Journal
RADIOTHERAPY AND ONCOLOGY
Volume 149, Issue -, Pages 249-258Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.radonc.2020.06.023
Keywords
BMI1; CCRT; Rectal cancers; Radioresistance
Funding
- Ministry of Science and Technology of Republic of China [106-2314-B-037-049-MY3, 109-2310-B-037-019, 109-2314-B-650-005-MY3]
- Kaohsiung Medical University [KMU-DK109003similar to1]
- KMU-KMUH Co-Project of Key Research [KMU-DK107013]
- KMUH [KMUH106-6M12]
- Taiwan Ministry of Health and Welfare [MOHW106-TDU-B-212-144007, MOHW107-TDU-B-212 -114020]
- E-Da Hospital, Kaohsiung, Taiwan [EDAHP107003]
- Health and Welfare surcharge of tobacco products
- Bio-Bank, Medical Research Department, E-DA Hospital
- Cancer Database of E-DA Hospital in Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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Purpose: Neoadjuvant concurrent chemoradiotherapy (CCRT) is a gold standard treatment for patients with stage II/III rectal cancer. B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) is a member of the polycomb group of proteins that are involved in regulating gene expression. High levels of BMI1 have been demonstrated to contribute to the malignant phenotypes of several cancers; however, its relevance in rectal cancer treated with CCRT is largely unknown. Methods and materials: We used two patient cohorts to address the clinical relevance of BMI1 in human cancers. In addition, HT-29 and HCT-116 cells were chosen as our in vitro models to verify the role of BMI1 in cell response to ionizing radiation. Stemness-related proteins were analyzed by western blotting and cell survival was determined using clonogenic assays. Results: BMI1 overexpression was found to significantly correlate with advanced pre-treatment nodal status (N1-N2; p < 0.001), post-treatment tumor stage (T1-T2; p = 0.015), inferior tumor regression grade (p = 0.001), and also an independent prognosis factor in 172 rectal cancer patients receiving CCRT. Serial cell-based functional examination indicated that BMI1 deficiency sensitized cells to radiation treatment by modulating the gene expression of Kruppel-like factor 4 (KLF4) and enhanced radiosensitivity in microsatellite stable (MSS) colorectal cancers. Overexpression of KLF4 partially overcame BMI1-deficiency-mediated gamma-H2AX expression after ionizing radiation exposure. Consistent with in vitro data, an analysis of an additional 30 rectal cancer tissue specimens revealed a positive correlation between BMI1 and KLF4 (p = 0.02). Conclusion: Higher levels of BMI1 are associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT. (C) 2020 Elsevier B.V. All rights reserved.
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