Abstract
The RNA-binding protein LIN28A regulates the translation and stability of a large number of mRNAs as well as the biogenesis of certain miRNAs in embryonic stem cells and developing tissues. Increasing evidence indicates that LIN28A functions as an oncogene promoting cancer cell growth. However, little is known about its molecular mechanism of cell cycle regulation in cancer. Using tissue microarrays, we found that strong LIN28A expression was reactivated in about 10% (7.1-17.1%) of epithelial tumors (six tumor types, n = 369). Both in vitro and in vivo experiments demonstrate that LIN28A promotes cell cycle progression in cancer cells. Genome-wide RNA-IP-chip experiments indicate that LIN28A binds to thousands of mRNAs, including a large group of cell cycle regulatory mRNAs in cancer and embryonic stem cells. Furthermore, the ability of LIN28A to stimulate translation of LIN28A-binding mRNAs, such as CDK2, was validated in vitro and in vivo. Finally, using a combined gene expression microarray and bioinformatics approach, we found that LIN28A also regulates CCND1 and CDC25A expression and that this is mediated by inhibiting the biogenesis of let-7 miRNA. Taken together, these results demonstrate that LIN28A is reactivated in about 10% of epithelial tumors and promotes cell cycle progression by regulation of both mRNA translation (let-7-independent) and miRNA biogenesis (let-7-dependent).
Highlights
LIN28A may function as a critical oncogene in human cancer
Strong LIN28A expression was detected in ϳ10% (7.1– 17.1%) of cases in all six tumor types (Fig. 1): breast (10.1%), colon (8.6%), liver (7.1%), lung (7.1%), ovarian (17.1%), and pancreatic cancer (15.0%)
To confirm that LIN28A was expressed in tumor cells, we examined LIN28A expression in a collection of human breast (n ϭ 17) and ovarian (n ϭ 19) cancer cell lines by real-time RT-PCR and Western blots
Summary
LIN28A may function as a critical oncogene in human cancer. Results: LIN28A controls expression of numerous cell cycle regulatory genes, including CDK2, CCND1, and CDC25A, in cancer. We found that strong LIN28A expression was reactivated in about 10% (7.1–17.1%) of epithelial tumors (six tumor types, n ؍369) Both in vitro and in vivo experiments demonstrate that LIN28A promotes cell cycle progression in cancer cells. Using a combined gene expression microarray and bioinformatics approach, we found that LIN28A regulates CCND1 and CDC25A expression and that this is mediated by inhibiting the biogenesis of let-7 miRNA Taken together, these results demonstrate that LIN28A is reactivated in about 10% of epithelial tumors and promotes cell cycle progression by regulation of both mRNA translation (let-7-independent) and miRNA biogenesis (let-7-dependent). Genome-wide RNA-IP-chip experiments demonstrate that LIN28A binds to thousands of mRNAs, including a large group of genes involved in cell cycle regulation, such as CDK2. We found that LIN28A regulates CCND1 and CDC25A expression and that this is mediated via the inhibition of let-7 miRNA biogenesis
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