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Cited by 347Telomeres, Telomerase, and SenescenceVirus-based gene therapy researchCancer-related Molecular Pathways

Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers

Open access
Kyo, Satoru, Takakura, Masahiro, Fujiwara, Toshiyoshi, Inoue, Masaki·2008·Cancer Science
DOI 10.1111/j.1349-7006.2008.00878.xPMC PMC11158053
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Abstract

Telomerase activation is a critical step for human carcinogenesis through the maintenance of telomeres, but the activation mechanism during carcinogenesis remains unclear. Transcriptional regulation of the human telomerase reverse transcriptase ( hTERT ) gene is the major mechanism for cancer‐specific activation of telomerase, and a number of factors have been identified to directly or indirectly regulate the hTERT promoter, including cellular transcriptional activators (c‐Myc, Sp1, HIF‐1, AP2, ER, Ets, etc.) as well as the repressors, most of which comprise tumor suppressor gene products, such as p53, WT1, and Menin. Nevertheless, none of them can clearly account for the cancer specificity of hTERT expression. The chromatin structure via the DNA methylation or modulation of nucleosome histones has recently been suggested to be important for regulation of the hTERT promoter. DNA unmethylation or histone methylation around the transcription start site of the hTERT promoter triggers the recruitment of histone acetyltransferase (HAT) activity, allowing hTERT transcription. These facts prompted us to apply these regulatory mechanisms to cancer diagnostics and therapeutics. Telomerase‐specific replicative adenovirus (Telomelysin, OBP‐301), in which E1A and E1B genes are driven by the hTERT promoter, has been developed as an oncolytic virus that replicates specifically in cancer cells and causes cell death via viral toxicity. Direct administration of Telomelysin was proved to effectively eradicate solid tumors in vivo , without apparent adverse effects. Clinical trials using Telomelysin for cancer patients with progressive stages are currently ongoing. Furthermore, we incorporated green fluorescent protein gene ( GFP ) into Telomelysin (TelomeScan, OBP‐401). Administration of TelomeScan into the primary tumor enabled the visualization of cancer cells under the cooled charged‐coupled device (CCD) camera, not only in primary tumors but also the metastatic foci. This technology can be applied to intraoperative imaging of metastatic lymphnodes. Thus, we found novel tools for cancer diagnostics and therapeutics by utilizing the hTERT promoter. ( Cancer Sci 2008; 99: 1528–1538)

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Crossref · 10.1111/j.1349-7006.2008.00878.x

Cites

18 of 18 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 59 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Tumor growth was severely retarded by treatment with Telomelysin.

    “Note that the tumor growth was severely retarded by the treatment with Telomelysin.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Active chromatin marks around the transcription start site of the hTERT promoter are tightly associated with unmethylated DNA in hTERT-positive cells.

    “It is of particular interest that active chromatin marks present around the transcription start site of the hTERT promoter are tightly associated with unmethlated DNA in hTERT-positive cells, suggesting a mechanism that is consistent with the usual dynamics of gene regulation via DNA methylation.”
    Quote in the paperSubstantial claim
  • Findingown data

    TelomeScan replicated only 2 orders of magnitude in normal human fibroblasts without significant GFP expression.

    “In contrast, it replicated only 2 orders of magnitude in normal human fibroblasts without significant GFP expression.”
    Quote in the paperSubstantial claim
  • Findingcitation

    No significant adverse effects on normal tissues have been reported so far, even in hematopoietic cells, which may be highly susceptible to Telomelysin due to telomerase-positive stem cells.

    “Although we have to wait for the final report of the clinical trial, no significant adverse effects on normal tissues have been reported so far, even in hematopoietic cells, which may be highly susceptible to Telomelysin due to the presence of telomerase-positive stem cells. (35)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] source

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  • Findingown data

    Some para-arotic lymph nodes exhibited GFP signals 24 h after intratumoral injection of TelomeScan into the primary site.

    “Some para-arotic lymph nodes exhibited GFP signals 24 h after intratumoral injection of TelomeScan into the primary site.”
    Quote in the paperSubstantial claim
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 4
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingcitation

    TelomeScan can replicate preferentially in hTERT-promoter-positive cancer cells and exhibit GFP signals detectable by fluorescent microscopy in exfoliated cells from certain tissues.

