ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression
Identifieur interne : 000201 ( Pmc/Corpus ); précédent : 000200; suivant : 000202ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression
Auteurs : Jaskaren S. Kohli ; Hira Mir ; Afsheen Wasif ; Heung Chong ; Victoria Akhras ; Rajiv Kumar ; Eduardo Nagore ; Dorothy C. BennettSource :
- Oncotarget [ 1949-2553 ] ; 2017.
Abstract
TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered
Url:
DOI: 10.18632/oncotarget.22254
PubMed: 29262649
PubMed Central: 5732815
Links to Exploration step
PMC:5732815Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression</title><author><name sortKey="Kohli, Jaskaren S" sort="Kohli, Jaskaren S" uniqKey="Kohli J" first="Jaskaren S." last="Kohli">Jaskaren S. Kohli</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6"> Current/Present address: European Research Institute for The Biology of Aging, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Mir, Hira" sort="Mir, Hira" uniqKey="Mir H" first="Hira" last="Mir">Hira Mir</name><affiliation><nlm:aff id="A2"> Department of Cellular Pathology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A7"> Current/Present address: King’s College Hospital Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Wasif, Afsheen" sort="Wasif, Afsheen" uniqKey="Wasif A" first="Afsheen" last="Wasif">Afsheen Wasif</name><affiliation><nlm:aff id="A2"> Department of Cellular Pathology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A7"> Current/Present address: King’s College Hospital Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Chong, Heung" sort="Chong, Heung" uniqKey="Chong H" first="Heung" last="Chong">Heung Chong</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Department of Cellular Pathology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Akhras, Victoria" sort="Akhras, Victoria" uniqKey="Akhras V" first="Victoria" last="Akhras">Victoria Akhras</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Department of Dermatology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Kumar, Rajiv" sort="Kumar, Rajiv" uniqKey="Kumar R" first="Rajiv" last="Kumar">Rajiv Kumar</name><affiliation><nlm:aff id="A4"> Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Nagore, Eduardo" sort="Nagore, Eduardo" uniqKey="Nagore E" first="Eduardo" last="Nagore">Eduardo Nagore</name><affiliation><nlm:aff id="A5"> Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Bennett, Dorothy C" sort="Bennett, Dorothy C" uniqKey="Bennett D" first="Dorothy C." last="Bennett">Dorothy C. Bennett</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29262649</idno><idno type="pmc">5732815</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732815</idno><idno type="RBID">PMC:5732815</idno><idno type="doi">10.18632/oncotarget.22254</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000201</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000201</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression</title><author><name sortKey="Kohli, Jaskaren S" sort="Kohli, Jaskaren S" uniqKey="Kohli J" first="Jaskaren S." last="Kohli">Jaskaren S. Kohli</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6"> Current/Present address: European Research Institute for The Biology of Aging, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Mir, Hira" sort="Mir, Hira" uniqKey="Mir H" first="Hira" last="Mir">Hira Mir</name><affiliation><nlm:aff id="A2"> Department of Cellular Pathology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A7"> Current/Present address: King’s College Hospital Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Wasif, Afsheen" sort="Wasif, Afsheen" uniqKey="Wasif A" first="Afsheen" last="Wasif">Afsheen Wasif</name><affiliation><nlm:aff id="A2"> Department of Cellular Pathology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A7"> Current/Present address: King’s College Hospital Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Chong, Heung" sort="Chong, Heung" uniqKey="Chong H" first="Heung" last="Chong">Heung Chong</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Department of Cellular Pathology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Akhras, Victoria" sort="Akhras, Victoria" uniqKey="Akhras V" first="Victoria" last="Akhras">Victoria Akhras</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Department of Dermatology, St George’s University Hospitals NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Kumar, Rajiv" sort="Kumar, Rajiv" uniqKey="Kumar R" first="Rajiv" last="Kumar">Rajiv Kumar</name><affiliation><nlm:aff id="A4"> Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Nagore, Eduardo" sort="Nagore, Eduardo" uniqKey="Nagore E" first="Eduardo" last="Nagore">Eduardo