Research IndicatorsGraph generated 31 August 2019 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 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
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: DKK1 (cancer-related)
van Andel H, Kocemba KA, Spaargaren M, Pals STAberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options.
Leukemia. 2019; 33(5):1063-1075 [PubMed
] Related Publications
Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.
Wnt antagonist genes hypermethylation has been found in several tumors. Accordingly, the events that occur during the progression of adenoma to carcinoma have been characterized and include activation of the Wnt-pathway. Further, gastric adenoma (GA) is a premalignant lesion of gastric adenocarcinoma (GAC). In this paper, we focused our interesting on Wnt signaling path function in the pathogenesis of GAC.We compared the differences between low grade adenoma (LGA), high grade adenoma (HGA), GACs and corresponding normal gastric tissue (NGT). Specific indexes include the pathological characteristics of gastric neoplasia, Helicobacter pylori infection, β-catenin mutation status, and methylation status of Wnt antagonist genes.There was significant difference of β-catenin expression in patient with NGT, LGA, HGA, and GAC, the results respectively were 4.2%, 41.7%, 83.3%, and 91.7%. Only 1 GACs was detected exon 3 of β-catenin mutation. Wnt antagonist genes mRNA expression levels, such as APC, sFRP-1, Wif-1, and Dkk-1, were significantly reduced in GAC. Promoter methylation levels of the 4 genes were significantly elevated in GAC and HGA compared to NGT and LGA. However, there was no significant difference between HGAs and GACs. The β-catenin abnormal expression was correlated with hypermethylation of these 4 genes. Multiple gene concurrent methylation phenomenon was increased from NGTs to GACs; the amount of methylation genes in GACs and HGAs was more than NGTs and LGAs. The more methylation of the above-mentioned genes, the more severity of local inflammation. The infection rate of H pylori was significantly higher in patient with HGA (66.7%, 16/24) and GAC (58.5%, 14/24) than in LGAs (16.7%,4/24) (PHGA-LGA = .024, PGAC-LGA = .032). In addition, the present of H pylori also correlated with the β-catenin abnormal expression and the hypermethylation status of Wnt antagonist genes (P < .001). But other parameters in adenoma cases had no significantly related with infection of H pylori.Hypermethylation of Wnt antagonist genes may have a tight relationship with gastric tumorigenesis. And these genes may increase the incidence of GAC. Additionally, H pylori may have promotion function in GA formation.
Fan X, Huang X, Li Z, Ma XMicroRNA-372-3p promotes the epithelial-mesenchymal transition in breast carcinoma by activating the Wnt pathway.
J BUON. 2018 Sep-Oct; 23(5):1309-1315 [PubMed
] Related Publications
PURPOSE: To explore the role of microRNA (miR)-372-3p in the epithelial-mesenchymal transition (EMT) of breast carcinoma and its potential mechanism.
METHODS: The expression of miR-372-3p was detected by real-time PCR (RT-PCR) in 48 samples of breast carcinoma tissues, 30 samples of normal breast tissues, normal breast cells (MCF-10A) and breast carcinoma cells (MCF-7, MDA-MB-231 and HCC38). Transfection efficacy of miR-372-3p mimic and miR-372-3p inhibitor was determined by RT-PCR. Cell viability and invasion were determined by CCK-8 assay and wound healing assay, respectively. The interaction between miR-372-3p and DDK1 was verified by the luciferase reporter assay. Expression levels of DDK1, Wnt3a, E-cadherin and N-cadherin in breast carcinoma cells transfected with miR-372-3p mimic, miR-372-3p inhibitor and DKK1 were detected by Western blot.
