Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TNKS (cancer-related)
Aberrant Wnt signaling pathway is associated with a wide array of tumor types and plays an important role in the drug resistance of cancer stem cells (CSCs). To explore the effects and mechanism of WNT signaling pathway inhibitor XAV939 on drug resistance in colon cancer cells, the colon cancer cells SW480 and SW620 were treated with 5-fluorouracil (5-FU)/cisplatin (DDP) alone or combined with XAV939. Cell cycle distribution, apoptosis level and the percentage of CD133+ cells were detected by flow cytometry. The protein expression of Axin, β-catenin, EpCAM, TERT and DCAMKL-1 was detected by western blotting. XAV939 upregulated Axin , decreased the total and nuclei of β-catenin in SW480 and SW620 cells. Furthermore, XAV939 significantly downregulated the CSC markers EpCAM, TERT and DCAMKL-1 in SW480 cells, as well as EpCAM in SW620 cells. No significant difference was found in the apoptosis of SW480 and SW620 cells with XAV939 treatment, but XAV939 significantly increased apoptosis induced by 5-FU/DDP in SW480 cells, whereas, the effects were slight in SW620 cells. Collectively, we show for the first time that the WNT signaling pathway inhibitor XAV939 was able to significantly increase the apoptosis induced by 5-FU/DDP, accompanied by the protein expression level alternation of β-catenin, Axin and CSC markers in colon cancer cells. Axin, an important component of Wnt/β-catenin signaling pathway could be a potential molecular target for reversing multidrug resistance in colon cancer.
Zeng X, Montoute M, Bee TW, et al.A High-Content Imaging Screen for Cellular Regulators of β-Catenin Protein Abundance.
J Biomol Screen. 2016; 21(3):260-8 [PubMed
] Related Publications
Abnormal accumulation of β-catenin protein, a key transcriptional activator required for Wnt signaling, is the hallmark of many tumor types, including colon cancer. In normal cells, β-catenin protein level is tightly controlled by a multiprotein complex through the proteosome pathway. Mutations in the components of the β-catenin degradation complex, such as adenomatous polyposis coli (APC) and Axin, lead to β-catenin stabilization and the constitutive activation of target genes. Since the signal transduction of Wnt/β-catenin is mainly mediated by protein-protein interactions, this pathway has been particularly refractory to conventional target-based small-molecule screening. Here we designed a cellular high-content imaging assay to detect β-catenin protein through immunofluorescent staining in the SW480 colon cancer cell line, which has elevated β-catenin endogenously. We demonstrate that the assay is robust and specific to screen a focused biologically diverse chemical library set against known targets that play diverse cellular functions. We identified a number of hits that reduce β-catenin levels without causing cell death. These hits may serve as tools to understand the dynamics of β-catenin degradation. This study demonstrates that detecting cell-based β-catenin protein stability is a viable approach to identifying novel mechanisms of β-catenin regulation as well as small molecules of therapeutic potential.
Deregulated WNT/β-catenin signaling contributes to the development of a subgroup of hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide. Within this pathway, the tankyrase enzymes (TNKS1 and TNKS2) degrade AXIN and thereby enhance β-catenin activity. We evaluate TNKS enzymes as potential therapeutic targets in HCC, and the anti-tumor efficacy of tankyrase inhibitors (XAV939, and its novel nitro-substituted derivative WXL-8) in HCC cells. Using semi-quantitative RT-PCR, we found significantly elevated levels of TNKS1/2 mRNA in tumor liver tissues compared to adjacent non-tumor livers, at protein levels only TNKS1 is increased. In HepG2, Huh7cells, siRNA-mediated knockdown suppression of endogenous TNKS1 and TNKS2 reduced cell proliferation, together with decreased nuclear β-catenin levels. XAV939 and WXL-8 inhibited cell proliferation and colony formation in HepG2, Huh7, and Hep40 cells (p < 0.05), with stabilization of AXIN1 and AXIN2, and decreased β-catenin protein levels. XAV939 and WXL-8 also attenuated rhWNT3A-induced TOPflash luciferase reporter activity in HCC cells, indicating reduced β-catenin transcriptional activity, consistent with decreased nuclear β-catenin levels. In vivo, intra-tumor injections of XAV939 or WXL-8 significantly inhibited the growth of subcutaneous HepG2 xenografts (P < 0.05). We suggest that tankyrase inhibition is a potential therapeutic approach for treating a subgroup HCC with aberrant WNT/β-catenin signaling pathway.
Gu C, Li Q, Zhu Y, et al.Genetic variants in the TEP1 gene are associated with prostate cancer risk and recurrence.
Prostate Cancer Prostatic Dis. 2015; 18(4):310-6 [PubMed
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BACKGROUND: Telomere-related genes play an important role in carcinogenesis and progression of prostate cancer (PCa). It is not fully understood whether genetic variations in telomere-related genes are associated with development and progression in PCa patients.