Nagore</name><affiliation><nlm:aff id="A5"> Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Bennett, Dorothy C" sort="Bennett, Dorothy C" uniqKey="Bennett D" first="Dorothy C." last="Bennett">Dorothy C. Bennett</name><affiliation><nlm:aff id="A1"> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</nlm:aff></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered <italic>TERT</italic> promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a <italic>TERT</italic> promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Oncotarget</journal-id><journal-id journal-id-type="iso-abbrev">Oncotarget</journal-id><journal-id journal-id-type="publisher-id">Oncotarget</journal-id><journal-id journal-id-type="publisher-id">ImpactJ</journal-id><journal-title-group><journal-title>Oncotarget</journal-title></journal-title-group><issn pub-type="epub">1949-2553</issn><publisher><publisher-name>Impact Journals LLC</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29262649</article-id><article-id pub-id-type="pmc">5732815</article-id><article-id pub-id-type="publisher-id">22254</article-id><article-id pub-id-type="doi">10.18632/oncotarget.22254</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kohli</surname><given-names>Jaskaren S.</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref ref-type="aff" rid="A6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mir</surname><given-names>Hira</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref><xref ref-type="aff" rid="A7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wasif</surname><given-names>Afsheen</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref><xref ref-type="aff" rid="A7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chong</surname><given-names>Heung</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Akhras</surname><given-names>Victoria</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref><xref ref-type="aff" rid="A3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kumar</surname><given-names>Rajiv</given-names></name><xref ref-type="aff" rid="A4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nagore</surname><given-names>Eduardo</given-names></name><xref ref-type="aff" rid="A5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bennett</surname><given-names>Dorothy C.</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><aff id="A1"><sup>1</sup> Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK</aff><aff id="A2"><sup>2</sup> Department of Cellular Pathology, St George’s University Hospitals NHS Foundation Trust, London, UK</aff><aff id="A3"><sup>3</sup> Department of Dermatology, St George’s University Hospitals NHS Foundation Trust, London, UK</aff><aff id="A4"><sup>4</sup> Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany</aff><aff id="A5"><sup>5</sup> Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain</aff><aff id="A6"><sup>6</sup> Current/Present address: European Research Institute for The Biology of Aging, University Medical Center Groningen, Groningen, The Netherlands</aff><aff id="A7"><sup>7</sup> Current/Present address: King’s College Hospital Foundation Trust, London, UK</aff></contrib-group><author-notes><corresp id="cor1"><bold><italic>Correspondence to:</italic></bold><italic>Dorothy C. Bennett,</italic><email>dbennett@sgul.ac.uk</email></corresp></author-notes><pub-date pub-type="collection"><day>28</day><month>11</month><year>2017</year></pub-date><pub-date pub-type="epub"><day>1</day><month>11</month><year>2017</year></pub-date><volume>8</volume><issue>61</issue><fpage>104408</fpage><lpage>104417</lpage><history><date date-type="received"><day>20</day><month>7</month><year>2017</year></date><date date-type="accepted"><day>3</day><month>10</month><year>2017</year></date></history><permissions><copyright-statement>Copyright: © 2017 Kohli et al.</copyright-statement><copyright-year>2017</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/3.0/">Creative Commons Attribution License</ext-link> 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered <italic>TERT</italic> promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a <italic>TERT</italic> promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. It can be acquired at various stages and by mechanisms other than promoter mutations.