RESULTS: The expression of miR-372-3p in breast carcinoma tissues was higher than that of normal breast tissues. Correlation analysis revealed that the miR-372-3p expression was negatively correlated with the postoperative survival, but positively correlated with the tumor size and stage of patients with breast carcinoma. No significant correlation was observed between the miR-372-3p expression and age, gender or lymph node metastasis. The receiver operating characteristics (ROC) curve indicated a high diagnostic sensitivity and specificity for miR-372-3p. CCK-8 assay and wound healing assay illustrated that miR-372-3p increased the viability and invasion of MDA-MB-231 and HCC38 cells, respectively. Luciferase activity assay suggested that miR-372-3p was specifically bound to the 3'UTR of DKK1. Overexpressed miR-372-3p markedly increased the expressions of Wnt3a and N-cadherin, but decreased the expressions of DKK1 and E-cadherin, which were reversed by miR-372-3p knockdown. The protein expressions of E-cadherin and N-cadherin were remarkably increased in cells co-transfected with miR-372-3p mimic and DKK1 in comparison with those transfected with miR-372-3p mimic only.
CONCLUSIONS: MiR-372-3p is upregulated in breast carcinoma tissues, which promotes the viability and invasion of breast carcinoma cells through the Wnt pathway.
Timbergen MJM, Janssen ML, Verhoef C, et al.Wnt targets genes are not differentially expressed in desmoid tumors bearing different activating β-catenin mutations.
Eur J Surg Oncol. 2019; 45(4):691-698 [PubMed
] Related Publications
INTRODUCTION: Sporadic desmoid-type fibromatosis (DTF) is a rare soft tissue tumor of mesenchymal origin. It is characterized by local invasive growth and unpredictable growth behavior. Three distinct mutations involving the CTNNB1 (β-catenin) gene have been identified in the vast majority of DTF tumors, which cause activation of the Wnt signaling pathway and impact prognosis. This study examines whether the different CTNNB1 mutants (T41A, S45F) occurring in DTF tumors differentially affect Wnt signaling activity, which might explain the different disease course between DTF patients harboring different CTNNB1 mutations.
MATERIALS AND METHODS: Real-time polymerase chain reaction (RT-PCR) on 61 formalin fixed paraffin embedded DTF samples with known CTNNB1 status was used to measure the relative mRNA expression level of Wnt target genes AXIN2, DKK1 and CCND1. Additionally, publicly available mRNA expression data retrieved from the Gene Expression Omnibus of 128 DTF samples were used for an unsupervised cluster analyses based on the expression of a selection of Wnt targets.
RESULTS: No statistically significant difference in relative expression levels of Wnt target genes AXIN2, DKK1 and CCND1 was identified between either CTNNB1 wild-type, S45F or T41A mutated DTF samples. Moreover, the hierarchical cluster analyses using selected Wnt targets did not discriminate between different CTNNB1 mutation types.
CONCLUSIONS: No differences in the expression levels of Wnt target genes were observed between the different CTNNB1 mutation types in DTF tumors. Further studies are needed to decipher the mechanism accounting for the diverse disease courses between DTF patients with different CTNNB1 variants.
Li H, Xu X, Liu Y, et al.MMP7 Induces T-DM1 Resistance and Leads to the Poor Prognosis of Gastric Adenocarcinoma
Anticancer Agents Med Chem. 2018; 18(14):2010-2016 [PubMed
] Related Publications
BACKGROUND: Gastric adenocarcinoma is one of the most common and lethal cancer types and is known as the second leading cause of cancer-related death of Asian adults, early diagnosis based on either pathology or molecular biology could be one of the most efficient ways to improve the outcomes of gastric adenocarcinoma patients.
METHODS: Quantitative Real-Time PCR and Western-blot were used in detection of mRNA and protein expression. Lentivirus infection was used to overexpression or knock down target gene. Alarma blue assay was used to monitor cells proliferation. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis.
RESULTS: MMP7 as one of the most up-regulated genes in T-DM1 resistant NCI-N87 gastric adenocarcinoma cells compared to matched naïve cell lines. T-DM1 resistant NCI-N87 cell lines by exposed to T-DM1 in vitro. Exogenous overexpression of MMP7 promotes T-DM1 resistance and tumor growth in NCI-N87 cell lines while MMP7 knockdown enhanced sensitivity to T-DM1 in T-DM1 resistant NCI-N87 cell lines established previously. MMP7 was enriched in high WHO grade GC samples and implies poor outcomes for these patients. DKK1 as one of the most correlated genes to MMP7 in gastric adenocarcinoma and knock-down of DKK1 or inhibition of Wnt/β-catenin pathway led to a decreased expression of MMP7 and resistance to T-DM1.