METHODS: Six potentially functional single-nucleotide polymorphisms (SNPs) of three key telomere-related genes were evaluated in 1015 PCa cases and 1052 cancer-free controls, to test their associations with risk of PCa. Among 426 PCa patients who underwent radical prostatectomy (RP), the prognostic significance of the studied SNPs on biochemical recurrence (BCR) was also assessed using the Kaplan-Meier analysis and Cox proportional hazards regression model. The relative telomere lengths (RTLs) were measured in peripheral blood leukocytes using real-time PCR in the RP patients.
RESULTS: TEP1 rs1760904 AG/AA genotypes were significantly associated with a decreased risk of PCa (odds ratio (OR): 0.77, 95% confidence interval (CI): 0.64-0.93, P=0.005) compared with the GG genotype. By using median RTL as a cutoff level, RP patients with TEP1 rs1760904 AG/AA genotypes tended to have a longer RTL than those with the GG genotype (OR: 1.55, 95% CI: 1.04-2.30, P=0.031). A significant interaction between TEP1 rs1713418 and age in modifying PCa risk was observed (P=0.005). After adjustment for clinicopathologic risk factors, the presence of heterozygotes or rare homozygotes of TEP1 rs1760904 and TNKS2 rs1539042 were associated with BCR in the RP cohorts (hazard ratio: 0.53, 95% CI: 0.36-0.79, P=0.002 and hazard ratio: 1.67, 95% CI: 1.07-2.48, P=0.017, respectively).
CONCLUSIONS: These data suggest that genetic variations in the TEP1 gene may be biomarkers for risk of PCa and BCR after RP.
Iglesias P, Costoya JAThe antimitotic potential of PARP inhibitors, an unexplored therapeutic alternative.
Curr Top Med Chem. 2014; 14(20):2346-65 [PubMed
] Related Publications
ADP-ribosylation or PARsylation is one of the most abundant modifications of proteins and DNA. Although the usual context for PARsylation involves the detection and repair of DNA damage in the cell, poly(ADP-ribose) polymerases are known to regulate a number of biological processes besides maintaining genome integrity. One of these processes is the assembly and maintenance of the mitotic spindle where the presence of PARP-1 and tankyrase 1 (TNKS1), two of the best-characterized members of the PARP superfamily, is of critical importance. Here, we recapitulate the biological implications of the absence of poly(ADP-ribose) polymerases and depletion of PARsylation occurrence in mitosis in order to better understand the antimitotic effects of PARP inhibitors. In this regard, we also present an overview of the existing and more relevant molecules, with a special attention to the historical development of their pharmacological properties and structures, as well as a brief summary of clinical trials involving PARP inhibitors.
Tian X, Hou W, Bai S, et al.XAV939 inhibits the stemness and migration of neuroblastoma cancer stem cells via repression of tankyrase 1.
Int J Oncol. 2014; 45(1):121-8 [PubMed
] Related Publications
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. One fundamental issue regarding NB recurrence and metastasis is the maintenance of cancer stem cells (CSCs) stemness. Tankyrase 1 (TNKS1) is overexpressed in several types of cancers and in NB cell lines. XAV939 is a small molecule inhibitor of TNKS1 and can induce apoptosis of NB cells. In this study, we showed that the surface marker CD133 method was more suitable for isolating NB CSCs than the side-population method, and 60 µM etoposide was optimal for enriching NB CSCs. The NB CSCs were demonstrated in juvenescence or stemness state by electron microscopy, which was in line with the characteristics of CSCs. Furthermore, we demonstrated that the expression of the CSCs marker CD133 and migration ability of CSCs decreased after XAV939 treatment or by RNAi‑mediated knockdown of the TNKS1 gene. These findings suggest that XAV939 treatment or RNAi-TNKS1 inhibits the stemness and migration of NB CSCs via the repression of TNKS1, and TNKS1 may be a potential molecular target for eliminating NB CSCs by small molecule drugs.
Lu H, Lei Z, Lu Z, et al.Silencing tankyrase and telomerase promotes A549 human lung adenocarcinoma cell apoptosis and inhibits proliferation.
Oncol Rep. 2013; 30(4):1745-52 [PubMed
] Related Publications
Telomeres are the end structures of chromosomes in mammalian cells; they play a pivotal role in maintaining the stability of the chromosome and become shorter with each cell division. However, several types of tumor cells express telomerase in very high levels to overcome this crisis and achieve the ability to proliferate endlessly. The telomerase inhibitors can partly inhibit tumor cell proliferation and promote apoptosis, but their roles are only limited. Tankyrase is a poly(ADP-ribose) polymerase which has synergistic effect on telomerase, and is expressed in lung cancer cells in high levels. In the present study, antisense oligonucleotides of telomerase (ashTERT) and tankyrase (asTANKS) were used as specific inhibitors to silence the expression of target genes in A549 human lung adenocarcinoma cells by transfection. The results showed that ashTERT and asTANKS suppressed the expression of telomerase and tankyrase significantly; both inhibited the activity of telomerase and the combination group achieved better effect, but only ashTERT shortened the length of telomeres, asTANKS did not. Further studies showed that ashTERT and asTANKS-promoted A549 apoptosis was not mediated by downregulation of the expression of the anti-apoptotic gene BCL-2 or upregulation of the expression of the pro-apoptotic gene BAX, but by adjusting the two isoforms proportion of myeloid cell leukemia-1 (MCL-1) which can interact with tankyrase directly. MCL-1short (MCL-1S), a pro-apoptotic gene, increased more than MCL-1Long (MCL-1L) which is an anti-apoptotic gene, leading to A549 cell apoptosis and a similar result was obtained in nude mice in vivo. The present study suggests that combination of the inhibitors of telomerase and tankyrase can be used as a strategy for the treatment of lung cancer in humans.
