BMI1-KLF4 axis deficiency improves responses to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer

Abstract

PurposeNeoadjuvant 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 materialsWe 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. ResultsBMI1 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 γ-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). ConclusionHigher levels of BMI1 are associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT.