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

Abstract

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 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).

CONCLUSION:

Higher levels of BMI1 are associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT.

• Authors: Yin-Chou Hsu, Chi-Wen Luo, Wei-Lun Huang, Chun-Chieh Wu, Chia-Lin Chou, Chih-I Chen, Shu-Jyuan Chang, Chee-Yin Chai, Hui-Ching Wang, Tzu-Yi Chen, Chien-Feng Li, Mei-Ren Pan
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 149 Pg. 249-258 (08 2020) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 32592893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• BMI1 protein, human
• Biomarkers, Tumor
• Bmi1 protein, mouse
• KLF4 protein, human
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Proto-Oncogene Proteins
• Polycomb Repressive Complex 1

Topics

• Animals
• Biomarkers, Tumor
• Chemoradiotherapy (adverse effects)
• Humans
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Mice
• Neoadjuvant Therapy
• Polycomb Repressive Complex 1 (genetics)
• Prognosis
• Proto-Oncogene Proteins (genetics)
• Rectal Neoplasms (drug therapy, therapy)