The Role of LIN28B-let-7-PBK Axis on the Growth and Metastasis of Group 3 Medulloblastoma
Shubin Shahab, MD/PhD
Young Investigator Grants
Type of Childhood Cancer:
Medulloblastoma (MB) is the most common cancerous brain tumor in children and is often fatal. The most aggressive MBs, those designated as Group 3 (G3), often present with metastasis and frequently recur after standard therapy. The pathways that contribute to this aggressive behavior are poorly understood. LIN28B is a protein known to promote the aggressive nature of many cancers. We have recently found that LIN28B levels are high in some G3 MB patients, and that this is associated with worse outcome, suggesting a similar role in this brain tumor. In preliminary experiments, we have found that reducing the levels of LIN28B and PBK, a protein regulated by LIN28B, in G3 MB cells causes them to divide slower; while, increasing the level of LIN28B makes these cells divide faster. LIN28B also regulates the levels of a set of microRNAs that in turn are important regulators of cancer. In this case, we find LIN28B regulating a microRNA let-7 that regulates PBK. In addition LIN28B may also be contributing to the ability of G3 MB cells to metastasize through its effects on PBK and let-7 and other proteins/RNAs. These experiments suggest that LIN28B and proteins/RNAs regulated by it may be involved in the development of G3 MBs, and that targeting these proteins may offer a new approach to treating this disease.
In this proposal we propose to:
1) Characterize the role of LIN28B-PBK-let-7 pathway in G3 MB by increasing or decreasing PBK and let-7 and measuring proliferation, cell death and cell cycle
2) To characterize the most important proteins/RNAs that contribute to LIN28B mediated metastasis in G3 MB.