CONCLUSION: DKK1 and Wnt/β-catenin-dependent activation of MMP7 induces T-DM1 resistance and leads to the poor prognosis of gastric adenocarcinoma, which might be a novel potential therapeutical target for T-DM1 resistant gastric adenocarcinoma.
Cervical cancer is one of the most common cancers among women around the world. However, the underlying mechanism involved in cervical cancer progression is incompletely known. In the present study, we determined the role of glycoprotein nonmetastatic melanoma protein B (GPNMB) in tumorigenesis of cervical cancer. According to the GEO database, we found that GPNMB expression was significantly higher in cervical cancer than in normal cervix epithelium. A similar pattern was observed in GPNMB expression in cultured cervical cancer cells and normal cervical epithelial cells. Compared with the control, GPNMB knockdown significantly decreased the proliferation and migration capacity, but enhanced the apoptosis capacity of SiHa and HeLa cells. Additionally, the activity of MMP-2 and MMP-9 were aberrantly increased in SiHa and HeLa cells compared with normal cervical epithelial cells, whereas their activities were strongly inhibited by GPNMB siRNA. Furthermore, Wnt/β-catenin signaling was activated by GPNMB in SiHa and HeLa cells. Increased MMP-2/MMP-9 expression was suppressed by Dkk-1, inhibitor of Wnt/β-catenin signaling, while it was enhanced by stimulator BIO. The proliferation, migration, and apoptosis capacity of HeLa cells were found to be affected by Dkk-1 and BIO to different extents. In conclusion, we demonstrated that GPNMB contributed to the tumorigenesis of cervical cancer, at least in part, by regulating MMP-2/MMP-9 activity in tumor cells via activation of canonical Wnt/β-catenin signaling. This might be a potential therapeutic target for treating human cervical cancer.
Yao Y, Hua Q, Zhou YCircRNA has_circ_0006427 suppresses the progression of lung adenocarcinoma by regulating miR-6783-3p/DKK1 axis and inactivating Wnt/β-catenin signaling pathway.
Biochem Biophys Res Commun. 2019; 508(1):37-45 [PubMed
] Related Publications
Recently, circular RNAs (circRNAs) are identified as a novel class of noncoding RNAs playing important roles in human malignant tumors. However, the regulatory function of circRNA in lung adenocarcinoma (LUAD) is still largely unknown. Present study aimed to explore the role of circ_0006427 in LUAD progression. Firstly, the downregulation of circ_0006427 in LUAD tissues and cell lines was revealed by microarray analysis and qRT-PCR analysis. And we also confirmed the circ_0006427 as a prognostic target in LUAD patients. Functionally, overexpression of circ_0006427 effectively suppressed cell proliferation, migration and invasion. Mechanistically, circ_0006427 was found to be predominantly located in the cytoplasm of LUCA cell, and was further revealed to positively regulate DKK1 in LUAD by sponging miR-6783-3p. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and western blot analysis revealed that circ_0006427 inactivated Wnt/β-catenin signaling pathway by upregulating DKK1. At last, rescue assays proved the function of circ_0006427/miR-6783-3p/DKK1 axis in LUAD progression. In conclusion, our study revealed that circ_0006427 suppressed lung adenocarcinoma progression through regulating miR-6783-3p/DKK1 axis.
Becer E, Hanoğlu DY, Kabadayı H, et al.The effect of Colchicum pusillum in human colon cancer cells via Wnt/β-catenin pathway.
Gene. 2019; 686:213-219 [PubMed
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OBJECTIVE: Colchicum pusillum belongs to the family Colchicaceae that particularly rich in tropolonic alkaloids. The aim of this study was to investigate the cytotoxicity and in vitro anticancer activity of Colchicum pusillum ethanolic extract on Colo-320 primer and Colo-741 metastatic colon adenocarcinoma cell lines.