T-oligo, an 11-base oligonucleotide homologous to the 3'-telomeric overhang, is a novel, potent therapeutic modality in melanoma and multiple other tumor types. T-oligo is proposed to function in a manner similar to experimental disruption of the telomere overhang and induces DNA damage responses including apoptosis, differentiation and senescence. However, important components involved in T-oligo induced responses are not defined, particularly the role of p53, TRF1 and TRF2 in mediating the T-oligo induced responses. In MU, PM-WK, and MM-MC melanoma cells, exposure to T-oligo upregulates p53 expression and phosphorylation, resulting in cellular differentiation and activation of a caspase-mediated apoptotic cascade. However, siRNA-mediated knockdown of p53 completely blocks T-oligo induced differentiation and significantly decreases apoptosis, suggesting that p53 is an important mediator of T-oligo induced responses. In addition, we characterized the roles of telomere binding proteins, TRF1, TRF2, and tankyrase-1, in T-oligo induced damage responses. We demonstrate that tankyrase-1 activity is required for initiation of T-oligo induced damage responses including p53 phosphorylation and reduction of cellular proliferation. These results highlight TRF1, TRF2, tankyrase-1 and p53 as important elements in T-oligo mediated responses and suggest new avenues for research into T-oligo's mechanism of action.
Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry.
BACKGROUND: New pharmacologic targets are urgently needed to treat or prevent lung cancer, the most common cause of cancer death for men and women. This study identified one such target. This is the canonical Wnt signaling pathway, which is deregulated in cancers, including those lacking adenomatous polyposis coli or β-catenin mutations. Two poly-ADP-ribose polymerase (PARP) enzymes regulate canonical Wnt activity: tankyrase (TNKS) 1 and TNKS2. These enzymes poly-ADP-ribosylate (PARsylate) and destabilize axin, a key component of the β-catenin phosphorylation complex.
METHODS: This study used comprehensive gene profiles to uncover deregulation of the Wnt pathway in murine transgenic and human lung cancers, relative to normal lung. Antineoplastic consequences of genetic and pharmacologic targeting of TNKS in murine and human lung cancer cell lines were explored, and validated in vivo in mice by implantation of murine transgenic lung cancer cells engineered with reduced TNKS expression relative to controls.
RESULTS: Microarray analyses comparing Wnt pathway members in malignant versus normal tissues of a murine transgenic cyclin E lung cancer model revealed deregulation of Wnt pathway components, including TNKS1 and TNKS2. Real-time PCR assays independently confirmed these results in paired normal-malignant murine and human lung tissues. Individual treatments of a panel of human and murine lung cancer cell lines with the TNKS inhibitors XAV939 and IWR-1 dose-dependently repressed cell growth and increased cellular axin 1 and tankyrase levels. These inhibitors also repressed expression of a Wnt-responsive luciferase construct, implicating the Wnt pathway in conferring these antineoplastic effects. Individual or combined knockdown of TNKS1 and TNKS2 with siRNAs or shRNAs reduced lung cancer cell growth, stabilized axin, and repressed tumor formation in murine xenograft and syngeneic lung cancer models.
CONCLUSIONS: Findings reported here uncovered deregulation of specific components of the Wnt pathway in both human and murine lung cancer models. Repressing TNKS activity through either genetic or pharmacological approaches antagonized canonical Wnt signaling, reduced murine and human lung cancer cell line growth, and decreased tumor formation in mouse models. Taken together, these findings implicate the use of TNKS inhibitors to target the Wnt pathway to combat lung cancer.
Lau T, Chan E, Callow M, et al.A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth.
Cancer Res. 2013; 73(10):3132-44 [PubMed
] Related Publications
Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.
Kato M, Nakayama M, Agata M, Yoshida KGene expression levels of human shelterin complex and shelterin-associated factors regulated by the topoisomerase II inhibitors doxorubicin and etoposide in human cultured cells.