    “Once exfoliated cells obtained from certain tissues are infected, the TelomeScan can replicate preferentially in hTERT-promoter-positive cancer cells and exhibit GFP signals that can easily been detected by fluorescent microscopy (Fig. 4c) (Maida et al., manuscript in preparation).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Maida et al., manuscript in preparation

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  • May combine two claims.

    Findingown data

    Lymph nodes with GFP signals had metastatic foci, while those without GFP signals had no metastatic foci.

    “Lymph nodes with GFP signals were dissected, followed by histological examination, and were found to have metastatic foci of the tumor cells, while those without GFP signals had no metastatic foci (Fig. 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TelomeScan replicated 5-6 orders of magnitude by 3 days after infection in human cancer cell lines and induced GFP expression.

    “TelomeScan replicated 5-6 orders of magnitude by 3 days after infection in human cancer cell lines and coordinately induced GFP expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When TelomeScan was injected into subcutaneous xenografts of human cancer cells, the xenografts exhibited GFP signals over their entire area and were easily visualized, indicating replication and spread throughout the tumors.

    “When TelomeScan was directly injected to subcutaneous xenografts of human cancer cells, the xenografts exhibited GFP signals over their entire area and were easily visualized, indicating that TelomeScan had replicated and spread throughout the tumors (Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TelomeScan has lesser but still sufficient cytotoxic effects compared with Telomelysin.

    “We confirmed that TelomeScan has lesser but still sufficient cytotoxic effects compared with Telomelysin (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The sensitivity and specificity of this imaging technique to detect metastatic foci are 92.3% and 86.6%, respectively.

    “The sensitivity and specificity of this imaging technique to detect metastatic foci are 92.3% and 86.6%, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Telomelysin selectively expresses E1A and E1B in cancer cells, replicates 5-6 orders of magnitude by 3 days after infection, and is attenuated up to 2 orders of magnitude in cultured normal cells.

    “In vitro replication assays revealed that Telomelysin induced selective expression of E1A and E1B in cancer cells, resulting in viral replication at 5-6 orders of magnitude by 3 days after infection, while it was attenuated by up to 2 orders of magnitude in cultured normal cells.(106,110)”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    • cites [110]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    A phase I clinical trial of Telomelysin as monotherapy has been performed in the United States.

    “A phase I clinical trial of Telomelysin as monotherapy has been performed in the United States.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Telomerase is active in roughly 90% of human cancers regardless of tumor type, whereas most normal tissues have inactive telomerase.

    “Telomerase activation is observed in approximately 90% of human cancers, irrespective of tumor type, while most normal tissues contain inactivated telomerase.(1)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    hTERT expression is highly specific to cancer cells and tightly associated with telomerase activity, while other telomerase subunits are constitutively expressed in both normal and cancer cells.

    “Numerous studies have demonstrated that hTERT expression is highly specific to cancer cells and tightly associated with telomerase activity, while the other subunits are constitutively expressed both in normal and cancer cells.(9)(10)(11)(12)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9]

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    • cites [10]

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    • cites [11]

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  • May combine two claims.

    Premisecitation

    HIF-2α enhances hTERT expression in renal-cell carcinoma but represses hTERT transcription in glioma cells.

    “While HIF2-α enhances hTERT expression in renal-cell carcinoma, it represses hTERT transcription in glioma cells, adding a further layer of complexity to the relationship between hypoxia and telomerase activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AP-2 is a transcriptional activator of the hTERT promoter and shows tumor-specific binding to the core promoter region.

    “Activating Enhancer-binding Protein-2 (AP-2) was recently identified as a transcriptional activator of the hTERT promoter (23) and, of particular interest, it exhibited tumor-specific doi: 10.1111/j.1349-7006.2008.00878.x© 2008 Japanese Cancer Association binding to the core promoter region.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23]

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Hypoxia activates hTERT mRNA in cancer cells in vitro, and HIF-1 acts as a critical transcription factor for this activation.

    “The presence of putative HIF-1 binding sites on the hTERT promoter prompted us to examine the involvement of HIF-1 in regulation of hTERT in tumor hypoxia: we found that hypoxia activated hTERT mRNA in cancer cells in vitro.(24,25)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24]

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    • cites [25]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HIF-1 can inhibit hTERT expression in colon cancer cells by counteracting Myc.

