Title | Doxycycline-induced exogenous Bmi-1 expression enhances tumor formation in a murine model of oral squamous cell carcinoma. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Kalish JM, Tang X-H, Scognamiglio T, Zhang T, Gudas LJ |
Journal | Cancer Biol Ther |
Volume | 21 |
Issue | 5 |
Pagination | 400-411 |
Date Published | 2020 05 03 |
ISSN | 1555-8576 |
Keywords | 4-Nitroquinoline-1-oxide, Animals, Anti-Bacterial Agents, Carcinogenesis, Carcinogens, Disease Models, Animal, Doxycycline, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Polycomb Repressive Complex 1, Proto-Oncogene Proteins, Squamous Cell Carcinoma of Head and Neck |
Abstract | B Cell-Specific Moloney Murine Leukemia Virus Integration Site 1 (Bmi-1, Bmi1), an epigenetic protein, is necessary for normal stem cell self-renewal in adult animals and for cancer stem cell (CSC) functions in adult animals. To elucidate the functions of Bmi-1 in the oral cavity we created a transgenic mouse line (KrTBmi-1) that expresses ectopic, Flag-tagged Bmi-1 in tongue basal epithelial stem cells only upon doxycycline (DOX) treatment. Genome wide transcriptomics and Ingenuity Pathway Analysis identified several pathways altered by exogenous Bmi-1 expression in the normal tongue epithelium, including EIF2 signaling ( value = 1.58 x 10), mTOR signaling ( value = 2.45 x 10), oxidative phosphorylation ( = 6.61 x 10) and glutathione redox reactions I ( = 1.74 x 10). Overall, our data indicate that ectopic Bmi-1 expression has an impact on normal tongue epithelial homeostasis. We then assessed the KrTBmi-1 mice in the 4-nitroquinoline 1-oxide (4-NQO) model of oral carcinogenesis. We found that 80% of mice expressing exogenous Bmi-1 (+DOX, +4-NQO KrTBmi-1; N = 10) developed tumors classified as grade 3 or higher, compared to 60% and 40% of mice expressing just endogenous Bmi-1 (+DOX, +4-NQO Kr and -DOX, +4-NQO KrTBmi-1 groups, respectively; N = 10/group; value = <0.0001); and 30% of mice expressing ectopic Bmi-1 mice developed 20 or more lesions compared to 10% of mice expressing only endogenous Bmi-1 ( = .009). This demonstrates that exogenous Bmi-1 expression increases the susceptibility of mice to 4-NQO-induced oral carcinogenesis, strengthening the evidence for Bmi-1 as a therapeutic target in human oral squamous cell carcinoma. |
DOI | 10.1080/15384047.2020.1720485 |
Alternate Journal | Cancer Biol Ther |
PubMed ID | 32037955 |
PubMed Central ID | PMC7515545 |
Grant List | R01 DE024394 / DE / NIDCR NIH HHS / United States T32 GM073546 / GM / NIGMS NIH HHS / United States F31 DE024925 / DE / NIDCR NIH HHS / United States |
Related Faculty:
Theresa Scognamiglio, M.D.