Tumour Biol. 2013; 34(2):723-33 [PubMed
] Related Publications
Human telomerase reverse transcriptase (hTERT) is responsible for telomere elongation, and its activity is strongly related to the expression level of the hTERT gene; however, the transcriptional regulation of telomeric genes, which play a central role in telomere maintenance and protection by facilitating replication and regulating telomerase access, is poorly understood. In this study, we aimed to reveal the changes in the mRNA expression of six components of the shelterin complex and three shelterin complex-associated factors in topoisomerase II inhibitor-treated human cultured cells. Using a quantitative gene expression analysis, we found that a reduction in telomeric repeat-binding factor 1 (TRF1), protection of telomeres (POT1), and TRF1-interacting ankyrin-related ADP-ribose polymerase 1 (TNKS1) mRNAs was observed in etoposide- and doxorubicin-treated HeLa and U-2 OS cells, while an increased TRF2-interacting telomeric protein (RAP1) mRNA level was observed in U-2 OS cells. Furthermore, doxorubicin suppressed TRF1 and POT1 mRNAs in both Saos-2 and WI-38 cells and increased RAP1 mRNA in WI-38 cells. In agreement with the results obtained in the quantitative gene expression analysis in U-2 OS cells, the topoisomerase II inhibitors negatively and positively regulated the POT1 and RAP1 gene promoters, respectively. Taken together, these results suggest the successful identification of unique topoisomerase II inhibitor-inducible telomeric genes and provide mechanistic insight into the regulation of telomeric gene expression by chemotherapeutic agents.
Yanowsky K, Barroso A, Osorio A, et al.Mutational analysis of telomere genes in BRCA1/2-negative breast cancer families with very short telomeres.
Breast Cancer Res Treat. 2012; 134(3):1337-43 [PubMed
] Related Publications
A majority of the familial breast cancer cases are not explained by mutations in the best-known high susceptibility genes BRCA1 and BRCA2. Since there is a link between DNA repair and telomere maintenance mechanisms, we have investigated for the first time the role of telomere genes in breast cancer predisposition. By a combination of DHPLC and direct sequencing, we screened for sequence variation in 14 telomere-related genes which included telomerase and shelterin complexes in index cases from 50 BRCA1/2-negative families previously characterized to have very short telomere length in peripheral blood leukocytes. Clear pathogenic changes were not detected in any of the genes analyzed. Most of the changes were non-coding variants and only nine corresponded to coding variants located in TPP1, TINF2, NHP2, TNKS, and RAD54B genes; although only two corresponded to coding missense changes leading to aminoacid changes in genes NHP2 and RAD54B. However, functional prediction analysis and control population studies of both variants ruled out its possible pathogenic role. Our results discard a major contribution of telomere-specific genes in hereditary breast cancer.
Aberrant activation of canonical Wingless-type MMTV integration site family (Wnt) signaling is pathognomonic of colorectal cancers (CRC) harboring functional mutations in either adenomatous polyposis coli or β-catenin. Coincident with Wnt cascade activation, CRCs also up-regulate the expression of Wnt pathway feedback inhibitors, particularly the putative tumor suppressor, Axin2. Because Axin2 serves as a negative regulator of canonical Wnt signaling in normal cells, recent attention has focused on the utility of increasing Axin2 levels in CRCs as a means to slow tumor progression. However, rather than functioning as a tumor suppressor, we demonstrate that Axin2 acts as a potent promoter of carcinoma behavior by up-regulating the activity of the transcriptional repressor, Snail1, inducing a functional epithelial-mesenchymal transition (EMT) program and driving metastatic activity. Silencing Axin2 expression decreases Snail1 activity, reverses EMT, and inhibits CRC invasive and metastatic activities in concert with global effects on the Wnt-regulated cancer cell transcriptome. The further identification of Axin2 and nuclear Snail1 proteins at the invasive front of human CRCs supports a revised model wherein Axin2 acts as a potent tumor promoter in vivo.
Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC.
Waaler J, Machon O, Tumova L, et al.A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice.
Cancer Res. 2012; 72(11):2822-32 [PubMed
] Related Publications
Increased nuclear accumulation of β-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/β-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the β-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the β-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the β-catenin destruction complex, followed by increased degradation of β-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of β-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/β-catenin signaling through inhibiting the PARP domain of TNKS1/2.
Tang B, Wang J, Fang J, et al.Expression of TNKS1 is correlated with pathologic grade and Wnt/β-catenin pathway in human astrocytomas.
J Clin Neurosci. 2012; 19(1):139-43 [PubMed
] Related Publications
Astrocytoma is the most common neoplasm of the central nervous system, and its malignancy is closely related to activation of the Wnt/β-catenin pathway. Accumulated evidence shows that tankyrase (TNKS) is necessary for the Wnt/β-catenin pathway, stabilizing β-catenin, and that TNKS1, a major member of the TNKS family, is involved in a wide range of human cancers. However, the expression of TNKS1 and the molecular relationship between TNKS1 and β-catenin in human astrocytomas is largely unknown. In the present study, we investigated the expression of TNKS1 in human astrocytomas using reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. The mRNA and protein expression levels of TNKS1 in astrocytomas were significantly higher compared with the normal brain tissues. Significant association between TNKS1 upregulation and pathological grade of astrocytomas was also confirmed. In addition, β-catenin immunostaining of the sampled tissues revealed a highly similar change to TNKS1. This study provides additional evidence for the involvement of TNKS1 gene and the Wnt/β-catenin signaling pathway in the genesis and progression of astrocytoma. TNKS1 may have a key role in astrocytomas.
