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      The Role of the 3' Untranslated Region in the Post-Transcriptional Regulation of KLF6 Gene Expression in Hepatocellular Carcinoma

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          Abstract

          KLF6 is ubiquitously expressed in human tissues and regulates many pathways such as differentiation, development, cellular proliferation, growth-related signal transduction, and apoptosis. We previously demonstrated that KLF6 expression is altered during liver carcinogenesis. More importantly, KLF6 invalidation results in cell cycle progression inhibition and apoptosis of liver cancer cells. On the other hand, enforced expression of KLF6 variant 2 (SV2) induces cancer cell death by apoptosis. Thus, we and others demonstrated that KLF6 and its splicing variants play a critical role in liver cancer. However, little is known on the mechanisms governing KLF6 expression in HCC. In the present work, we asked whether the 3' untranslated region (3'UTR) of the KLF6 mRNA may be responsible for regulation of KLF6 expression in HCC. We found that KLF6 mRNA stability was altered in liver-derived cell lines as compared to cervical cancer-derived cell lines and human embryonic fibroblasts. Interestingly, KLF6 mRNA was highly unstable in liver cancer-derived cell lines as compared to normal hepatocytes. We next cloned the KLF6 mRNA 3'UTR into luciferase-expressing vectors and found that gene expression and activity were strongly impaired in all liver-derived cell lines tested. In addition, we found that most the KLF6 3'UTR destabilisation activity resides between nt 1,835 and nt 2,615 of the KLF6 gene. Taken together, we provide the first steps towards better understanding of the regulation of KLF6 expression in HCC. Further work is needed to identify the factors that bind to KLF6 3'UTR to regulate its expression in liver cancer-derived cell lines.

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          Most cited references25

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          Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.

          Comprehensive identification of all functional elements encoded in the human genome is a fundamental need in biomedical research. Here, we present a comparative analysis of the human, mouse, rat and dog genomes to create a systematic catalogue of common regulatory motifs in promoters and 3' untranslated regions (3' UTRs). The promoter analysis yields 174 candidate motifs, including most previously known transcription-factor binding sites and 105 new motifs. The 3'-UTR analysis yields 106 motifs likely to be involved in post-transcriptional regulation. Nearly one-half are associated with microRNAs (miRNAs), leading to the discovery of many new miRNA genes and their likely target genes. Our results suggest that previous estimates of the number of human miRNA genes were low, and that miRNAs regulate at least 20% of human genes. The overall results provide a systematic view of gene regulation in the human, which will be refined as additional mammalian genomes become available.
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            Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer.

            The Sp/KLF family contains at least twenty identified members which include Sp1-4 and numerous krüppel-like factors. Members of the family bind with varying affinities to sequences designated as 'Sp1 sites' (e.g., GC-boxes, CACCC-boxes, and basic transcription elements). Family members have different transcriptional properties and can modulate each other's activity by a variety of mechanisms. Since cells can express multiple family members, Sp/KLF factors are likely to make up a transcriptional network through which gene expression can be fine-tuned. 'Sp1 site'-dependent transcription can be growth-regulated, and the activity, expression, and/or post-translational modification of multiple family members is altered with cell growth. Furthermore, Sp/KLF factors are involved in many growth-related signal transduction pathways and their overexpression can have positive or negative effects on proliferation. In addition to growth control, Sp/KLF factors have been implicated in apoptosis and angiogenesis; thus, the family is involved in several aspects of tumorigenesis. Consistent with a role in cancer, Sp/KLF factors interact with oncogenes and tumor suppressors, they can be oncogenic themselves, and altered expression of family members has been detected in tumors. Effects of changes in Sp/KLF factors are context-dependent and can appear contradictory. Since these factors act within a network, this diversity of effects may arise from differences in the expression profile of family members in various cells. Thus, it is likely that the properties of the overall network of Sp/KLF factors play a determining role in regulation of cell growth and tumor progression. Copyright 2001 Wiley-Liss, Inc.
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              Krüppel-like factors: three fingers in many pies.

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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                19 December 2013
                March 2014
                : 6
                : 1
                : 28-41
                Affiliations
                [1 ]INSERM UMR 1037, Toulouse 31432, France; E-Mails: thoria.diab@ 123456inserm.fr (T.D.); naima.hanoun@ 123456inserm.fr (N.H.); bureau.c@ 123456chu-toulouse.fr (C.B.); christol.c@ 123456chu-toulouse.fr (C.C.); buscail.l@ 123456chu-toulouse.fr (L.B.); jerome.torrisani@ 123456inserm.fr (J.T.)
                [2 ]Paul Sabatier University, Toulouse 31000, France
                [3 ]Department of Hepatology, Toulouse University Hospital Centre, Toulouse 31409, France
                [4 ]Department of Gastroenterology, Toulouse University Hospital Centre, Toulouse 31409, France
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: pierre.cordelier@ 123456inserm.fr ; Tel.: +33-5-61-32-24-04.
                Article
                cancers-06-00028
                10.3390/cancers6010028
                3980593
                24378751
                2c06ddb8-a63c-4851-aa73-be2306328312
                © 2013 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 17 October 2013
                : 25 November 2013
                : 26 November 2013
                Categories
                Article

                hepatocellular carcinoma,klf factors,klf6,untranslated region,gene expression

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