    “In contrast to these findings, Koshiji et al. observed that HIF-1 inhibited hTERT expression in colon cancer cells.(26)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] source

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  • May combine two claims.

    Premisecitation

    An E-box-mediated repression mechanism functions in various normal human cells but is inactive in some hTERT-positive cancer cells.

    “This E-box-mediated repression functions in various types of normal human cells, while it is inactive in some, but not all, hTERT-positive cancer cells, providing evidence for an endogenous mechanism for hTERT transcriptional repression that becomes inactivated during carcinogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86]

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationnone given

    The hTERT promoter is ideal for overcoming the limitations of other tumor-specific promoters because it is broadly active in many tumor types and can drive strong transgene expression.

    “The hTERT promoter is ideal to overcome the shortcoming of these promoters.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Tamoxifen regulates hTERT expression in a cell-type-specific manner, inhibiting hTERT mRNA in breast cancer cells with estrogen but activating it in endometrial cancer cells.

    “Tamoxifen, a selective estrogen receptor modulator, also regulates hTERT expression in a celltype-specific manner; (32) tamoxifen inhibits the growth of breast cancer cells, as well as hTERT mRNA expression in the presence of estrogen (E2), antagonizing the E2 effects, in which the ERE on the promoter is involved.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

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    Premisecitation

    SMYD3 binds to CCCTCCC motifs in the hTERT core promoter and activates hTERT transcription.

    “In fact, SMYD3 was confirmed to bind some of the CCCTCCC motifs within the core promoter of hTERT and activate hTERT transcription.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 5' promoter region of hTERT was cloned, and its transcriptional activity is up-regulated specifically in cancer cells while silent in most normal cells.

    “In 1999 we and other groups successfully cloned the 5′-promoter region of the hTERT gene.(13)(14)(15) Transient expression assays using the 3.0 kb of the flanking sequences of the hTERT gene revealed that the transcriptional activity was up-regulated specifically in cancer cells, while it was silent in most normal cells.(13)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The GC-boxes in the hTERT core promoter bind Sp1 and function synergistically to maintain promoter activity.

    “There are at least five GC-boxes within the core promoter of hTERT, proven by EMSA to bind Sp1.(22) Introduction of mutations in these GC-boxes significantly decreased the transcriptional activity of the promoter, while overexpression of Sp1 in cells that contain relatively low levels of endogenous Sp1 enhanced the promoter activity.(17)”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    In cells lacking genome checkpoint functions, telomere dysfunction accelerates genomic instability and promotes cancer initiation.

    “Thus, in the absence of genome checkpoint functions, telomere dysfunction accelerates genomic instability, facilitating cancer initiation.(4)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] source

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    Premisecitation

    High-risk HPV E6 activates hTERT transcription without up-regulating c-Myc.

    “However, subsequent studies confirmed that high-risk HPV E6 activates hTERT transcription but is not associated with up-regulation of c-Myc.(51)(52)(53)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51]

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    • cites [52]

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    • cites [53]

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  • May combine two claims.

    Premisecitation

    Androgen activates hTERT mRNA in androgen-sensitive prostate cancer cells, but this regulation is not due to hTERT promoter activation.

    “Androgen was also shown to activate hTERT mRNA in androgen-sensitive prostate cancer cells but this regulation was not due to hTERT promoter activation.(33)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    c-Myc binds to E-boxes on the hTERT promoter and activates its transcription.

    “In fact, several groups confirmed that c-Myc binds to E-boxes on the hTERT promoter and activates the transcription (15)(16)(17)(18)(19) which established the scenario that c-Myc is a key regulator of hTERT transcription during carcinogenesis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15]

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    • cites [16]

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    • cites [17] source

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  • May combine two claims.

    Interpretationreasoning

    Sp1 is ubiquitously expressed in normal cells and is therefore not a strong candidate for causing cancer-specific hTERT expression.

    “However, Sp1 is ubiquitously expressed in a wide range of normal cells, and is not therefore a strong candidate to cause cancer-specific hTERT expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FR901228 increased Telomelysin replication and led to synergistic antitumor effects.

