Loss of let-7 binding sites resulting from truncations of the 3 ' untranslated region of HMGA2 mRNA in uterine leiomyomas

Center for Human Genetics, University of Bremen, Leobener Strasse ZHG, 28359 Bremen, Germany.
Cancer genetics and cytogenetics (Impact Factor: 1.93). 01/2010; 196(2):119-23. DOI: 10.1016/j.cancergencyto.2009.09.021
Source: PubMed

ABSTRACT A subset of uterine leiomyomas (UL) shows chromosomal rearrangements of the region 12q14 approximately q15, leading to an overexpression of the high-mobility group protein A2 gene (HMGA2). Recent studies identified microRNAs of the let-7 family as post-transcriptional regulators of HMGA2. Intragenic chromosomal breakpoints might cause truncated HMGA2 transcripts lacking part of the 3' UTR. The corresponding loss of let-7 complementary sites (LCS) located in the 3' UTR would therefore stabilize HMGA2 mRNA. The aim of this study was to check UL with rearrangements of the chromosomal region 12q14 approximately 15 for truncated HMGA2 transcripts by real-time reverse-transcription polymerase chain reaction. In 8/13 leiomyomas with aberrations of chromosomal region 12q15, the results showed the presence of the complete 3' UTR with all LCS. A differential expression with highly reduced 3' untranslated region levels was found in 5/13 myomas. In two of these, full-length transcripts were almost undetectable. Truncated transcripts were apparently predominant in roughly one-third of UL with chromosomal rearrangements affecting the HMGA2 locus, where they lead to a higher stability of its transcripts and subsequently contribute to the overexpression of the protein. The assay used is also generally suited to detect submicroscopic alterations leading to truncated transcripts of HMGA2.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Noncoding RNAs are key players in the regulation of complex cellular processes. Over the years, it has been demonstrated that their abnormal expression is associated with many human pathologies including developmental and neurobehavioral disorders, diabetes, obesity, and cancer. A wide spectrum of activities and a large number of genes that are regulated by RNA-dependent mechanisms makes the ncRNA molecules attractive targets for developing next generation therapeutic agents. This chapter outlines the principles of RNA regulation, the involvement of various RNAs in human diseases, and the strategies of application of ncRNA-targeted therapeutic approaches. KeywordsCancer-Noncoding RNAs-Therapy
    09/2010: pages 393-418;
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Human leiomyomata (fibroids) are benign tumors of the uterus, represent the most common neoplasms of reproductive-aged women and have a prevalence of ∼70% in the general population. This disorder conveys a significant degree of morbidity and remains the leading indication for hysterectomy in the USA. Prior investigations of aberrant microRNA (miRNA) expression in various malignancies have provided invaluable insight into the role of this class of small non-coding RNAs in tumor growth. Evidence of irregular miRNA expression in uterine fibroids has garnered recent interest for diagnostic and therapeutic applications. Since miRNA gene targets modulate several processes implicated in the genesis of uterine fibroids, more focused investigation has the potential to elucidate the functional significance of miRNA in the genesis and pathology of the disease.METHODS Comprehensive electronic searches of peer reviewed published literature in PubMed (US National Library of Medicine, National Institute of Health; were performed for content related to the biologic functions of miRNA, the roles of miRNA in human disease and studies investigating miRNA in the context of uterine leiomyomata. Herein, this article will review the current evidence supporting the use of miRNA expression profiling as an investigative tool to assess the pathobiology of uterine fibroids and will discuss potential future applications of miRNAs as biomarkers and therapeutic targets.RESULTSMounting evidence supports a functional role for miRNA as either indirect or direct regulators of gene expression which impacts the pathobiology of uterine fibroids. Specifically, miRNAs let-7, 200a, 200c, 93, 106b and 21 have been implicated in cellular proliferation, apoptosis, extracellular matrix turnover, angiogenesis and inflammation. Preliminary data provide evidence to suggest that respective in vitro miRNA expression in leiomyomata and myometrium is regulated by sex steroids.CONCLUSIONS Collectively, the identification of aberrantly expressed miRNAs in uterine leiomyomata and accumulating data derived from mining of gene target prediction models and recent functional studies support the concept that miRNAs might impact the genesis and progression of disease. However, the specific biologic functions of differential miRNA expression have yet to be confirmed in vivo. Further functional studies and developing miRNA technology may provide the basis for future applications of miRNAs in clinical medicine as biomarkers and therapeutic targets.
    Human Reproduction Update 04/2014; 20(5). DOI:10.1093/humupd/dmu017 · 8.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Long-term in vitro maintenance of embryonic stem cell (ESC) pluripotency enables the pluripotency and differentiation of ESCs in animals to be investigated. The ability to successfully maintain and differentiate chicken embryonic stem cells (cESCs) would provide a useful tool for avian biology research and would be a resource directly applicable to agricultural production. In this study, endogenous chicken pluripotency transcription factors, POUV, Sox-2, Nanog and Lin28 were cloned and expressed as recombinant proteins containing a nine consecutive arginine protein transduction domain (PTD). cESCs were cultured with these recombinant proteins to maintain cESC pluripotency in vitro. Cultured cESCs exhibited typical characteristics of pluripotency, even after six generations of rapid doubling, including positive staining for stage-specific embryonic antigen I, and strong staining for alkaline phosphatase. Expression levels of the pluripotency markers, POUV, Nanog, C-Myc, Sox-2 and Lin28 were the same as in uncultured stage X blastoderm cells, and most significantly, the formation of embryoid bodies (EBs) by 6th generation cESCs confirmed the ability of these cultured cESCs to differentiate into cells of all three embryonic germ layers. Thus, transcription factors could be translocated through the cell membrane into the intracellular space of cESCs by using a PTD of nine consecutive arginines and the pluripotency of cESCs could be maintained in vitro for at least six generations.
    Science China. Life sciences 01/2013; 56(1):40-50. DOI:10.1007/s11427-012-4426-4 · 1.51 Impact Factor