MATERIALS AND METHODS: Colchicum pusillum was collected and extracted with ethanol. Different concentrations of Colchicum pusillum extract were incubated for 24 h and 48 h with Colo-320 and Colo-741 cells. Cell growth and cytotoxicity were measured by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assays. Anticancer and antiproliferative activities of Colchicum pusillum were investigated by immunocytochemistry using antibodies directed against to β-catenin, Ki-67, LGR-5 Ki-67, DKK1, Frizzled-4, Wnt4, Wnt7a and caspase3 in Colo-741 cells.
RESULTS: All concentrations of Colchicum pusillum extract had toxic effect in Colo-320 cells. Because of this, we used Colchicum pusillum extract at 20 μg/ml for evaluate anticancer activities only in Colo-741 cells. As a result of immunohistochemical staining, β-catenin, LGR-5 and caspase-3 immunoreactivities were significantly increased while Wnt7a immunostaining intensity was decreased in Colo-741 cells. Conclusion We conclude that Colchicum pusillum extract increased β-catenin and LGR-5 via Wnt/β-catenin pathway in colon cancer cells. Interestingly, it decreased other signaling molecule, Wnt7a which is assumed to play protective role during carcinogenesis. Also, it increased significantly caspase-3 immunoreactivity showing that apoptotic pathways were triggered.
BACKGROUND: Hypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has not been elucidated.
METHODS: The mRNA and protein expressions of HIF-1α, HIF-2α, Wnt and Notch pathway were determined using qRT-PCR and western blot. Cell viability and renew ability were assessed by MTT, Flow cytometric analysis and soft agar colony formation.
RESULTS: In our study, acute hypoxia (6-12 h) briefly increased HIF-1α expression, while chronic hypoxia (48 h) continuously enhanced HIF-2α expression and induced the resistance of breast cancer cells to Paclitaxel (PTX). Furthermore, HIF-2α overexpression induced a stem cell phenotype, the resistance to PTX and enhanced protein expression of stem cell markers, c-Myc, OCT4 and Nanog. Most importantly, Wnt and Notch signaling, but not including Shh, pathways were both activated by HIF-2α overexpression. Dickkopf-1 (DKK-1), a Wnt pathway inhibitor, and L685,458, an inhibitor of the Notch pathway, reversed the resistance to PTX and stem phenotype conversion induced by HIF-2α overexpression. In addition, HIF-2α overexpression enhanced tumorigenicity and resistance of xenograft tumors to PTX, increased activation of the Wnt and Notch pathways and induced a stem cell phenotype in vivo.
CONCLUSION: In conclusion, HIF-2α promoted stem phenotype conversion and induced resistance to PTX by activating Wnt and Notch pathways.
Dickkopf-1(DKK-1) has been identified as a secretory protein that can inhibit the Wnt signaling transduction pathway. It is well known that the Wnt signaling pathway plays an important role in embryogenesis, organogenesis and homeostasis. This signaling cascade is essential for many normal physiological processes such as cellular proliferation, tissue regeneration, embryonic development and many other systemic and local effects, and it can be regulated at different levels. Therefore, defects in the pathway may lead to some complicated effects. In addition, it has been demonstrated that defects in this pathway are closely linked to some diseases including cancer, rheumatism, bone disease, diabetes, and Alzheimer disease. Since DKK-1 is an antagonist of the Wnt pathway, it may be related to these diseases; in fact, many studies have identified this fact. This review will summarize the current knowledge of DKK-1 and DKK-1-mediated regulation of Wnt signaling in the development of these related diseases.
Yang Z, Li K, Liang Q, et al.Elevated hydrostatic pressure promotes ameloblastoma cell invasion through upregulation of MMP-2 and MMP-9 expression via Wnt/β-catenin signalling.
