish and characterize radioresistant isogenic human pharyngeal squamous carcinoma cells and to evaluate early radiation response in isogenic parental, radioresistant and radiosensitive cells. Methods: Radioresistant cells were derived from parental FaDu cells by repeated exposure to ionizing radiation. Radiosensitivity of the established isogenic radioresistant FaDu-RR cells was evaluated by clonogenic assay and compared to isogenic parental FaDu and radiosensitive 2A3 cells. Additional phenotypic characterization of these isogenic cells with different radiosensitivity included evaluation of chemosensitivity, cell proliferation, cell cycle, radiation-induced apoptosis, resolution of DNA double-strand breaks, and DNA damage and repair signalling gene expression before and after irradiation. Results: In the newly established radioresistant cells in response to 5 Gy irradiation, we observed no alteration in cell cycle regulation, but delayed induction and enhanced resolution of DNA double-strand breaks, lower induction of apoptosis, and pronounced over-expression of DNA damage signalling genes in comparison to parental cells. On the other hand, radiosensitive 2A3 cells were arrested in G 2 /M-phase in response to 5 Gy irradiation, had a prominent accumulation of and slower resolution of DNA double-strand breaks, and no change in DNA damage signalling genes expression. Conclusions: We concluded that the emergence of the radioresistance in the established radioresistant isogenic cells can be at least partially attributed to the enhanced DNA double-strand break repair, altered expression of DNA damage signalling and repair genes. On the other hand, in radiosensitive isogenic cells the reduced ability to repair a high number of induced DNA double-strand breaks and no transcriptional response in DNA damage signalling genes indicate on a lack of adaptive response to irradiation. Altogether, our results confirmed that these isogenic cells with different radiosensitivity are an appropriate model to study the mechanisms of radioresistance.

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“…The cell cycle progression and arrest in response to irradiation may determine the sensitivity of cells to irradiation. 31 Jérome Doyen et al 25 demonstrated that silencing of CAIX resulted in decreased number of cells in the radioresistant S phase and showed a 50% increase in cell death induced by radiation. This led to the conclusion that absence of CAIX was related with radiosensitivity, and the probable mechanism was thought to be by decreasing the proportion of cells in the S phase of cell cycle because of problems in the DNA double-strand break repair systems, such as homologous recombination, that usually occur in the S phase.…”

Section: Discussionmentioning

confidence: 99%

RNAi-mediated knockdown of CAIX enhances the radiosensitivity of nasopharyngeal carcinoma cell line, CNE-2

Liji

et al. 2017

OTT

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Although radiotherapy remains the most powerful as well as the primary treatment modality for nasopharyngeal carcinoma (NPC), approximately 20% of NPC patients still have local recurrence. Carbonic anhydrase IX (CAIX)-related signaling pathways that mediate radioresistance have been found in various kinds of cancer. However, the role of CAIX in NPC radioresistance is still unknown. In this study, we investigated the effect of CAIX silencing on sensitization to ionizing radiation in NPC by using Lipofectamine 2000, which delivers small interfering ribonucleic acid (siRNA) that targets CAIX. Results showed that Lipofectamine 2000 effectively delivered siRNA into the CNE-2 cells, which resulted in the decrease of CAIX expression and cell viability, decrease in cell proliferation and colony formation, and increase in the number of CNE-2 cells stuck in the G2/M phase of the cell cycle upon induction of ionizing radiation. Increased sensitivity of radiotherapy in CNE-2 cells under hypoxic conditions was correlated with the suppression of CAIX. Cells treated with irradiation in addition to CAIX-siRNA1 demonstrated reduced radiobiological parameters (survival fraction at 2 Gy [SF2]) compared with those treated with irradiation only, with a sensitization-enhancing ratio of 1.47. These findings suggest that CAIX can be a promising therapeutic target for the treatment of radioresistant human NPC.

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shRNA-Mediated XRCC2 Gene Knockdown Efficiently Sensitizes Colon Tumor Cells to X-ray Irradiation in Vitro and in Vivo

Cited by 10 publications

References 22 publications

XRCC2-Deficient Cells are Highly Sensitive to 5-Fluorouracil in Colorectal Cancer

XRCC2-Deficient Cells are Highly Sensitive to 5-Fluorouracil in Colorectal Cancer

Mechanisms of different response to ionizing irradiation in isogenic head and neck cancer cell lines

RNAi-mediated knockdown of CAIX enhances the radiosensitivity of nasopharyngeal carcinoma cell line, CNE-2

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