</p></abstract><kwd-group><kwd>TERT</kwd><kwd>ETS1</kwd><kwd>melanoma</kwd><kwd>nevus</kwd><kwd>nucleolus</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>INTRODUCTION</title><p>One of the proposed hallmarks of cancer cells is immortality: the ability to proliferate indefinitely by bypassing cell senescence [<xref rid="R1" ref-type="bibr">1</xref>]. Cell senescence is a stable proliferative arrest following extensive cell division and telomere attrition, or other triggers including oncogene overexpression or genotoxic stresses [<xref rid="R2" ref-type="bibr">2</xref>]. Senescence can be triggered by short, dysfunctional telomeres, through DNA-damage signaling. In the germline and some stem cells, replicative senescence is prevented through telomere maintenance by active telomerase. TERT (telomerase reverse transcriptase), the catalytic component of telomerase, is transcriptionally repressed in normal adult somatic cells, which thus do senesce; but is reportedly re-expressed in 85-90% of human cancers, permitting immortality [<xref rid="R3" ref-type="bibr">3</xref>]. This re-expression seems to play a central role in carcinogenesis, making TERT and telomerase potentially important as drivers and therapeutic targets.</p><p>Benign and malignant primary pigmented lesions can be classified histologically into four main types with increasing malignancy, namely benign/banal melanocytic nevi, dysplastic nevi, thin, early melanomas termed radial growth phase (RGP) melanomas, and thicker, invasive or vertical growth phase (VGP) melanomas [<xref rid="R4" ref-type="bibr">4</xref>]. These types show progressively more genetic changes, disrupting characteristic molecular pathways, notably senescence, as reviewed in [<xref rid="R5" ref-type="bibr">5</xref>]. A benign nevus consists of a clonal mass of melanocytes that have senesced after proliferation triggered by an oncogenic mutation, usually in <italic>BRAF</italic> or <italic>NRAS,</italic> activating the MAPK pathway [<xref rid="R6" ref-type="bibr">6</xref>-<xref rid="R10" ref-type="bibr">10</xref>]. The cell-cycle inhibitor CDKN2A (isoform 1), hereafter called by its common name p16, appears the primary effector of senescence in melanocytes [<xref rid="R11" ref-type="bibr">11</xref>, <xref rid="R12" ref-type="bibr">12</xref>], and is commonly expressed strongly in nevi [<xref rid="R6" ref-type="bibr">6</xref>, <xref rid="R7" ref-type="bibr">7</xref>]. <italic>CDKN2A</italic> is a frequent site of mutations in familial melanoma [<xref rid="R5" ref-type="bibr">5</xref>-<xref rid="R7" ref-type="bibr">7</xref>]. Mutations or epigenetic disruption of the p16 pathway appear increasingly through the series, dysplastic nevi, RGP and VGP melanoma [<xref rid="R7" ref-type="bibr">7</xref>, <xref rid="R9" ref-type="bibr">9</xref>]. VGP melanomas also tend to accumulate mutations suppressing apoptosis, discussed elsewhere [<xref rid="R13" ref-type="bibr">13</xref>, <xref rid="R5" ref-type="bibr">5</xref>]. p16 deficiency contributes to senescence bypass, but telomere extension is also essential. Functional tests indicate that immortality emerges only late in melanoma progression [<xref rid="R13" ref-type="bibr">13</xref>]. Average telomerase activity rises strongly in later progression [<xref rid="R14" ref-type="bibr">14</xref>, <xref rid="R15" ref-type="bibr">15</xref>]. Much interest was generated by recent findings that this rise is commonly mediated through mutations at hotspots in the <italic>TERT</italic> promoter, creating binding sites for ETS-family transcription factors [<xref rid="R16" ref-type="bibr">16</xref>-<xref rid="R18" ref-type="bibr">18</xref>] and facilitating <italic>TERT</italic> transcription [<xref rid="R19" ref-type="bibr">19</xref>]. Such mutations appear much more common in metastatic than primary melanomas [<xref rid="R16" ref-type="bibr">16</xref>, <xref rid="R20" ref-type="bibr">20</xref>], yet are also detected in some early lesions intermediate between nevi and melanomas [<xref rid="R9" ref-type="bibr">9</xref>], and also (rarely) in the germline of some melanoma-prone families [<xref rid="R16" ref-type="bibr">16</xref>, <xref rid="R18" ref-type="bibr">18</xref>].</p><p>Little is understood of TERT protein expression in relation to these mutations and to progression. Availability of a reliable anti-TERT antibody [<xref rid="R21" ref-type="bibr">21</xref>] has enabled us to investigate this by TERT immunohistochemistry (IHC) in nevi and melanomas. ETS1 expression was also re-examined. ETS1 has been implicated as a predominant factor activating mutant <italic>TERT</italic> promoters in melanoma [<xref rid="R19" ref-type="bibr">19</xref>], but previous studies have reached differing conclusions on ETS1 expression relative to melanoma progression [<xref rid="R22" ref-type="bibr">22</xref>-<xref rid="R24" ref-type="bibr">24</xref>].