J Oral Pathol Med. 2018; 47(9):836-846 [PubMed
] Related Publications
BACKGROUND: The process of marsupialization involves the release of intracystic pressure and the fluid contained within. Marsupialization of cystic ameloblastoma is controversial; therefore, we investigated how hydrostatic pressure influences biological behaviours of ameloblastoma cells and its underlying mechanisms.
MATERIALS AND METHODS: An ameloblastoma epithelial cell line, hTERT
RESULTS: Elevated hydrostatic pressure promoted migration and invasion of ameloblastoma cells, but inhibited proliferation. Expression of MMP-2, MMP-9, LEF-1, cyclin D1, c-Jun and c-Myc was significantly upregulated under elevated hydrostatic pressure, and these effects could be abolished by DKK1. Expression of RANKL, which is thought to be a downstream target of Wnt signalling, did not significantly change under elevated hydrostatic pressure.
CONCLUSIONS: This study indicates that elevated hydrostatic pressure promotes the migration and invasion of ameloblastoma cells by activating the Wnt/β-catenin pathway, thereby increasing expression of MMP-2, MMP-9 and other Wnt signalling downstream targets. This suggests that marsupialization may reduce invasiveness and reverse the bone resorption process by lowering intracystic hydrostatic pressure in cystic ameloblastoma.
Marimuthu M, Andiappan M, Wahab A, et al.Canonical Wnt pathway gene expression and their clinical correlation in oral squamous cell carcinoma.
Indian J Dent Res. 2018 May-Jun; 29(3):291-297 [PubMed
] Related Publications
Aim: The aim of this study is to explore the prognostic significance and clinicopathological correlations of the Wnt pathway genes in a cohort of surgically treated patients with oral squamous cell carcinoma (OSCC) patients.
Settings and Design: A prospective genetic study on patients with OSCC was carried out during the period from July 2014 to January 2016. Informed consent from patients and institutional ethical approval for the study was obtained and the guidelines were strictly followed for collection of samples.
Subjects and Methods: Clinical data and mRNA expression analysis of ten genes in the canonical Wnt pathway were evaluated and their relationships with clinical and demographic variables were studied in 58 tissue samples. Wnt-3a, β-catenin, secreted frizzled-related proteins sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wnt inhibitory factor 1, dickkopf-1, c-MYC, and cyclin-D1 from cancer (n = 29) and normal (n = 29) tissue samples were investigated using quantitative reverse transcription-polymerase chain reaction.
Statistical Analysis: Descriptive statistics were used to summarize the sample characteristics and clinical variables. If the data were normal, then parametric tests were used; otherwise, nonparametric alternatives were used. All the analyses were carried out using SPSS version 23.0 (IBM SPSS Inc., USA).
Results: Expression of sFRP-1, sFRP-2, and sFRP-5 in control samples and expression of c-MYC and cyclin D1 in cancer samples showed statistical significance. Significant expression of Wnt3A was observed among patients who had recurrence and were deceased.
Conclusion: Wnt3A, β-catenin, and cyclin D1 are recognized as key components of Wnt/β-catenin signaling. However, in this study, there was no significant expression of all the three genes in OSCC. The proto-oncogene c-MYC showed statistically significant upregulation in cancer tissue samples suggesting that the OSCC among South Indian population is primarily not mediated by the canonical Wnt signaling pathway.
Zhao X, Sun S, Xu J, et al.MicroRNA-152 inhibits cell proliferation of osteosarcoma by directly targeting Wnt/β-catenin signaling pathway in a DKK1-dependent manner.
Oncol Rep. 2018; 40(2):767-774 [PubMed
] Related Publications
The function of microRNA‑152 for a cohort of patients with osteosarcoma and the influence on cell growth of osteosarcoma were studied. The expression of microRNA‑152 was downregulated in patients with osteosarcoma. The downregulation of microRNA‑152 promotes cell proliferation, decreases apoptosis, and suppresses LDH activity, caspase-3/9 activities and Bax/Bcl-2 and p53 protein expression levels of osteosarcoma through activation of the Wnt/β-catenin signaling pathway by targeting DKK1. Whereas, overexpression of microRNA‑152 targets DKK1 to inhibit cell proliferation, induce apoptosis, and promote LDH activity, caspase-3/9 activities and Bax/Bcl-2 and p53 protein expression levels of osteosarcoma through inactivation of the Wnt/β-catenin signaling pathway. The promotion of DKK1 reversed the anticancer function of microRNA‑152 over-expression through Wnt/β-catenin signaling pathway. We demonstrated that microRNA‑152 inhibits cell proliferation of osteosarcoma through DKK1 by directly targeting Wnt/β‑catenin signaling pathway.