Ouelaa-Benslama R, Emami SPinworm and TNKS inhibitors, an eccentric duo to derail the oncogenic WNT pathway.
Clin Res Hepatol Gastroenterol. 2011; 35(8-9):534-8 [PubMed
] Related Publications
The WNT/β-catenin pathway underlies many human cancers through mutations in the APC, β-catenin, and Axin genes. Activation of WNT signalling can also occur due to the localization of glycogen synthase kinase 3β(GSK3β) to the multivesicular bodies, which prevents the degradation of β-catenin. This leads to accumulation of β-catenin within the cytoplasmic matrix and nucleus of cancer cells, which triggers the transactivation of genes involved in cell proliferation, including various oncogenes. Recent research into the mechanistic regulations of molecule homeostasis and identification of new small-targeted inhibitors has provided further insights into the WNT signalling pathway and its role in human cancers. Novel WNT inhibitors target unsuspected cellular enzymes, such as tankyrases, or casein kinase 1α/γ, which controls the destruction of β-catenin and GSK3β. These could lead to the identification of new biomarkers and WNT-targeted inhibitors for the treatment of cancer.
Kim MS, An CH, Kim SS, et al.Frameshift mutations of poly(adenosine diphosphate-ribose) polymerase genes in gastric and colorectal cancers with microsatellite instability.
Hum Pathol. 2011; 42(9):1289-96 [PubMed
] Related Publications
Poly(adenosine diphosphate-ribose) polymerases consist of 16 members that modify nuclear proteins by building adenosine diphosphate-ribose polymers. Poly(adenosine diphosphate-ribose) polymerase 1, the prototype poly(adenosine diphosphate-ribose) polymerase, and some poly(adenosine diphosphate-ribose) polymerases are involved in many cellular processes including DNA damage response/repair, cell death, and inflammation. Inactivation of poly(adenosine diphosphate-ribose) polymerase proteins frequently enhances genomic instability and apoptosis inactivation, suggesting their roles in cancer development. However, genetic alterations of poly(adenosine diphosphate-ribose) polymerase genes have not been reported in cancers. In a public database, we found that poly(adenosine diphosphate-ribose) polymerase 1, poly(adenosine diphosphate-ribose) polymerase 11, poly(adenosine diphosphate-ribose) polymerase 14, poly(adenosine diphosphate-ribose) polymerase 15, tankyrase-1 (TNKS1), and tankyrase-2 (TNKS2) genes have mononucleotide repeats in coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability, we analyzed the mononucleotide repeats in 30 gastric cancers with high microsatellite instability, 13 gastric cancers with low microsatellite instability, 45 gastric cancers with stable microsatellite instability, 40 colorectal cancers with high microsatellite instability, 14 colorectal cancers with low microsatellite instability, and 45 colorectal cancers with stable microsatellite instability by single-strand conformation polymorphism. We found poly(adenosine diphosphate-ribose) polymerase 14, TNKS1, and TNKS2 mutations in 8, 4, and 18 cancers, respectively. They were detected in cancers with high microsatellite instability but not in cancers with low microsatellite instability or stable microsatellite instability. The gastric cancers and colorectal cancers with high microsatellite instability harbored one or more mutations of the poly(adenosine diphosphate-ribose) polymerase genes in 50.0% and 27.5%, respectively. Of the genes with mutations, we analyzed poly(adenosine diphosphate-ribose) polymerase 14 protein expression in gastric and colorectal cancers with high microsatellite instability. Loss of poly(adenosine diphosphate-ribose) polymerase 14 expression was observed in 33% of the gastric cancers and 35% of the colorectal cancers with high microsatellite instability, whereas its loss was observed in 31% of the gastric cancers and 36% of the colorectal cancers with low microsatellite instability/stable microsatellite instability. Our data indicate that frameshift mutations of poly(adenosine diphosphate-ribose) polymerases genes and losses of expression of poly(adenosine diphosphate-ribose) polymerase 14 protein are features of gastric and colorectal cancers with high microsatellite instability and suggest that these alterations might contribute to development of cancers with high microsatellite instability by deregulating poly(adenosine diphosphate-ribose) polymerase-mediated signaling.