</p></sec><sec id="s2"><title>RESULTS</title><sec id="s2_1"><title>Role of antigen-retrieval pH; revisiting p16 expression in melanoma progression</title><p>Antigen retrieval for IHC is commonly done at pH 6. However optimization tests showed strongest immunostaining after retrieval at pH 9, for all antibodies used here (<xref ref-type="supplementary-material" rid="SD1">Supplementary Figures 1-4</xref>). Retrieval at pH 9 was therefore used throughout this study.</p><p>For comparison with TERT expression, we re-examined p16 immunostaining, also to test whether the strong staining would increase apparent prevalence, as p16 is detected heterogeneously in nevi [<xref rid="R6" ref-type="bibr">6</xref>, <xref rid="R7" ref-type="bibr">7</xref>]. However, while more cells were positive, the results (<xref ref-type="supplementary-material" rid="SD1">Supplementary Figure 5</xref>) were comparable to those reported before [<xref rid="R25" ref-type="bibr">25</xref>, <xref rid="R27" ref-type="bibr">27</xref>-<xref rid="R29" ref-type="bibr">29</xref>], strengthening evidence that p16 expression is heterogeneous in many nevi and absent from most VGP melanomas.</p></sec><sec id="s2_2"><title>ETS1 expression with melanoma progression</title><p>Nuclear ETS1 was expressed extensively and strongly in all lesions at all five tested stages of progression, except for a few metastases (Figure <xref ref-type="fig" rid="F1">1A, 1B</xref>). To compare normal melanocytes <italic>in vivo</italic> we examined normal epidermis in benign nevus sections. No ETS1 was detected. To test normal melanocytes specifically, double immunohistochemistry was performed on normal human skin for ETS1 and the melanosomal protein MART1 (MLANA) (Figure <xref ref-type="fig" rid="F1">1C</xref>). Epidermal melanocytes, identified by cytoplasmic MART1, were confirmed negative for nuclear ETS1. Thus, in melanocytes <italic>in vivo</italic>, ETS1 expression appears to be activated upon nevogenesis.</p><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>ETS1 expression with melanoma progression</title><p><bold>(A)</bold> Percentage of lesions showing high (>50% cells) (black) and moderate (5-50%) prevalence (grey). Prevalence <5% was not reproducibly distinguished from 0 by independent observers and thus had uncertain significance [<xref rid="R25" ref-type="bibr">25</xref>]; not shown. BN: benign nevus (n=10); DN: dysplastic nevus (n=10); RGP (n=8); VGP (n=9); METS: metastatic melanoma samples (n=9). <bold>(B)</bold> Representative highly prevalent ETS1 immunostaining in a benign nevus and VGP melanoma, with parallel MART1 IHC to show position of lesional cells. <bold>(C)</bold> ETS1 and MART1 double IHC in normal skin. Epidermal normal melanocytes express cytoplasmic MART1 (red) but no nuclear ETS1 (brown); expanded in inset. A group of lymphoid cells in the dermis (brown nuclei) provides a positive ETS1 control. Scale bars: 100 μm.</p></caption><graphic xlink:href="oncotarget-08-104408-g001"></graphic></fig></sec><sec id="s2_3"><title>TERT expression with melanoma progression: nucleolar and non-nucleolar</title><p>TERT levels in the various lesional types are shown in Figure <xref ref-type="fig" rid="F2">2A</xref>. There was a numerical positive trend in total TERT prevalence, but with borderline statistical significance (p=0.0545). Benign and dysplastic nevi often displayed surprisingly widespread TERT positivity.</p><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>TERT expression and localization with melanoma progression</title><p>Abbreviations and bar color coding as in Figure <xref ref-type="fig" rid="F1">1</xref>. BN (n=27), DN (n=34), RGP (n=29), VGP (n=25) and METS (n=27). <bold>(A)</bold> Total TERT prevalence, showing a borderline trend with progression (p=0.054). <bold>(B)</bold> Nucleolar TERT in a benign nevus nest (brown granules are melanin). <bold>(C, D)</bold> Non-nucleolar TERT in melanomas, diffuse in nucleoplasm (arrows) or in punctate nuclear foci (arrowheads). Scale bars: 50 μm. <bold>(E)</bold> Nucleolar TERT prevalence, showing no trend with progression (p=0.41). <bold>(F)</bold> Non-nucleolar TERT prevalence, showing a highly significant rise with progression (p=0.006). Significance testing was by χ<sup>2</sup> tests.</p></caption><graphic xlink:href="oncotarget-08-104408-g002"></graphic></fig><p>However, it was noticed that subcellular TERT location varied between lesions. In benign nevi TERT was typically localized solely to the nucleolus (Figure <xref ref-type="fig" rid="F2">2B</xref>). However in melanomas the protein was often found in distinct subnuclear foci, or diffusely across the nucleus (Figure <xref ref-type="fig" rid="F2">2C, 2D</xref>), designated ‘non-nucleolar’. Lesions were then recounted, discriminating nucleolar and non-nucleolar TERT (Figure <xref ref-type="fig" rid="F2">2E, 2F</xref>). There was no trend for nucleolar expression (p=0.41), but a statistically highly significant positive trend for non-nucleolar TERT detection with melanoma progression (p=0.006).