Presentation Lack of XRCC4 Remarkably Sensitizing Radioresistant Human Colon Cancer Stem-Like Cells to X-rays and Carbon Ion Beams

崔, 星  ,  Vares, Guillaume

XRCC4, a member of NHEJ for double strand breaks, is very important in maintaining the overall genome stability, and may play an important role in tumor initiation and progression. In the present study, we try to elucidate how lack of XRCC4 affects cancer stem cell (CSC) properties and radiosensitivity of CSCs to X-ray and carbon ion beam. Putative cancer stem cells sorted from HCT116-wild type (WT) and XRCC4 knockout (KO) cells were treated with or without carbon ion beam or X-ray irradiation and then colony and spheroid formation assay, FACS analysis, gamma-H2AX foci assay were performed. FACS analysis showed that the CSCs (CD133+, CD44+/ESA+) were significantly altered in XRCC4 KO cells compared to HCT116-WT cells. The number of colony and spheroid formed from CSCs were significantly higher compared to that from non-CSCs in XRCC4 KO cells, but extremely decreased compared to HCT116-WT cells. The proportion of CSCs was more extremely increased in XRCC4 KO cells compared to HCT116-WT cells after X-ray irradiation. Survival fraction analysis showed that lack of XRCC4 remarkably sensitized HCT116 cells to both X-ray and carbon ion beam irradiation (the doses at D10 levels of CSCs sorted from XRCC4-KO and HCT116-WT cells were 1.4 and 4.2 Gy for X-ray and 1.0 and 1.9 Gy for carbon ion beam, respectively). A much more large number and large-sized gamma-H2AX foci were observed in CSCs sorted from XRCC4 KO cells compared to that from HCT116-WT cells, after 24 h carbon ion beam compared to X-ray irradiation. Taken together, lack of XRCC4 significantly interfered with expression of CSC markers, radiosensitized CSCs to both X-ray and carbon ion beam, implying that targeted inhibition of XRCC4 has emerged as an attractive strategy in eliminating radioresistant CSCs.

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