Linkage between Twist1 and Bmi1: Molecular mechanism of cancer metastasis/stemness and clinical implications

1. Cancer metastasis is the major cause of cancer-related death despite significant improvements in multimodal cancer therapy. Epithelialmesenchymal transition (EMT), a major mechanism of cancer metastasis, is a process that generates cells with stem cell-like properties (cancer stemness). 2. Cancer stemness is a concept that describes a minor population of cells (cancer stem cells) residing within a tumour that are able to self-renew and are resistant to conventional therapy. The mechanisms delineating the generation of cancer stemness and its connection to cancer metastasis remain largely unknown. 3. Twist1 is an EMT regulator and increased Twist1 expression, which has prognostic significance in various human cancers, has been widely reported. Bmi1 is a critical component of polycomb repressive complex (PRC) 1, which maintains self-renewal and stemness. Bmi1 is frequently overexpressed in different types of human cancers and can induce drug resistance (Table 2). 2 Expression and clinical implication of Twist1 and Bmi1 in human cancers Cancer site Twist1 overexpression Bmi1 overexpression Head and neck squamous cell carcinoma Metastasis Poor overall survival Poor overall survival Breast carcinoma Poor overall survival Poor overall survival Cervical carcinoma Poor overall survival Poor overall survival Gastric cancer Histological type Poor overall survival Hepatocarcinomas Distant metastasis Recurrence Poor overall survival Non-small cell lung cancer Poor overall survival Tumour progression Poor overall survival Colon cancer Tumour progression Poor overall survival Poor overall survival Bladder cancer Poor progression-free survival Poor overall survival Oesophageal squamous cell carcinoma Distant metastasis Poor overall survival Poor overall survival Ovarian cancer Tumour progression Poor overall survival Prostate cancer Metastasis Chronic myeloid leukaemia Disease progression Medulloblastoma Poor overall survival 4. Recent studies have shown that Twist1 directly activates Bmi1 expression and that these two molecules function together to mediate cancer stemness and EMT. These results present a unique mechanism of EMT-induced cancer metastasis and stemness. 5. Further investigation of the mechanisms of EMT-mediated cancer metastasis and stemness will contribute to the management and treatment of metastatic cancers.