</p><p>Non-nucleolar TERT was typically present heterogeneously, in 5-50% of cells within a lesion (grey areas, Figure <xref ref-type="fig" rid="F2">2F</xref>). It was found in less than 20% of benign nevi, in 40-50% of dysplastic nevi and primary melanomas, but in nearly 80% of metastatic samples. Prevalence differed significantly between benign nevi and all other lesions combined (p=0.004); also between metastatic melanomas and all other lesions combined (p=0.001). Taken together, these results suggest that gain of non-nucleolar TERT occurs in a few benign nevi, in some dysplastic nevi, but most commonly at the transition to metastasis.</p><p>To ensure specificity, TERT peptide blocking was performed, on two lesions with exclusively nucleolar (<xref ref-type="supplementary-material" rid="SD1">Supplementary Figure 6A</xref>), and predominantly non-nucleolar immunostaining respectively (<xref ref-type="supplementary-material" rid="SD1">Supplementary Figure 6B</xref>). Nuclear TERT detection was greatly reduced or absent in both cases, supporting high antibody specificity and that the antigen in both subnuclear locations is indeed TERT.</p></sec><sec id="s2_4"><title>Non-nucleolar TERT does not associate with cellular proliferation</title><p>Hypothesizing that non-nucleolar TERT might be linked to immortalization, we tested whether its presence correlated with proliferation, by immunostaining adjacent sections for proliferative marker Ki-67.</p><p>Ki-67 expression was well correlated with melanoma progression (p<0.0001), as expected [<xref rid="R30" ref-type="bibr">30</xref>]. Expression was rare in nevi but common in primary melanomas; nearly all metastases were >50% positive (Figure <xref ref-type="fig" rid="F3">3A</xref>). There was poor statistical agreement however between Ki-67 and non-nucleolar TERT in individual lesions (Figure <xref ref-type="fig" rid="F3">3B</xref>; κ=0.15). Examples of divergence between Ki-67 and TERT are shown in Figure <xref ref-type="fig" rid="F3">3C</xref>. Still, all lesions with >50% cells positive for non-nucleolar TERT, and most of those with 5-50%, were also Ki-67 positive. The lack of correlation was attributable to frequent lesions with Ki-67 but no/rare (<5%) non-nucleolar TERT.</p><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Ki-67 expression and lack of association with non-nucleolar TERT</title><p><bold>(A)</bold> Ki-67 prevalence, highly significantly rising with melanoma progression (p<0.0001, χ<sup>2</sup> test). Abbreviations and bar color coding as in Figure <xref ref-type="fig" rid="F1">1</xref>. BN (n=10), DN (n=10), RGP (n=8), VGP (n=9) and METS (n=10). <bold>(B)</bold> Grouped scatter plot illustrating poor agreement between Ki-67 and non-nucleolar TERT prevalence (κ=0.15). The area of each circle is proportional to the number of lesions with the indicated prevalence for each marker. <bold>(C)</bold> Examples of lesions displaying poor agreement. Top: highly prevalent TERT but no Ki-67 expression. Bottom: widespread Ki-67 but very little non-nucleolar (although much nucleolar) TERT expression. Arrows: melanophages (macrophages which have engulfed melanin). Scale bars: 50 μm.</p></caption><graphic xlink:href="oncotarget-08-104408-g003"></graphic></fig></sec><sec id="s2_5"><title>Non-nucleolar TERT expression does not associate with <italic>TERT</italic> promoter mutation status in primary melanomas</title><p>Since prevalence of both non-nucleolar TERT and TERT promoter mutations correlate with melanoma progression, we investigated whether non-nucleolar TERT might be a marker for these mutations. Primary melanomas with known <italic>TERT</italic> mutation status were now also analyzed by TERT IHC.</p><p>No significant differences were found however between melanomas with or without a <italic>TERT</italic> promoter mutation, in either total (p=0.59, Figure <xref ref-type="fig" rid="F4">4A</xref>), nucleolar (p=0.60, Figure <xref ref-type="fig" rid="F4">4B</xref>), or non-nucleolar TERT detection (p=0.45, Figure <xref ref-type="fig" rid="F4">4C</xref>). These results indicate that TERT can also be upregulated in melanoma through mechanisms other than promoter mutations.</p><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>TERT expression in primary melanomas with and without a <italic>TERT</italic> promoter mutation</title><p>No significant difference was observed between primary melanomas with (n=27) or without a <italic>TERT</italic> promoter mutation (n=28), for <bold>(A)</bold> total TERT (p=0.59), <bold>(B)</bold> nucleolar TERT (p=0.62) or <bold>(C)</bold> non-nucleolar TERT (p=0.45), by χ<sup>2</sup> tests. Bar color coding as in Figure <xref ref-type="fig" rid="F1">1</xref>.