Scientific letter
E2F4 as susceptibility factor in the early onset colorectal cancer
E2F4 como factor de susceptibilidad en el cáncer colorrectal de inicio temprano
Antonio Ríosa,b,c,
, José Manuel Rodrígueza,b,c, Pablo Carboneld, Pascual Parrillaa,b,c
Corresponding author
a Departamento de Cirugía, Universidad de Murcia, Murcia, Spain
b Servicio de Cirugía General y de Aparato Digestivo, Hospital Clínico Universitario Virgen de la Arrixaca, Servicio Murciano de Salud, El Palmar, Murcia, Spain
c Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB), Murcia, Spain
d Centro de Bioquímica y Genética Clínica, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca, Servicio Murciano de Salud, El Palmar, Murcia, Spain
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In resting cells, E2F4 is mainly located in the nucleus, where it forms a complex with p130.<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.<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.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> These are encoded by a series of triplets (AGC) whose number is frequently altered in colorectal cancers (CRC) with microsatellite instability phenotype.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,6</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.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Furthermore, E2F4 overexpression has proliferative and tumorigenic effects.<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.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">9,10</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.</p><p id="par0010" class="elsevierStylePara elsevierViewall">44 patients with CRC diagnosed before the age of 51 years were selected. None of the 44 patients had germline mutations (Lynch syndrome). DNA extraction was performed from peripheral blood (germline) and tumour tissue (tumour line). The Nushift (EMSA) kit by Geneka Biotechnology, Inc. was used to test the transcription factors of the E2F family. (Cat. N° 2006690). 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. Immunohistochemistry was performed using a standard technique. The DNA extracted from the peripheral blood of 344 healthy unrelated individuals was used as control group. Given the low allele frequencies, they were grouped according to the size of variation, regardless of whether they were insertions or deletions: V (1) variations of a triplet (both, insertions and deletions); V (2) of 2 triplets, and so on. Statistics: <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test where possible and Fisher exact test in the other cases.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The tumour line DNA showed no differences with germline DNA regarding the microsatellite instability under study. In terms of the total E2F4 altered alleles in the germline, 9% is observed in the CRC group (8 out of 88 alleles) compared to 7% of the population group (48 out of 688) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.05) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Regarding the distribution of the alleles in the population group, there were more insertions than deletions, while in the CRC group their numbers were similar. As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, there is an imbalance in the distribution of allele frequencies, being more frequent those representing larger variations in the CRC population. Thus, in the population group, 75% (36/48) of the variations correspond to insertions and/or deletions of one single triplet, while this variation only represents 12% in the CRC group (1/8) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.003). The assay of mRNA synthesized by different E2F4 alleles showed no differences in the expression or the half-life of the same. 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. There is a gradation from high to low, which correlates with the greatest difference regarding 13.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">In humans, the AGC repetitive sequence of E2F4 is polymorphic in 4–6% of the population.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">9,10</span></a> Thus, in our study, 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 (9 versus 7%). However, differences are observed in the distribution of the different alleles. Thus, in the population group, 75% of the variations (36/48) corresponded to expansions and contractions of a single triplet, whereas in the CRC group, these were only 12% (1/8). Furthermore, the distribution of alleles between the two populations is different for all major variations of a triplet, allowing speculation on the hypothesis that the alleles which move away from 13 in more than one triplet provide increased susceptibility to CRC development.</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, nor in their half-life. Immunohistochemistry was used to assess the influence of this polymorphism in the distribution and concentration of E2F4 protein at cellular level, observing an increase in staining intensity when the E2F4 alleles were smaller in the germline. The staining was exclusively cytoplasmic, primarily affecting glandular cells, especially neoplastic cells. Likewise, the staining was strong in macrophages, in all cases, probably due to their phagocytic activity on tumour cells. The absence of nuclear staining is, possibly, 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. The regulatory activity of E2F4 is partly modulated by its cellular location (mainly nuclear in resting cells and cytoplasmic in dividing cells). Therefore, the presence of E2F4 in the cytoplasm of glandular cells could be related to the high proliferative activity of these cells, especially the neoplastic ones.</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. In this case the activity of the protein seems to be closely linked to the active transport through the nuclear membrane, mediated by members of the pRB family as a result of their accumulation, which may alter the cell cycle regulatory activity of other members of the E2F family. Using paraffin-embedded specimens has disadvantages, like the poor quality of the DNA extracted or the inability to analyze mRNA or proteins, except when immunohistochemistry techniques are applied. However, it allows to select the different tumour tissues areas in a more precise way, and in some cases, address the sequencing of not very extensive DNA fragments.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In conclusion, 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, although there is insufficient data to suspect that the alleles that differ from the common of 13 repeats (AGC) in more than one triplet can provide some degree of susceptibility to the development of CRC, possibly as a result of the alteration in protein concentration.</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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Ríos A, Rodríguez JM, Carbonel P, Parrilla P. E2F4 como factor de susceptibilidad en el cáncer colorrectal de inicio temprano. Med Clin (Barc). 2016;146:230–231.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>688) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Colorectal cancer (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>88)<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; 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entry_with_role_rowhead " align="left" valign="top">V (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">V (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (2i<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (2i<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1d) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">V (6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1d) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1110609.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">This is twice the number of patients, as the analysis involves alleles.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Allelic frequencies for each of the variations in the general population and in colorectal carcinoma cases.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple members of the E2F transcription factor family are the products of oncogenes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G. 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