Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop.

Oncogene (Impact Factor: 8.56). 02/2012; doi: 10.1038/onc.2012.28. [Epub ahead of print].

ABSTRACT Dysregulated microRNAs (miRNAs) have an important role in many malignant tumors. However, elucidating the roles of miRNAs in cancer biology, especially in epithelial cancers, remains an ongoing process. In this study, we show that both miR-143 and miR-145, which belong to the same miRNA cluster, can negatively modulate expression of their target gene, MDM2. The miR-143 and miR-145 is posttranscriptionally activated by upregulated p53, thereby generating a short miRNAs-MDM2-p53 feedback loop. Re-expression of these miRNAs suppresses cellular growth and triggers the apoptosis of epithelial cancer, in vitro and in vivo, by enhancing p53 activity via MDM2 turnover. Moreover, the miRNA-dependent MDM2 turnover contributes to the equilibrium of repeated p53 pulses in response to DNA damage stress. These findings suggest that MDM2 dysregulation caused by downregulation of miR-143 and miR-145 contributes to epithelial cancer development and has a key role in regulating cellular proliferation and apoptosis. Re-expression of miR-143 and miR-145 may be a reasonable strategy for treatment of epithelial cancers.Oncogene advance online publication, 13 February 2012; doi:10.1038/onc.2012.28.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Significance: The well-studied sequences in the human genome are those of protein-coding genes, which account for only 1-2% of the total genome. However, with the advent of high-throughput transcriptome sequencing technology, we now know that about 90% of our genome is extensively transcribed and that the vast majority of them are transcribed into noncoding RNAs (ncRNAs). It is of great interest and importance to decipher the functions of these ncRNAs in humans. Recent Advances: In the last decade, it has become apparent that ncRNAs play a crucial role in regulating gene expression in normal development, stress responses to internal and environmental stimuli, and in human diseases. Critical Issues: In addition to those constitutively expressed structural RNA, such as ribosomal and transfer RNAs, regulatory ncRNAs can be classified as microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs) and long noncoding RNAs (lncRNAs). However, little is known about the biological features and functional roles of these ncRNAs in DNA repair and genome instability although a number of miRNAs and lncRNAs are regulated in the DNA damage response. Future Directions: A major goal of modern biology is to identify and characterize the full profile of ncRNAs with respect to normal physiological functions and roles in human disorders. Clinically relevant ncRNAs will also be evaluated and targeted in therapeutic applications.
    Antioxidants & Redox Signaling 07/2013; · 8.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteosarcoma (OS) is the most common primary malignant bone tumor, particularly in adolescents and young adults. Early diagnosis remains a significant problem in the clinical treatment of OS as we remain far from a comprehensive understanding of the molecular genetic mechanisms and the biology involved. In addition, microRNAs (miRNAs or miRs), a large family of small non-coding RNAs, may provide a greater understanding of OS as they play a complex role in gene expression regulation in vitro and in vivo. In the current study, the differential expression profiles of miRNAs between OS and osteoblast cell lines were investigated by miRNA microarrays and real-time quantitative PCR (RT-qPCR). A total of 268 miRNAs were identified that were significantly dysregulated in OS compared with the osteoblast cell line, including miR-9, miR-99, miR-195, miR-148a and miR-181a, which had been validated as overexpressed, and miR-143, miR-145, miR-335 and miR-539, which were confirmed to be downregulated. This differential expression may aid future OS diagnosis and prognosis prediction and illustration of the potential mechanisms in the oncogenesis, development and metastasis of OS. Bioinformatic research on these differentially expressed miRNAs suggests that they are able to regulate the biological behaviors of OS in a complex and effective manner. Further study on the function of these miRNAs is likely to provide new insights into OS biology and treatment.
    Oncology letters 11/2012; 4(5):1037-1042. · 0.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: The results of cancer-associated miRNA research have yielded surprising insights into the pathogenesis of a range of different cancers. Many of the dysregulated miRNAs are involved in the regulation of genes that are essential for carcinogenesis. AREAS COVERED: This review discusses the latest discovery of miRNAs acting as oncogenes and tumor suppressor genes, as well as the potential applications of miRNA regulations in cancer therapy. Several translational studies have demonstrated the feasibility of targeting oncogenic miRNAs and restoring tumor-suppressive miRNAs for cancer therapy using in vivo model systems. EXPERT OPINION: miRNAs are extensive regulators of cancer progression. With increasing understanding of the miRNA target genes and the cellular behaviors influenced by them, modulating the miRNA activities may provide exciting opportunities for cancer therapy. Despite the hurdles incurred in acquiring effective systemic drug delivery systems, in vivo delivery of miRNAs for therapeutic purposes in preclinical animal models is rapidly developing. Accumulating evidences indicate that using miRNA expression alterations to influence molecular pathways has the potential of being translated into clinical applications.
    Expert Opinion on Therapeutic Targets 06/2012; 16(8):747-59. · 4.90 Impact Factor


Available from
May 28, 2014