</p></caption><graphic xlink:href="oncotarget-08-104408-g004"></graphic></fig></sec><sec id="s2_6"><title>Nucleolar TERT location in cultured melanocytic cells</title><p>We next investigated TERT via immunocytochemistry in melanocytic cell cultures, to compare normal and malignant cells and test the hypothesis that non-nucleolar TERT might indicate cell immortality. We used A375P melanoma cells, Hermes 3A TERT/CDK4-immortalized human melanocytes [<xref rid="R7" ref-type="bibr">7</xref>], and SGML-2 normal human melanocytes. Cells were also immunostained for nucleolar marker nucleolin, and for coilin, a marker of Cajal bodies, a reported site of telomerase assembly [<xref rid="R31" ref-type="bibr">31</xref>].</p><p>Interestingly, in all three cell lines TERT was present and localized entirely to nucleoli (Figure <xref ref-type="fig" rid="F5">5</xref>). No co-localization was observed with coilin, indicating TERT is not (or only very transiently) found in Cajal bodies in these cells. The finding also seemed inconsistent with non-nucleolar TERT as an indicator of immortality. We tested whether the nucleolar location here might be an artefact of fixation, given TERT’s high isoelectric point (∼11.3) [<xref rid="R32" ref-type="bibr">32</xref>] and hence positive charge at near-neutral pH. The nucleolus (rich in negatively charged RNA) has been reported to accumulate positively charged proteins [<xref rid="R33" ref-type="bibr">33</xref>]. Cells were therefore now fixed at pH 10 to neutralize TERT. No change in TERT location was observed however (<xref ref-type="supplementary-material" rid="SD1">Supplementary Figure 7</xref>), suggesting it was not artefactual. The expression of TERT in non-immortal melanocytes in culture but not <italic>in vivo</italic> remains unexplained, and these data indicate no simple link between non-nucleolar TERT and immortality or active telomerase.</p><fig id="F5" orientation="portrait" position="float"><label>Figure 5</label><caption><title>TERT colocalization with nucleolin, not coilin, in cultured human melanoma cells and melanocytes</title><p>A375P is an immortal melanoma line, Hermes 3A cells are immortalized melanocytes and SGML-2 is a diploid adult melanocyte strain. All cells were proliferating. Panels show double immunofluorescence for TERT (red) with nucleolin or Cajal body marker coilin (green). Nuclei visualized with DAPI (blue). Scale bars: 5 μm. TERT localized to nucleoli, not Cajal bodies, in all cells in these cultures.</p></caption><graphic xlink:href="oncotarget-08-104408-g005"></graphic></fig></sec></sec><sec id="s3"><title>DISCUSSION</title><p>ETS1 expression was detected in all nevi and but not in normal epidermal melanocytes, agreeing with [<xref rid="R24" ref-type="bibr">24</xref>] but not with [<xref rid="R23" ref-type="bibr">23</xref>]. This upregulation may occur because nevi are senescent; ETS1 upregulation was reported in senescent fibroblasts [<xref rid="R34" ref-type="bibr">34</xref>]. It may also be because nevi carry an activated oncogene, activating ETS1 by phosphorylation downstream of RAS/RAF/MAPK signaling [<xref rid="R5" ref-type="bibr">5</xref>], and possibly increasing its abundance. At any rate, this presence of ETS1 could allow TERT expression in a nevus cell acquiring an oncogenic <italic>TERT</italic> promoter mutation, since these mutations reportedly associate with increased TERT transcription and protein expression, in the presence of ETS-family factors [<xref rid="R20" ref-type="bibr">20</xref>, <xref rid="R35" ref-type="bibr">35</xref>]. This would activate telomerase, potentially impairing senescence stability and being clonally selective.</p><p>TERT immunostaining has not to our knowledge previously been analyzed as nucleolar or non-nucleolar relative to melanoma progression. We found that only non-nucleolar TERT increased significantly in prevalence with melanoma progression. Benign nevi had predominantly nucleolar TERT, aligning with a report that nucleolar TERT is not functional [<xref rid="R36" ref-type="bibr">36</xref>]. However the “melanoma-like” non-nucleolar TERT was also found in 20% of benign nevi, and 40% of dysplastic nevi. <italic>TERT</italic> promoter mutations have also been detected as an early event in some “intermediate” (dysplastic-like) lesions [<xref rid="R9" ref-type="bibr">9</xref>], indicating remarkably that active telomerase may be selective even within a largely senescent tissue. Dysplastic nevi were estimated to transform very rarely into melanoma (∼1 in 30,000) [<xref rid="R37" ref-type="bibr">37</xref>], implying that the non-nucleolar TERT seen here in about 40% of dysplastic lesions is not sufficient for immortality. This conforms with the finding that some <italic>p16</italic> mutations apparently arise only after <italic>TERT</italic> promoter mutations [<xref rid="R9" ref-type="bibr">9</xref>]. One wonders how such TERT mutations can become clonally expanded, in a nevus with unmutated p16. Perhaps in these cases one or both p16 copies are silenced by methylation, or TERT allows some repair of telomeric DNA damage even during arrest, and this reduces p16 activation.