β‑catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E‑cadherin/CDH1, N‑cadherin/CDH2, VE‑cadherin/CDH5 and α‑catenins), transmembrane‑type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain‑of‑function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss‑of‑function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative β‑catenin target genes. β‑catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β‑catenin and NF‑κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. β‑catenin‑targeted therapeutics are functionally classified into β‑catenin inhibitors targeting upstream regulators (AZ1366, ETC‑159, G007‑LK, GNF6231, ipafricept, NVP‑TNKS656, rosmantuzumab, vantictumab, WNT‑C59, WNT974 and XAV939), β‑catenin inhibitors targeting protein‑protein interactions (CGP049090, CWP232228, E7386, ICG‑001, LF3 and PRI‑724), β‑catenin inhibitors targeting epigenetic regulators (PKF118‑310), β‑catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β‑catenin inhibitors targeting transmembrane‑type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first‑line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β‑catenin inhibitors may be applicable for the prevention of organ fibrosis, second‑line HCC prevention and treating β‑catenin‑driven cancer. The multi‑layered prevention and treatment strategy of β‑catenin‑related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.
Sato A, Ueno H, Fusegi M, et al.A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells.
Pharmacology. 2018; 102(1-2):26-36 [PubMed
] Related Publications
BACKGROUND: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of α-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1).
METHODS: WST-1 and cell analyzers were employed to analyze the effects of T3E on cell viability and apoptosis of human MM cell lines (H2452, H28). Real-time PCR and Western blot were performed to evaluate the expression at mRNA and protein levels. Methylation status and epigenetic modifications of DKK1's promoter regions after T3E treatment in MM cells were studied using methylation-specific PCR and Chromatin immunoprecipitation. Small interfering RNA-mediated knockdown -(siRNA), and specific inhibitors, were used to validate DKK1 as a target of T3E.
RESULTS: T3E markedly impaired MM cell viability, increased the expression of phosphorylated-JNK and DKK1 and suppressed cyclin D, a downstream target gene of Wnt signaling. Knockdown of DKK1 expression by siRNA or a specific JNK inhibitor confirmed the contribution of DKK1 and JNK to T3E-induced cytotoxicity in MM cells. On the other hand, cytoskeleton-associated protein 4 (CKAP4) expression, which promotes cell proliferation as a Wnt-independent DKK1 receptor was inhibited by T3E. Silencing CKAP4 by -siRNA did not appear to directly affect MM cell viability, thereby indicating that expression of both DKK1 and CKAP4 is required. Furthermore, T3E-mediated inhibition of both DNA methyltransferases (DNMT1, 3A, and 3B) and histone deacetylases (HDAC1, 2, 3, and 8) in MM cells leads to increased DKK1 expression, thereby promoting tumor growth inhibition. MM cells treated with Zebularine (a DNMT inhibitor) and sodium butyrate (an HDAC inhibitor) exhibited cytotoxic effects, which may explain the inhibitory action of T3E on MM cells. In addition, an enhanced expression of DKK1 in MM cells following T3E treatment is positively correlated with the methylation status of its promoter; T3E decreased DNA methylation and increased histone acetylation. Moreover, T3E specifically increased histone H3 lysine 4 (H3K4) methylation activity, whereas no effects were observed on histone H3K9 and H3K27.
CONCLUSIONS: Targeting the epigenetic induction of DKK1 may lead to effective treatment of MM, and T3E has great potential to induce anti-MM activity.