In this study, we explored changes in the expression of the telomere maintenance genes, TRF1, TRF2 and TANK1 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Results were correlated with human telomerase reverse transcriptase (hTERT ) expression, telomere length (TL) and clinicopathological characteristics. Bone marrow (BM) samples from 132 patients, 64 with MGUS and 68 with MM, were studied. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify gene expression. TL was evaluated by terminal restriction fragment length analysis. MGUS patients showed increased TRF1 levels (P = 0.006) and lower expression of TRF2 (P = 0.005) and TANK1 (P = 0.003) compared with MM patients. For hTERT analysis, patients were divided into three groups by use of receiver operating characteristics: low (group I [GI]), intermediate (group II [GII]) and high (group III [GIII]) expression. We observed increasing expression of TRF2 and TANK1 from GI to GIII in MGUS and MM, with differences for both genes in MM (P < 0.01) and for TRF2 in MGUS (P < 0.01). GIII patients with the highest telomerase expression had the shortest TL. In both entities, a positive association between TRF2-TANK1, TRF2-hTERT and TANK1-hTERT (P ≤ 0.01) was observed. In MM, the percentage of BM infiltration and Ki-67 index were positively associated with TRF2, TANK1 and hTERT expression (P ≤ 0.03) and negatively with TL (P = 0.02), whereas lactate dehydrogenase was significantly correlated with TRF2 mRNA (P = 0.008). Our findings provide the first evidence of a modification in the expression of telomeric proteins in plasma cell disorders, and suggest that mechanisms other than telomerase activation are involved in TL maintenance in these pathologies.
Telomeres cap chromosome ends and are critical for genomic stability. Many telomere-associated proteins are important for telomere length maintenance. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins (RTEL1 and TERT-CLPTM1) as markers of cancer risk. We conducted an association study of telomere length and 743 SNPs in 43 telomere biology genes. Telomere length in peripheral blood DNA was determined by Q-PCR in 3,646 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Nurses' Health Study. We investigated associations by SNP, gene, and pathway (functional group). We found no associations between telomere length and SNPs in TERT-CLPTM1L or RTEL1. Telomere length was not significantly associated with specific functional groups. Thirteen SNPs from four genes (MEN1, MRE11A, RECQL5, and TNKS) were significantly associated with telomere length. The strongest findings were in MEN1 (gene-based P=0.006), menin, which associates with the telomerase promoter and may negatively regulate telomerase. This large association study did not find strong associations with telomere length. The combination of limited diversity and evolutionary conservation suggest that these genes may be under selective pressure. More work is needed to explore the role of genetic variants in telomere length regulation.
Ning X, Yang S, Wang R, et al.POT1 deficiency alters telomere length and telomere-associated gene expression in human gastric cancer cells.
Eur J Cancer Prev. 2010; 19(5):345-51 [PubMed
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Telomeres are the end structures of linear chromosomes in eukaryotic cells. The integrity of a telomere is essential for the overall stability of the chromosome. The human protection of telomeres 1 (hPOT1) protein, a single-stranded telomeric DNA binding protein, plays an important role in telomere protection and telomere length regulation. Here, we show that the loss of hPOT1 by RNA interference in BGC823 (poorly differentiated human gastric adenocarcinoma) cells leads to an increase in multinucleated giant cells, a decrease in cell proliferation and colony formation, induction of senescence and apoptosis, shortened telomere length, upregulation of the TRF1 gene and downregulation of the TRF2, tankyrase1 and hTERT genes. These results suggest that the loss of hPOT1 results in a decrease in the viability of BGC823 cells; hPOT1 regulates telomere length positively and has an influence on the expression of other telomere-associated genes in the cells.
Appierto V, Tiberio P, Cavadini E, et al.Antimitotic effect of the retinoid 4-oxo-fenretinide through inhibition of tubulin polymerization: a novel mechanism of retinoid growth-inhibitory activity.
Mol Cancer Ther. 2009; 8(12):3360-8 [PubMed
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The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR-treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unlike 4-HPR, causes marked cell accumulation in G2-M phase. Here, we investigated the molecular events involving 4-oxo-4-HPR-induced cell cycle perturbation in ovarian (A2780 and IGROV-1) and breast (T47D, estrogen receptor+ and BT-20, estrogen receptor-) cancer cells. 4-Oxo-4-HPR induced a delay of mitosis (with mitotic index increasing 5- to 6-fold in all cell lines) without progression beyond the anaphase, as shown by cyclin B1 expression. 4-Oxo-4-HPR induced multipolar spindle formation and phosphorylation of BUBR1, resulting in activation of the spindle checkpoint. Multipolar spindles were not due to impairment of pole-focusing process, loss of centrosome integrity, or modulation of the expression levels of molecules associated with spindle aberrations (Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp). We show here that 4-oxo-4-HPR targets microtubules because, in treated cells, it interfered with the reassembly of cold-depolymerized spindle microtubules and decreased the polymerized tubulin fraction. In cell-free assays, 4-oxo-4-HPR inhibited tubulin polymerization (50% inhibition of microtubule assembly at 5.9 micromol/L), suggesting a direct molecular interaction with tubulin. In conclusion, by showing that 4-oxo-4-HPR causes mitotic arrest through antimicrotubule activities, we delineate a new molecular mechanism for a retinoid.
Choi JE, Kang HG, Jang JS, et al.Polymorphisms in telomere maintenance genes and risk of lung cancer.
Cancer Epidemiol Biomarkers Prev. 2009; 18(10):2773-81 [PubMed
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This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (P(trend) < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer.
Varadi V, Brendle A, Brandt A, et al.Polymorphisms in telomere-associated genes, breast cancer susceptibility and prognosis.