</p><p>No significant difference in TERT protein expression was observed between primary melanomas with or without a mutated <italic>TERT</italic> promoter; thus IHC cannot be used as an assay for the presence of the mutation, as has been hoped. This initially seemed surprising, but findings were similar in recent studies of glioblastoma [<xref rid="R38" ref-type="bibr">38</xref>] and a previous report on melanoma [<xref rid="R39" ref-type="bibr">39</xref>] (although without stated validation of their antibody, which gave strong cytoplasmic staining). Evidently <italic>TERT</italic> expression can be activated by mechanisms other than mutation. For example, Fan et al [<xref rid="R40" ref-type="bibr">40</xref>] reported a positive correlation between multiple cytosine methylation in part of the <italic>TERT</italic> promoter (667-482 bp upstream of the ATG start site) and TERT expression, in melanomas arising from congenital nevi or lacking a TERT promoter mutation. They cited similar previous findings in brain tumors. Conversely, the -146 C>T <italic>TERT</italic> promoter mutation has been reported to require non-canonical NF- κB signaling to co-operate with ETS1 [<xref rid="R41" ref-type="bibr">41</xref>]. Thus lesions carrying this mutation but negative for TERT protein may lack this signaling, or another co-operating factor. Moreover it was recently reported that these promoter mutations alone lead to low levels of TERT mRNA expression, below detection limits and insufficient for maintenance of all telomeres, so that additional changes seem to be needed for further upregulation and cell immortalization [<xref rid="R42" ref-type="bibr">42</xref>], consistent with the present data.</p><p>Nucleolar TERT expression did not alter with melanoma progression. The nucleolus was reported as a site of telomerase assembly, from where it would relocate to telomeres during DNA replication [<xref rid="R31" ref-type="bibr">31</xref>, <xref rid="R43" ref-type="bibr">43</xref>]. This might predict a correlation of non-nucleolar TERT immunostaining with cell proliferation (Ki-67 prevalence), which we therefore tested for, but did not see, suggesting additional reasons for extranucleolar location. Others have suggested that the nucleolus regulates telomerase activity. Transfection of exogenous <italic>TERT</italic> into various malignant cells gave a pan-nuclear localization (i.e. including non-nucleolar), but in normal diploid fibroblasts it localized solely to the nucleolus [<xref rid="R36" ref-type="bibr">36</xref>, <xref rid="R44" ref-type="bibr">44</xref>-<xref rid="R46" ref-type="bibr">46</xref>]. These results suggest dysregulation of TERT localization in malignant cells. Nucleolin and PINX1 are reportedly both required for localizing TERT to the nucleolus [<xref rid="R44" ref-type="bibr">44</xref>, <xref rid="R46" ref-type="bibr">46</xref>]. We reported increasing nucleolin expression with melanoma progression [<xref rid="R25" ref-type="bibr">25</xref>], which does not readily explain the trend for TERT; however we know of no data on PINX1 expression in melanoma.</p><p>In summary, we report strong ETS1 expression in all nevi and melanomas but not normal melanocytes, providing a mechanism for how early TERT promoter mutations can be selective following oncogene activation. We also report for the first time a pathologically significant aspect of TERT localization relative to the nucleolus: only non-nucleolar TERT increases in prevalence with melanoma progression. It will be important to investigate in future the mechanism and significance of this non-nucleolar location, which did not seem to be linked directly to cellular immortality, at least in our cell cultures. No significant difference in TERT expression or location was observed between primary melanomas with or without a <italic>TERT</italic> promoter mutation, consistent with the conclusion that <italic>TERT</italic> upregulation is more important for the development of a melanoma than the mechanism of upregulation.