    “In fact, FR901228, a potent HDAC inhibitor, activated CAR levels on target tumor cells, increasing the amounts of Telomelysin replication, leading to synergistic antitumor effects.(114)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Several barriers appear to limit the efficacy of Telomelysin, including some tumor types being refractory to infection due to low CAR expression, and adverse effects on normal hTERT-positive cells.

    “Several barriers appear to limit the efficacy of Telomelysin, probably including some tumor types being refractory to infection with Telomelysin due to low CAR expression, as well as the adverse effects on normal hTERTpositive cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Multiple factors are involved in hTERT regulation, probably in combination, and chromatin remodeling appears to play a critical role.

    “It is obvious that multiple factors are involved in its regulation, probably in combination, and chromatin remodeling appears to play a critical role.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The mechanism of Telomelysin-docetaxel synergism is unclear, but residual viable cells after docetaxel treatment permit Telomelysin replication, leading to effective cell death.

    “The mechanism of this synergism remains unclear at present, but residual viable cells that survived after the treatment with docetaxel permit the replication of Telomelysin, leading to effective cell death.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Intraoperative monitoring and detection of TelomeScan signals in metastatic lymph nodes may provide revolutionary change in diagnostic modality during surgery.

    “Intraoperative monitoring and detection of TelomeScan signals in the metastatic lymph nodes may provide revolutionary change in diagnostic modality during surgery.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Key to success of hTERT-dependent oncolytic virotherapy as a novel cancer agent is combining it with conventional therapies.

    “Key to success of hTERT-dependent oncolytic virothrapy as a novel agent for cancer is a means of combining it with conventional therapies such as chemotherapy, radiotherapy, immunotherapy, surgery, or recently established molecular target therapies.”
    Quote in the paperNot a substantial claim
31 of 31

  • The authors state this as an assumption.

    Replicated TelomeScan can pass through the lymphatic pathway from primary tumors to regional or sentinel lymph nodes and can replicate in metastatic foci.

    “Theoretically, replicated TelomeScan can pass through the lymphatic pathway from the primary tumors to the regional or sentinel lymph nodes and can replicate in metastatic foci.”

  • The paper relies on this without support.

    Adenoviral spread and subsequent replication at distal sites may be useful to visualize metastatic foci of cancers.

    “Adenoviral spread and subsequent replication at distal sites may also be useful to visualize the metastatic foci of cancers.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The TERT promoter is regulated in some contexts by c-Myc, estrogen receptor, and Sp1.

    “The TERT promoter is controlled in some contexts by the c-Myc oncogene, which recognizes E-boxes within the promoter (56,57), and by estrogen receptor and Sp1 (58).”

    From Telomeres and telomerase in cancer (2010) · cites this paper as [57]

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Sorted by citations

Authors
Kyo, S., Takakura, M., Fujiwara, T., & Inoue, M.
Affiliations
  • Kanazawa University (JP)
  • Okayama University Hospital (JP)
Corresponding author
Kyo, Satoru
ORCID
Venue
Cancer Science
Publisher
Wiley
Published
2008-08
Volume
99
Issue
8
Pages
1528-1538
ISSN
  • 1347-9032 (ISSN-L)
  • 1349-7006
DOI
10.1111/j.1349-7006.2008.00878.x
PMC
PMC11158053
OpenAlex
W2092712702
Semantic Scholar
405ae7af53cd108ad8aa5894e1823e4b9ca3cc15
Cited by
347
References
18
Citations by year
2026: 3 · 2025: 8 · 2024: 8 · 2023: 15 · 2022: 16 · 2021: 18 · 2020: 20 · 2019: 17 · 2018: 18 · 2017: 21 · 2016: 36 · 2015: 31 · 2014: 31 · 2013: 25 · 2012: 22
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 13 d)
Locations
  • Cancer Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
  • Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) (submittedVersion, cc-by-nc-nd)
Funders
Kanazawa University
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
hTERT promoter, telomerase activation, transcriptional regulation, cancer-specific gene expression, DNA methylation, histone methylation, histone acetyltransferase, oncolytic adenovirus, OBP-301, c-Myc, p53, carcinogenesis
MeSH terms
Adenoviridae, Animals, Humans, Lymphatic Metastasis, Neoplasms, Promoter Regions, Genetic, Gene Expression Regulation, Neoplastic, Telomerase, Green Fluorescent Proteins, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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