Eur J Cancer. 2009; 45(17):3008-16 [PubMed
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Telomeres are essential structures for maintaining chromosomal stability and their length has been reported to correlate with cancer risk and clinical outcome. Single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins could affect telomere length and chromosomal stability by influencing gene expression or protein configuration in the telomeres. Here, we report the results of the first association study on genetic variation in telomere-associated genes and their effect on telomere length, breast cancer (BC) susceptibility and prognosis. We genotyped 14 potentially functional and most informative SNPs in nine telomere-associated genes (TERT, TEP1, TERF1, TERF2, TERF2IP, ACD, POT1, TNKS and TNKS2) in 782 incident BC cases and 1559 matched controls. Relative telomere length (RTL) varied statistically significantly between the genotypes of the SNPs rs446977 (TEP1, p=0.04), rs938886 (TEP1, p=0.04) and rs6990097 (TNKS, p=0.04). However, none of them was associated with BC susceptibility and only rs6990097 correlated with regional lymph node metastasis (odds ratio (OR) 1.38, 95% confidence interval (CI) 1.08-1.77). The strongest association with BC susceptibility was observed for rs3785074 (TERF2, OR 0.51, 95% CI 0.31-0.83) and rs10509637 (TNKS2, OR 1.33, 95% CI 1.08-1.62). Haplotype and diplotype analysis confirmed the association of the TNKS2 gene with BC susceptibility. rs3785074 (TERF2) was additionally associated with histologic grade (OR 1.44, 95% CI 1.08-1.92) and negative oestrogen receptor status (OR 2.93, 95% CI 1.13-7.58). None of the SNPs showed a significant correlation with survival of the breast cancer patients. With these results, none of the SNPs represents any valuable prognostic marker for BC.
McCabe N, Cerone MA, Ohishi T, et al.Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer.
Oncogene. 2009; 28(11):1465-70 [PubMed
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The BRCA1 and BRCA2 proteins are involved in the maintenance of genome stability and germ-line loss-of-function mutations in either BRCA1 or BRCA2 strongly predispose carriers to cancers of the breast and other organs. It has been demonstrated previously that inhibiting elements of the cellular DNA maintenance pathways represents a novel therapeutic approach to treating tumors in these individuals. Here, we show that inhibition of the telomere-associated protein, Tankyrase 1, is also selectively lethal with BRCA deficiency. We also demonstrate that the selectivity caused by inhibition of Tankyrase 1 is associated with an exacerbation of the centrosome amplification phenotype associated with BRCA deficiency. We propose that inhibition of Tankyrase 1 could be therapeutically exploited in BRCA-associated cancers.
Poonepalli A, Banerjee B, Ramnarayanan K, et al.Telomere-mediated genomic instability and the clinico-pathological parameters in breast cancer.
Genes Chromosomes Cancer. 2008; 47(12):1098-109 [PubMed
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A study was undertaken to correlate telomere dysfunction and genomic instability with the histopathological grades and the estrogen and progesterone receptor status in breast cancer. Sixty-one archived breast tissues (38 cancer tissues and 23 paired normal tissues) were used in the study. The breast tumor tissues showed significantly shorter telomeres (7.7 kb) compared with the paired adjacent tissues (9.0 kb) by Southern blot analysis. Moreover, telomere shortening was more significant in Grade III tumors than in the Grade II tumors (P = 0.05). Quantitative fluorescence in situ hybridization on paraffin tissue sections revealed a similar trend in telomere shortening. Telomere attrition was associated with telomere dysfunction as revealed by the presence of significantly higher anaphase bridges in tumor cells which was tumor grade dependent. Furthermore, estrogen receptive negative tumors displayed higher anaphase and internuclear bridges. Selected samples from each grade showed greater genomic imbalances in the higher grades than the lower grade tumors as detected by array-comparative genomic hybridization. Telomerase activity was found to be higher in the higher grades (Grade II and III) compared with the lower grade (Grade I). The average mRNA expression of TRF1 and POT1 was lower in the tumor tissues than in the normal tissues. Tankyrase 1 mRNA expression showed a grade-dependent increase in tumor tissues and its expression was also high in estrogen and progesterone negative tumors. The data support the notion that telomere dysfunction might be of value as a marker of aggressiveness of the tumors in breast cancer patients.
Angileri FF, Aguennouz M, Conti A, et al.Nuclear factor-kappaB activation and differential expression of survivin and Bcl-2 in human grade 2-4 astrocytomas.
Cancer. 2008; 112(10):2258-66 [PubMed
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BACKGROUND: Antiapoptotis resulting from hyperactivation of the transcription factor NF-kappaB has been described in several cancer types. It is triggered by the interaction of the tumor necrosis factor (TNF) with its receptors and recruitment of the intermediate factor TNF-receptor associated factor (TRAF) 2. The NF-kappaB transcriptional activity could amplify the expression of antiapoptotic genes. The authors investigated the activity of NF-kappaB, and the mRNA expression of TNFalpha, TNFalpha receptor, TRAF1, TRAF2, and TRAF-associated NF-kappaB activator (TANK), and the antiapoptotic genes Bcl-2, c-IAP 1 and 2, and Survivin in human astrocytic tumors.