Verdelli C, Forno I, Morotti A, et al.The aberrantly expressed miR-372 partly impairs sensitivity to apoptosis in parathyroid tumor cells.
Endocr Relat Cancer. 2018; 25(7):761-771 [PubMed
] Related Publications
Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas (PAds) in most of atypical adenomas and carcinomas (
In multiple myeloma, abnormal plasma cells accumulate and proliferate in the bone marrow. Recently, we observed that Runx2, a bone-specific transcription factor, is highly expressed in multiple myeloma cells and is a major driver of multiple myeloma progression in bone. The primary goal of the present study was to identify Runx2-targeting miRNAs that can reduce tumor growth. Expression analysis of a panel of miRNAs in multiple myeloma patient specimens, compared with healthy control specimens, revealed that metastatic multiple myeloma cells express low levels of miR-342 and miR-363 but high levels of Runx2. Reconstituting multiple myeloma cells (CAG) with miR-342 and miR-363 reduced the abundance of Runx2 and the expression of metastasis-promoting Runx2 target genes RANKL and DKK1, and suppressed Runx2 downstream signaling pathways Akt/β-catenin/survivin, which are required for multiple myeloma tumor progression. Intravenous injection of multiple myeloma cells (5TGM1), stably overexpressing miR-342 and miR-363 alone or together, into syngeneic C57Bl/KaLwRij mice resulted in a significant suppression of 5TGM1 cell growth, decreased osteoclasts and increased osteoblasts, and increased antitumor immunity in the bone marrow, compared with mice injected with 5TGM1 cells expressing a miR-Scramble control. In summary, these results demonstrate that enhanced expression of miR-342 and miR-363 in multiple myeloma cells inhibits Runx2 expression and multiple myeloma growth, decreases osteolysis, and enhances antitumor immunity. Thus, restoring the function of Runx2-targeting by miR-342 and miR-363 in multiple myeloma cells may afford a therapeutic benefit by preventing multiple myeloma progression.
INTRODUCTION: Since the majority of patients are diagnosed at an advanced stage, ovarian cancer remains the most lethal gynecologic malignancy. There is no single biomarker with the sensitivity and specificity required for effective cancer screening; therefore, we investigated a panel of novel biomarkers for the early detection of high-grade serous ovarian carcinoma.
METHODS: Twelve serum biomarkers with high differential gene expression and validated antibodies were selected: IL-1Ra, IL-6, Dkk-1, uPA, E-CAD, ErbB2, SLPI, HE4, CA125, LCN2, MSLN, and OPN. They were tested using Simple Plex™, a multi-analyte immunoassay platform, in samples collected from 172 patients who were either healthy, had benign gynecologic pathologies, or had high-grade serous ovarian adenocarcinomas. The receiver operating characteristic (ROC) curve, ROC area under the curve (AUC), and standard error (SE) of the AUC were obtained. Univariate ROC analyses and multivariate ROC analyses with the combination of multiple biomarkers were performed.
RESULTS: The 4-marker panel consisting of CA125, HE4, E-CAD, and IL-6 had the highest ROC AUC. When evaluated for the ability to distinguish early stage ovarian cancer from a non-cancer control, not only did this 4-marker panel (AUC=0.961) performed better than CA 125 alone (AUC=0.851; P=0.0150) and HE4 alone (AUC=0.870; P=0.0220), but also performed significantly better than the 2- marker combination of CA125+HE4 (AUC=0.922; P=0.0278). The 4-marker panel had the highest average sensitivity under the region of its ROC curve corresponding to specificity ranging from 100% down to ~95%.
CONCLUSION: The four-marker panel, CA125, HE4, E-CAD, and IL-6, shows potential in detecting serous ovarian cancer at earlier stages. Additional validation studies using the biomarker combination in ovarian cancer patients are warranted.
Ortiz-Matamoros A, Arias CChronic infusion of Wnt7a, Wnt5a and Dkk-1 in the adult hippocampus induces structural synaptic changes and modifies anxiety and memory performance.
