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Expression of CD44 3'-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis.

ABSTRACT: The non-coding 3'-untranslated region (UTR) plays an important role in the regulation of microRNA (miRNA) functions, since it can bind and inactivate multiple miRNAs. Here, we show the 3'-UTR of CD44 is able to antagonize cytoplasmic miRNAs, and result in the increased translation of CD44 and downstream target mRNA, CDC42. A series of cell function assays in the human breast cancer cell line, MT-1, have shown that the CD44 3'-UTR inhibits proliferation, colony formation and tumor growth. Furthermore, it modulated endothelial cell activities, favored angiogenesis, induced tumor cell apoptosis and increased sensitivity to Docetaxel. These results are due to the interaction of the CD44 3'-UTR with multiple miRNAs. Computational algorithms have predicted three miRNAs, miR-216a, miR-330 and miR-608, can bind to both the CD44 and CDC42 3'-UTRs. This was confirmed with luciferase assays, western blotting and immunohistochemical staining and correlated with a series of siRNA assays. Thus, the non-coding CD44 3'-UTR serves as a competitor for miRNA binding and subsequently inactivates miRNA functions, by freeing the target mRNAs from being repressed.

SUBMITTER: Jeyapalan Z

PROVIDER: S-EPMC3082902 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Expression of CD44 3'-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis.

Jeyapalan Zina Z Deng Zhaoqun Z Shatseva Tatiana T Fang Ling L He Chengyan C Yang Burton B BB

Nucleic acids research 20101210 8

The non-coding 3'-untranslated region (UTR) plays an important role in the regulation of microRNA (miRNA) functions, since it can bind and inactivate multiple miRNAs. Here, we show the 3'-UTR of CD44 is able to antagonize cytoplasmic miRNAs, and result in the increased translation of CD44 and downstream target mRNA, CDC42. A series of cell function assays in the human breast cancer cell line, MT-1, have shown that the CD44 3'-UTR inhibits proliferation, colony formation and tumor growth. Further ...[more]

PMID: 21149267

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Project description:The endonucleolytic cleavage step of the eukaryotic mRNA 3'-end processing is considered imprecise, which leads to heterogeneity of cleavage site (CS) with hitherto unknown function. Contrary to popular belief, we show that this imprecision in the cleavage is tightly regulated, resulting in the CS heterogeneity (CSH) that controls gene expression in antioxidant response. CSH centres around a primary CS, followed by several subsidiary cleavages determined by CS's positions. Globally and using reporter antioxidant mRNA, we discovered an inverse relationship between the number of CS and the gene expression, with the primary CS exhibiting the highest cleavage efficiency. Strikingly, reducing CSH and increasing primary CS usage induces gene expression. Under oxidative stress (we employ three conditions that induce antioxidant response, tBHQ, H2O2, and NaAsO2) conditions, there is a decrease in the CSH and an increase in the primary CS usage to induce antioxidant gene expression. Key oxidative stress response genes (NQO1, HMOX1, PRDX1, and CAT) also show higher CSH compared to the non-stress response genes and that the number of CSs are reduced to impart cellular response to oxidative stresses. Concomitantly, ectopic expression of one of the key antioxidant response gene (NQO1) driven by the primary CS but not from other subsidiary CSs, or reduction in CSH imparts tolerance to cellular oxidative stresses (H2O2, and NaAsO2). Genome-wide CS analysis of stress response genes also shows a similar result. Compromised CSH or CSH-mediated gene control hampers cellular response to oxidative stress. We establish that oxidative stress induces affinity/strength of cleavage complex assembly, increasing the fidelity of cleavage at the primary CS, thereby reducing CSH inducing antioxidant response. Together, our study reports a novel cleavage imprecision- or CSH-mediated anti-oxidant response mechanism that is distinct and operates downstream but in concert with the transcriptional pathway of oxidative stress induction.

Dataset Information

Expression of CD44 3'-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis.

Publications

Expression of CD44 3'-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis.

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