Lin28b Is Sufficient to Drive Liver Cancer and Necessary for Its Maintenance in Murine Models

Abstract

SUMMARY Lin28a/b are RNA-binding proteins that influence stem cell maintenance, metabolism, and oncogenesis. Poorly differentiated, aggressive cancers often overexpress Lin28, but its role in tumor initiation or maintenance has not been definitively addressed. We report that LIN28B overexpression is sufficient to initiate hepatoblastoma and hepatocellular carcinoma in murine models. We also detected Lin28b overexpression in MYC-driven hepatoblastomas, and liver-specific deletion of Lin28a/b reduced tumor burden, extended latency, and prolonged survival. Both intravenous siRNA against Lin28b and conditional Lin28b deletion reduced tumor burden and prolonged survival. Igf2bp proteins are upregulated and Igf2bp3 is required in the context of LIN28B overexpression to promote growth. Thus, multiple murine models demonstrate that Lin28b is both sufficient to initiate liver cancer and necessary for its maintenance.

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…Our data show that while Lin28a overexpression affected both TD and TI antigen-induced IgM production, deletion of the let-7adf cluster only altered TI antigen-induced IgM, suggesting that the let-7-independent functions of Lin28a may contribute to the observed phenotype in response to TD antigen challenge. Indeed, it has been reported that Lin28a protein binds to various mRNAs and regulates their translation (Jiang and Baltimore, 2016;Nguyen et al, 2014;Zhu et al, 2011), although the physiological significance of these findings remains to be determined in future studies. However, it is also possible that other let-7 clusters, although not the let-7bc cluster, might contribute to control of antibody synthesis.…”

“…Whether the multiple let-7 clusters represent a gene redundancy or contribute to different functions in different cellular contexts remains to be fully addressed. In support of a contextual role of individual let-7 gene clusters, liver cell-specific loss of the let-7bc cluster is sufficient to enhance liver regeneration in mice (Nguyen et al, 2014). Conditional depletion of the let-7bc cluster in mouse intestines promotes tumorigenesis of the intestinal epithelium (Madison et al, 2013).…”

Identification of small molecule inhibitors of Zcchc11 TUTase activity

“…[16][17][18] Indeed, Lin28A/B are classical oncogenes that can promote cellular transformation and tumorigenesis when ectopically expressed in vitro and in vivo. 16,[19][20][21] Moreover, depletion of Lin28A or Lin28B expression results in decreased cell proliferation, and invasion in cancer cells and reverts tumorigenesis in mouse model. 16,21,22 Importantly, this oncogenic effect of Lin28A/B can be abrogated when let-7 is reintroduced into these cells, suggesting that Lin28A/B-mediated cellular transformation is directly dependent on let-7 levels.…”

“…16,[19][20][21] Moreover, depletion of Lin28A or Lin28B expression results in decreased cell proliferation, and invasion in cancer cells and reverts tumorigenesis in mouse model. 16,21,22 Importantly, this oncogenic effect of Lin28A/B can be abrogated when let-7 is reintroduced into these cells, suggesting that Lin28A/B-mediated cellular transformation is directly dependent on let-7 levels. 16 Therefore, the Lin28-let-7 oncogenic pathway represents an important novel therapeutic target for effective cancer treatment.…”

Caracterização do efeito anti-neoplásico do butirato em duas linhagens celulares de rato derivadas de tumores hepáticos com diferente ní­vel de diferenciação

“…O lin28b foi descoberto em amostras de HCC humano, cuja expressão encontra-se elevada (GUO et al, 2006). Este aumento tem sido associado com mau prognóstico em tumores de ovário, cólon, pulmão, HCC, adenoma gástrico e carcinoma oral de célula escamosa (WANG et al, 2015) e se considera um gene driver na carcinogênese hepática (NGUYEN et al, 2014). Acredita-se que ele estimule a proliferação de células neoplásicas por meio de ao menos cinco mecanismos: modulação de reguladores do ciclo celular, estimulação de vias de sinalização, ativação de fatores de transcrição, aumento da síntese de proteínas ribossomais e estimulação do metabolismo (THORNTON;GREGORY, 2012;WANG et al, 2015).…”