Hsu Yin-Chou, Luo Chi-Wen, Huang Wei-Lun, Wu Chun-Chieh, Chou Chia-Lin, Chen Chih-I, Chang Shu-Jyuan, Chai Chee-Yin, Wang Hui-Ching, Chen Tzu-Yi, Li Chien-Feng, Pan Mei-Ren
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Radiother Oncol. 2020 Aug;149:249-258. doi: 10.1016/j.radonc.2020.06.023. Epub 2020 Jun 24.
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.
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.
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).
Higher levels of BMI1 are associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT.
新辅助同步放化疗（CCRT）是II/III期直肠癌患者的金标准治疗方法。B细胞特异性莫洛尼鼠白血病病毒插入位点1（BMI1）是参与调节基因表达的多梳蛋白家族成员。已证明高水平的BMI1促成几种癌症的恶性表型；然而，其在接受CCRT治疗的直肠癌中的相关性很大程度上未知。
我们使用两个患者队列来探讨BMI1在人类癌症中的临床相关性。此外，选择HT-29和HCT-116细胞作为我们的体外模型，以验证BMI1在细胞对电离辐射反应中的作用。通过蛋白质印迹分析干性相关蛋白，并使用克隆形成试验确定细胞存活率。
发现BMI1过表达与治疗前晚期淋巴结状态（N1-N2；p<0.001）、治疗后肿瘤分期（T1-T2；p=0.015）、较差的肿瘤退缩分级（p=0.001）显著相关，并且也是172例接受CCRT的直肠癌患者的独立预后因素。基于细胞的系列功能检查表明，BMI1缺陷通过调节Kruppel样因子4（KLF4）的基因表达使细胞对放射治疗敏感，并增强了微卫星稳定（MSS）结直肠癌的放射敏感性。KLF4的过表达部分克服了电离辐射暴露后BMI1缺陷介导的γ-H2AX表达。与体外数据一致，对另外30例直肠癌组织标本的分析显示BMI1与KLF4之间呈正相关（p=0.02）。
在接受CCRT的直肠癌患者中，较高水平的BMI1与较差的治疗反应和不良预后相关。
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