E2F4 as susceptibility factor in the early onset colorectal cancer

Ríos, Antonio; Rodríguez, José Manuel; Carbonel, Pablo; Parrilla, Pascual
doi:10.1016/j.medcle.2016.05.020
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">E2F is a family of 6 transcription factors &#40;E2F6 E2F1&#41; that regulates the expression of genes involved in the development of the cell cycle&#44; and whose dysregulated synthesis induces the neoplastic transformation of some cell lines&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> E2F4 is the one expressed most abundantly&#44; accounting for 50&#37; of these proteins&#46; In resting cells&#44; E2F4 is mainly located in the nucleus&#44; where it forms a complex with p130&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> The cell entry in the division process coincides with the active transport of the protein from the nucleus to the cytoplasm&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> The E2F4 protein contains a sequence of 13 consecutive serine residues in its transactivation domain&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> These are encoded by a series of triplets &#40;AGC&#41; whose number is frequently altered in colorectal cancers &#40;CRC&#41; with microsatellite instability phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> The E2F4 proteins encoded by genes with an altered number of AGC triplets show increased transactivator capacity and are capable of producing a cell proliferation stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Furthermore&#44; E2F4 overexpression has proliferative and tumorigenic effects&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> It has been reported that E2F4 alleles with a number of triplets other than 13 in the germline favour the development of CRC&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">9&#44;10</span></a> The aim is to analyze the relationship between the presence of <span class="elsevierStyleItalic">E2F4</span> gen alleles with a number of ACG triplets other than 13 and greater susceptibility to develop CRC&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">44 patients with CRC diagnosed before the age of 51 years were selected&#46; None of the 44 patients had germline mutations &#40;Lynch syndrome&#41;&#46; DNA extraction was performed from peripheral blood &#40;germline&#41; and tumour tissue &#40;tumour line&#41;&#46; The Nushift &#40;EMSA&#41; kit by Geneka Biotechnology&#44; Inc&#46; was used to test the transcription factors of the E2F family&#46; &#40;Cat&#46; N&#176; 2006690&#41;&#46; The DNA of the tumour line is used as a control to assess that there is no difference with the germline due to microsatellite instability&#46; Immunohistochemistry was performed using a standard technique&#46; The DNA extracted from the peripheral blood of 344 healthy unrelated individuals was used as control group&#46; Given the low allele frequencies&#44; they were grouped according to the size of variation&#44; regardless of whether they were insertions or deletions&#58; V &#40;1&#41; variations of a triplet &#40;both&#44; insertions and deletions&#41;&#59; V &#40;2&#41; of 2 triplets&#44; and so on&#46; Statistics&#58; <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test where possible and Fisher exact test in the other cases&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The tumour line DNA showed no differences with germline DNA regarding the microsatellite instability under study&#46; In terms of the total E2F4 altered alleles in the germline&#44; 9&#37; is observed in the CRC group &#40;8 out of 88 alleles&#41; compared to 7&#37; of the population group &#40;48 out of 688&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Regarding the distribution of the alleles in the population group&#44; there were more insertions than deletions&#44; while in the CRC group their numbers were similar&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; there is an imbalance in the distribution of allele frequencies&#44; being more frequent those representing larger variations in the CRC population&#46; Thus&#44; in the population group&#44; 75&#37; &#40;36&#47;48&#41; of the variations correspond to insertions and&#47;or deletions of one single triplet&#44; while this variation only represents 12&#37; in the CRC group &#40;1&#47;8&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; The assay of mRNA synthesized by different E2F4 alleles showed no differences in the expression or the half-life of the same&#46; The in situ E2F4 protein assay by immunohistochemistry showed greater E2F4 protein concentration in the preparations derived from tumour tissue from individuals with altered E2F4 alleles&#46; There is a gradation from high to low&#44; which correlates with the greatest difference regarding 13&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">In humans&#44; the AGC repetitive sequence of E2F4 is polymorphic in 4&#8211;6&#37; of the population&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">9&#44;10</span></a> Thus&#44; in our study&#44; no differences were observed in the frequency with which the E2F4 alleles were identified other than 13 repeats in the CRC group when compared to the population group &#40;9 versus 7&#37;&#41;&#46; However&#44; differences are observed in the distribution of the different alleles&#46; Thus&#44; in the population group&#44; 75&#37; of the variations &#40;36&#47;48&#41; corresponded to expansions and contractions of a single triplet&#44; whereas in the CRC group&#44; these were only 12&#37; &#40;1&#47;8&#41;&#46; Furthermore&#44; the distribution of alleles between the two populations is different for all major variations of a triplet&#44; allowing speculation on the hypothesis that the alleles which move away from 13 in more than one triplet provide increased susceptibility to CRC development&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The MRNA assay in individuals carrying different-sized alleles showed no difference in the expression of each one of them&#44; nor in their half-life&#46; Immunohistochemistry was used to assess the influence of this polymorphism in the distribution and concentration of E2F4 protein at cellular level&#44; observing an increase in staining intensity when the E2F4 alleles were smaller in the germline&#46; The staining was exclusively cytoplasmic&#44; primarily affecting glandular cells&#44; especially neoplastic cells&#46; Likewise&#44; the staining was strong in macrophages&#44; in all cases&#44; probably due to their phagocytic activity on tumour cells&#46; The absence of nuclear staining is&#44; possibly&#44; a result of the inability of the antibody used in the immunohistochemical technique to recognize its epitope when E2F4 is dimerized with any of the DP proteins and bound to DNA&#46; The regulatory activity of E2F4 is partly modulated by its cellular location &#40;mainly nuclear in resting cells and cytoplasmic in dividing cells&#41;&#46; Therefore&#44; the presence of E2F4 in the cytoplasm of glandular cells could be related to the high proliferative activity of these cells&#44; especially the neoplastic ones&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The diversity of mechanisms by which the transcription factors of the E2F family are able to regulate gene expression makes interpreting the consequences of E2F4 accumulation difficult&#46; In this case the activity of the protein seems to be closely linked to the active transport through the nuclear membrane&#44; mediated by members of the pRB family as a result of their accumulation&#44; which may alter the cell cycle regulatory activity of other members of the E2F family&#46; Using paraffin-embedded specimens has disadvantages&#44; like the poor quality of the DNA extracted or the inability to analyze mRNA or proteins&#44; except when immunohistochemistry techniques are applied&#46; However&#44; it allows to select the different tumour tissues areas in a more precise way&#44; and in some cases&#44; address the sequencing of not very extensive DNA fragments&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In conclusion&#44; there is no evidence supporting that the expansion or contraction in the number of triplets of the <span class="elsevierStyleItalic">E2F4</span> gene have a trigger effect on the tumour development process of CRC&#44; although there is insufficient data to suspect that the alleles that differ from the common of 13 repeats &#40;AGC&#41; in more than one triplet can provide some degree of susceptibility to the development of CRC&#44; possibly as a result of the alteration in protein concentration&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Allelic frequencies for each of the variations in the general population and in colorectal carcinoma cases&#46;</p>"
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