A study published recently in the journal Science Translational Medicine, conducted by researchers at the National University of Singapore (Singapore, Malaysia) in collaboration with Harvard Stem Cell Institute (MA, USA), has identified the oncogenic protein BMI1 as a potential new therapeutic target within a new subtype of lung adenocarcinoma – a type of non-small-cell lung cancer (NSCLC).
The team had previously discovered that NSCLC cells frequently express little or no C/EBPα, a transcription factor thought to act as a tumor suppressor. However, the mechanism by which C/EBPα achieved this was unknown. In this current study, the team demonstrated that C/EBPα carries out its tumor-suppressing effects by limiting the expression of an oncogenic protein termed BMI1.
To reach this conclusion, the team first altered a line of human adenocarcinoma cells to overexpress C/EBPα, resulting in a marked reduction in the expression of BMI1.
The researchers then studied tissue from 261 NSCLC patients, determining that when tumors expressed low levels of C/EBPα, in excess of 80% were positive for BMI1 expression. They also utilized tissue samples from lung adenocarcinoma patients who expressed no or low levels of C/EBPα and confirmed that those patients with lower levels of BMI1 were more likely to survive.
To affirm their findings the team then conducted a preclinical study in mice engineered to express no C/EBPα, in which they demonstrated that decreasing BMI1 expression was enough to fully inhibit tumor formation and even significantly arrest tumor growth.
Overall, these findings show a pattern of prognostic value and demonstrate that restraining the expression of BMI1 in certain NSCLC patient cohorts could have the potential to inhibit tumor formation and significantly arrest tumor growth.
Lead author Elena Levantini commented: “BMI1 plays a substantial role in many solid tumors, including one of the most aggressive models of lung cancer, and its expression is linked with tumor growth, invasion, metastasis, prognosis and recurrence. Our findings could help us design better therapies for the subset of adenocarcinoma patients with low C/EBPα and high BMI1 expression pattern.”
Sources: Neuberg D, Tenen DG, Levantini E et al. Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression Sci. Transl. Med. DOI: 10.1126/scitranslmed.aad6066 (2016); Beth Israel Deaconess Medical Center press release