</p></sec><sec id="s4"><title>MATERIALS AND METHODS</title><sec id="s4_1"><title>Patients and specimens</title><p>This study was approved by the West London and GTAC Research Ethics Committee (ref. 08/H0803/154). Samples were obtained from patients at St George’s Hospital, with written consent. A total of 142 lesional samples were used for TERT IHC: 27 benign nevi, 34 dysplastic nevi, 29 RGP melanomas, 25 VGP melanomas and 27 metastatic melanomas. Smaller numbers of lesions were available for IHC of other proteins (see figure legends). Blinded samples of primary melanomas with a wild-type (n=28) or mutated <italic>TERT</italic> promoter (n=27) were sent to London from the Biobank of the Instituto Valenciano de Oncología. Samples were obtained from patients at the Institute with written consent.</p></sec><sec id="s4_2"><title>Immunohistochemistry</title><p>Detailed protocols for immunohistochemistry and peptide-blocking are given in the <xref ref-type="supplementary-material" rid="SD1">Supplementary Materials</xref>. Sections were examined by microscope and classed as containing either <5%, 5-50% or >50% positive lesional cells, a system giving high agreement between two independent scorers [<xref rid="R25" ref-type="bibr">25</xref>]. All specimens were evaluated by two scorers. Where scores did differ, lesions were re-examined jointly to reach agreement. Statistical analyses, using GraphPad Prism version 6.07, were χ<sup>2</sup> tests for significance of differences between categories and a kappa test for concordant immunostaining of two proteins. <italic>p</italic><0.05 was considered significant.</p></sec><sec id="s4_3"><title>Cell cultures</title><p>A375P melanoma cells and Hermes 3A immortal human melanocytes were from the Wellcome Trust Functional Genomics Cell Bank at St George’s. Cell Bank cultures are validated by IDEXX Bioresearch and were grown by us for less than 6 months from recovery of cryopreserved stocks. SGML-2 was a normal adult epidermal melanocyte strain explanted at St George’s from an abdominoplasty; cells were cultured as described [<xref rid="R26" ref-type="bibr">26</xref>].</p></sec><sec id="s4_4"><title>Double immunofluorescence</title><p>Cells were grown on glass coverslips in 16-mm wells, washed twice in PBSD (complete Dulbecco’s PBS with CaCl<sub>2</sub> and MgCl<sub>2</sub>) and fixed in 4% paraformaldehyde in PBSD for 20 minutes. After two washes in PBSD, cells were permeabilized with 0.1% Triton X-100 in PBSD for 4 minutes. Three washes in PBSD were carried out before blocking in 10 mg/ml BSA in PBSD. Cells were left overnight in primary antibody diluted in 10 mg/ml BSA in PBSD, at 4°C in a humidified chamber. Primary antibodies used were against TERT (EST21-A, Alpha Diagnostic International, 1:500), coilin (ab87913, Abcam, 1:1000) and nucleolin (ab136649, Abcam, 1:2000). After five brief washes with PBSD, cells were incubated in Alexa Fluor 594-conjugated goat anti-rabbit IgG (A-11012, Life Technologies, 1:400) for detection of TERT and Alexa Fluor 488-conjugated goat anti-mouse IgG (A-11008, Life Technologies, 1:400) for nucleolin or coilin. After 3 washes in PBSD, cells were counterstained with 1 μg/ml DAPI for 10 min, washed 3x in PBSD and once in dH<sub>2</sub>O, then mounted on slides in Citifluor. A LSM 510 Zeiss confocal microscope and ZEN 2009 software (Zeiss) were used to capture images.</p></sec></sec><sec sec-type="supplementary-material" id="s5"><title>SUPPLEMENTARY MATERIALS FIGURES</title><supplementary-material content-type="local-data" id="SD1"><media mimetype="application" mime-subtype="pdf" xlink:href="oncotarget-08-104408-s001.pdf" orientation="portrait" id="d35e794" position="anchor"></media></supplementary-material></sec></body><back><fn-group><fn fn-type="con"><p><bold>Author contributions</bold></p><p>JSK and DCB designed the project and drafted the manuscript. JSK performed the experiments. JSK, HM and AW scored the IHC slides using pathological expertise. HC and VA obtained, identified and provided suitable archival specimens from the St George’s Hospital tissue bank. RK and EN provided specimens with known TERT promoter status and all authors provided critical input to the manuscript.</p></fn></fn-group><ack><p>We are grateful to staff of Cell Pathology, St George’s University Hospitals NHS Trust, for valuable advice and assistance.</p></ack><fn-group><fn fn-type="COI-statement"><p><bold>CONFLICTS OF INTEREST</bold></p><p>The authors declare no conflicts of interest.</p></fn><fn fn-type="supported-by"><p><bold>FUNDING</bold></p><p>JSK was supported by St George’s, University of London, Wellcome Trust Grant 097832/Z/11/Z and a Mara Nahum Scholarship from Emme Rouge Onlus, Milan. 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