The Relationship Between LIN28B and RAN

LIN28B is a gene involved in normal cell development. It allows cells to develop normally and then differentiate.

When the gene is overexpressed, however, it contributes to the development of malignancies. Using a large neuroblastoma tumor database, for which gene expression information was available, researchers at the Center for Childhood Cancer Research, including Robert W. Schnepp, MD, PhD, looked at samples that had LIN28B expressed in an attempt to elucidate the biochemical pathways that drove the development of neuroblastoma. 

They characterized the samples by the amount of gene expression present, low versus high. They noticed that in cells where there was a high expression of LIN28B, there was a correspondingly high amount of RAS-related nuclear protein (RAN), a protein that had not been thoroughly characterized in the context of cancer.

In an attempt to determine causative effect, scientists used in vitro techniques to see what would happen if LIN28B was increased or decreased. They found corresponding increases and decreases in RAN, respectively, suggesting that LIN28B directly regulated RAN. 

Researchers showed that LIN28B binds directly to the RNA responsible for the synthesis of RAN, hence promoting its expression. RAN, they found, was directly responsible for the phosphorylation of aurora kinase A, a protein that was known to be involved in cancer but whose regulation was poorly understood. Thus these findings linked together LIN28B, RAN and AURKA in a pathway, which had not been previously done.

Elucidation of this pathway offers potential targets for therapeutic intervention, although at present there are no inhibitors of LIN28B or RAN. There is, however, an inhibitor for a RAN-associated protein (CRM1), and there is presently an aurora kinase A inhibitor that has shown some promise in the treatment of neuroblastoma. It is possible that using a combination of these inhibitors could constitute an effective chemotherapeutic intervention in neuroblastoma and perhaps other malignancies (but further investigation is required/ongoing).