METHODS: Eight low-grade astrocytomas (LGA), 10 anaplastic astrocytomas (AAs), 10 glioblastoma multiforme (GBM) samples were used; 4 samples of normal brain tissue were used as controls. The NF-kappaB activation was analyzed by electrophoretic mobility shift assay; TRAF1, TRAF2, TANK/I-TRAF, Bcl-2, c-IAP 1 and 2, and Survivin mRNA expressions were studied using real-time quantitative reverse-transcriptase polymerase chain reaction.
RESULTS: NF-kappaB hyperactivity was detected in tumor samples. mRNA of antiapoptotic genes, particularly BCL-2 and Survivin, was hyperexpressed in gliomas. Interestingly, BCL-2 was hyperexpressed in LGAs, whereas a very high level of Survivin featured high-grade gliomas. The differential expression of antiapoptotic genes yielded a tight clustering of all LGA and nearly all GBM samples in cluster analysis.
CONCLUSIONS: NF-kappaB and factors involved in its intracellular activation were up-regulated in gliomas. NF-kappaB-activated antiapoptotic genes were hyperexpressed in tumor samples, but showed a differential expression with higher levels of Bcl-2 in LGAs and higher levels of Survivin in GBMs.
Gelmini S, Quattrone S, Malentacchi F, et al.Tankyrase-1 mRNA expression in bladder cancer and paired urine sediment: preliminary experience.
Clin Chem Lab Med. 2007; 45(7):862-6 [PubMed
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BACKGROUND: The enzyme tankyrase-1 (TNKS-1), a member of the growing family of poly(ADP-ribose) polymerases (PARPs), was identified as a component of the human telomeric complex. PARPs catalyze the formation of long chains of poly(ADP-ribose) onto protein acceptors using NAD(+) as a substrate. TNKS-1 interacts with the telomeric DNA-binding protein TTAGGG repeat-binding factor 1 (TRF1), which is a negative regulator of telomere length. TNKS-1 is a positive regulator of telomere elongation and its activity appears to be upregulated in some human cancers.
METHODS: We evaluated for the first time TNKS-1 mRNA expression by real time RT-PCR in tumor tissue, paired normal mucosa and urine sediment in patients with transitional cell carcinoma (TCC) of the bladder. Samples were collected from 41 consecutive patients, 20 with non-muscle-invasive (pTa-pT1) and 21 with muscle-invasive (>/=pT2) bladder TCC. Results obtained in urine sediment were compared with those from 40 healthy subjects matched for age and sex.
RESULTS: In pTa-pT1 tumor tissues, TNKS-1 mRNA levels were significantly higher than in >/=pT2 patients (p<0.0001). In urine sediment from TCC patients, independent of tumor stage, TNKS-1 mRNA levels were significantly higher than in healthy controls, with maximal levels in >/=pT2 patients. In particular, TNKS-1 mRNA levels in urine were elevated in 31/41 patients with a sensitivity of 81% in >/=pT2 tumors and 65% in pTa-pT1 TCC. Of patients with pTa-pT1 tumors, 11 had a recurrence within 18 months after initial transurethral resection. In these patients, urine levels of TNKS-1 mRNA were higher than in non-relapsing patients (p=0.038).
CONCLUSIONS: In this preliminary study, TNKS-1 mRNA in urine sediment from patients with bladder TCC correlated with tumor stage, and higher preoperative levels were associated with increased risk of early recurrence.
Shervington A, Patel R, Lu C, et al.Telomerase subunits expression variation between biopsy samples and cell lines derived from malignant glioma.
Brain Res. 2007; 1134(1):45-52 [PubMed
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Although scientific advances have recognised the prognostic power of telomerase activity in different cancers, as yet there has been no investigation regarding the expression variation of telomerase subunits in glioma tissues and cell lines. In this study, a recurrent anaplastic ependymoma and seven glioblastoma biopsy samples, four cell lines and four controls including two normal brain tissues were analysed for telomerase subunit expression profiles together with telomerase activity. Since telomerase activity is linked to tumourgenesis, the genes were analysed with respect to their expression variation. TEP1 was expressed in all glioma cell lines and 70% of glioblastoma tissues, in addition to the control brain tissues. Tankyrase was expressed in 85% of the glioblastoma tissues and was down-regulated in the recurrent anaplastic ependymoma tissue control cell lines. However, it was expressed in the control tissues. Dyskerin was expressed in all cell lines and tissues apart from U87-MG and NHA cells and the recurrent anaplastic ependymoma tissue. As expected, PARP1 and GAPDH showed constitutive expression throughout all cell lines and tissues since both are known to be housekeeping genes. hTERT was expressed in all glioma cell lines and tissues but was absent in the control cells and tissues. Telomerase activity was absent in IPDDC-A2 cells and 57% of the glioblastoma tissues. These results suggest that hTERT expression and not telomerase activity possibly represents a simple and reliable biological diagnostic tool.