The RNA-Binding Protein LIN28B Drives Liver Tumorigenesis

LIN28A and LIN28B are RNA-binding proteins that regulate growth, metabolism, and stem-cell maintenance during embryonic development via the regulation of a network of RNAs, such as the let-7 family of tumor suppressor miRNAs. In addition, overexpression of LIN28A and LIN28B is associated with poor prognosis in many advanced cancers, including liver cancer; however, the role of these proteins in endogenous liver tumorigenesis, as well as whether they represent therapeutic targets, is unclear. Nguyen, Robinton, Seligson, and colleagues found that hepatocyte-specific overexpression of LIN28B was sufficient to induce liver tumors that were pathologically similar to aggressive human hepatocellular carcinoma (HCC) and pediatric hepatoblastoma and that exhibited a poorly differentiated histology, embryonic hematopoiesis, expression of fetal markers, and a high mitotic index. Furthermore, LIN28B expression was significantly induced in mouse models of MYC-driven hepatoblastoma and was associated with suppression of let-7, suggesting that LIN28B may promote liver tumor formation by reactivating embryonic growth programs. Consistent with this idea, genetic deletion of Lin28a/b decreased MYC-induced tumor growth and prolonged survival. Furthermore, sustained LIN28B expression was required for tumor maintenance in these mouse models, as conditional genetic ablation or siRNA-mediated depletion of Lin28b induced apoptosis and impaired MYC-driven hepatoblastoma growth. The ability of LIN28B to promote liver tumorigenesis was mediated in part by suppression of let-7 family members, but was also dependent on let-7–independent mechanisms, and required upregulation of insulin-like growth factor 2 mRNA binding protein 3 (Igf2bp3), which is highly expressed in human liver tumors. LIN28B and IGF2BP3 were coexpressed in advanced human HCCs, and IGF2BP3 expression was necessary for enhanced cell proliferation in the context of LIN28B overexpression. These findings identify LIN28B as an oncogenic driver in liver cancer and suggest that targeted inhibition of this RNA-binding protein may be an effective therapeutic strategy.

Nguyen LH, Robinton DA, Seligson MT, Wu L, Li L, Rakheja D, et al. Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell 2014;26:248–61.