Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28

Abstract

Tristetraprolin (TTP) is a AU-rich element (ARE) binding protein and exhibits suppressive effects on cell growth through down-regulation of ARE-containing oncogenes. The let-7 microRNA has emerged as a significant factor in tumor suppression. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. In this work, an unexpected link between TTP and let-7 has been found in human cancer cells. TTP promotes an increase in expression of mature let-7, which leads to the inhibition of let-7 target gene CDC34 expression and suppresses cell growth. This event is associated with TTP-mediated inhibition of Lin28, which has emerged as a negative modulator of let-7. Lin28 mRNA contains ARE within its 3′-UTR and TTP enhances the decay of Lin28 mRNA through binding to its 3′-UTR. This suggests that the TTP-mediated down-regulation of Lin28 plays a key role in let-7 miRNA biogenesis in cancer cells.

Systematic Analysis of AU-Rich Element Expression in Cancer Reveals Common Functional Clusters Regulated by Key RNA-Binding Proteins

“…A deficiency of TTP can lead to the increased growth of cancer cells, because TTP targets those mRNAs involved in cellular proliferation, such as the previously identified cyclin D1 myc, E2F1, and IL6 (32,33) and also the M cell cycle ARE-mRNAs newly identified here. Modulation of TTP in breast and other cancer cells by ectopic expression impacts cellular growth and attenuates tumor xenografts in mice (28,34,35), which is in agreement with the patients' data here.…”

Tristetraprolin: a novel mediator of the anticancer properties of resveratrol

“…TTP can reduce the protein expression of a variety of cytokines by promoting mRNA degradation. Upregulation of TTP is a new method of cancer prevention (Griseri et al, 2011;Kim et al, 2012). TTP expression can be regulated through NF-kB, p38MAPK, STATs and other signaling pathways Joe et al, 2011).…”

The LIN28/let-7 Pathway in Cancer

“…Intriguingly, TTP was shown to increase levels of mature let-7a, let-7b, let-7f, and let-7g miRNA by post-transcriptionally inhibiting LIN28A expression in ovarian cancer cells. Overexpression of TTP in PA1 ovarian cancer cells successfully suppressed cell growth via let-7b-meidated inhibition of CDC34, which is a downstream target gene of the let-7 family (Kim et al, 2012). In another study, depletion of LIN28A by shRNA reduced in vitro invasion ability of bone metastatic breast cancer cells (Dangi-Garimella et al, 2009).…”