Key Early Changes in Oral Squamous Cell Carcinogenesis Are Accelerated by Ectopic BMI1 Expression

Although 5-year relative survival rates for oral squamous cell carcinoma (OSCC) have moderately increased in the last 30 years, most patients are diagnosed during the later stages of the disease. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a biomarker of OSCC that is increased in epithelial basal stem cells (SC) of premalignant oral lesions. However, the molecular functions of BMI1 in early-stage OSCC have not been fully elucidated. In this study, we used a transgenic mouse line (KrTB) that overexpresses BMI1 in the tongue epithelial SCs to delineate BMI1 actions during these early stages. We observed more oncogenic changes in mice with ectopic BMI1 expression after only a short, 4-week treatment with the carcinogen 4-nitroquinoline 1-oxide (4-NQO). For example, we detected increased proliferation, oxidative stress, and expression of multiple transcripts and proteins linked to human OSCCs in murine tongue epithelia with high, ectopic BMI1 expression. Furthermore, increases in mRNAs encoding multiple metabolic targets, such as SLC16A3, PKM, and GPI1, were greater upon BMI1 overexpression with 4 weeks of 4-NQO treatment. In a human OSCC model (SCC-25 cell line) in which we deleted the BMI1 gene, we observed decreases in proliferation, oxidative stress, and expression of the glycolysis-associated protein GLUT1. Thus, BMI1 expression leads to increases in key features of early-stage, carcinogen-induced tumorigenesis, including metabolic reprogramming. Consequently, limiting BMI1 could be a potential target for cancer prevention approaches that merits further consideration and additional functional studies.

Most OSCC diagnoses occur in advanced stages. Our data indicate that BMI1 overexpression, as detected in premalignant oral lesions, increases proliferation, oxidative stress, and expression of human OSCC-associated targets in our murine model after a short, 4-week carcinogen treatment. Thus, BMI1 could be a potential target for cancer prevention approaches.