Brain Res Bull. 2018; 139:243-255 [PubMed
] Related Publications
Wnt signaling plays an important role in the adult brain function and its dysregulation has been implicated in some neurodegenerative pathways. Despite the functional role of the Wnt signaling in adult neural circuits, there is currently no evidence regarding the relationships between exogenously Wnt signaling activation or inhibition and hippocampal structural changes in vivo. Thus, we analyzed the effect of the chronic infusion of Wnt agonists, Wnt7a and Wnt5a, and antagonist, Dkk-1, on different markers of plasticity such as neuronal MAP-2, Tau, synapse number and morphology, and behavioral changes. We observed that Wnt7a and Wnt5a increased the number of perforated synapses and the content of pre-and postsynaptic proteins associated with synapse assembly compared to control and Dkk-1 infusion. These two Wnt agonists also reduced anxiety-like behavior. Conversely, the canonical antagonist, Dkk-1, increased anxiety and inhibited spatial memory recall. Therefore, the present study elucidates the potential participation of Wnt signaling in the remodeling of hippocampal circuits underlying plasticity events in vivo, and provides evidence of the potential benefits of Wnt agonist infusion for the treatment of some neurodegenerative conditions.
Szigeti KA, Galamb O, Kalmár A, et al.[Role and alterations of DNA methylation during the aging and cancer].
Orv Hetil. 2018; 159(1):3-15 [PubMed
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Besides the genetic research, increasing number of scientific studies focus on epigenetic phenomena - such as DNA methylation - regulating the expression of genes behind the phenotype, thus can be related to the pathomechanism of several diseases. In this review, we aim to summarize the current knowledge about the evolutionary appearance and functional diversity of DNA methylation as one of the epigenetic mechanisms and to demonstrate its role in aging and cancerous diseases. DNA methylation is also characteristic/also appear to prokaryotes, eukaryotes and viruses. In prokaryotes and viruses, it provides defence mechanisms against extragenous DNA. DNA methylation in prokaryotes plays a significant role in the regulation of transcription, the initiation of replication and in Dam-directed mismatch repair. In viruses, it participates not only in defence mechanisms, but in the assembly of capsids as well which is necessary for spreading. In eukaryotes, DNA methylation is involved in recombination, replication, X chromosome inactivation, transposon control, regulation of chromatin structure and transcription, and it also contributes to the imprinting phenomenon. Besides the above-mentioned aspects, DNA methylation also has an evolutionary role as it can change DNA mutation rate. Global hypomethylation appearing during aging and in cancerous diseases can lead to genetic instablility and spontaneous mutations through its role in the regulation of transposable elements. Local hypermethylated alterations such as hypermethylation of SFRP1, SFRP2, DKK1 and APC gene promoters can cause protein expression changes, thus contribute to development of cancer phenotype. DNA methylation alterations during aging in cancerous diseases support the importance of epigenetic research focusing on disease diagnostics and prognostics. Orv Hetil. 2018; 159(1): 3-15.
Hamzehzadeh L, Caraglia M, Atkin SL, Sahebkar ADickkopf homolog 3 (DKK3): A candidate for detection and treatment of cancers?
J Cell Physiol. 2018; 233(6):4595-4605 [PubMed
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Wnt signaling is an evolutionary highly conserved pathway that is modulated by several inhibitors and activators, and plays a key role in numerous physiological processes. One of the extracellular Wnt inhibitors is the DKK (Dickkopf Homolog) family which has four members (Dkk1-4) and a unique Dkk3-related gene, Dkkl1 (soggy). DKK3 is a divergent member of the DKK protein family. Evidence suggests that DKK3 may serve as a potential therapeutic target in several types of human cancers. We review here the biological role of DKK3 as a tumor suppressor gene (TSG) or oncogene, and its correlation with various miRNAs. In addition, we discuss the role of polymorphisms and promoter methylation of the DKK3 gene, and of its expression in regulating cancer cell proliferation. Finally, we propose that DKK3 may be considered as both a biomarker and a therapeutic target in different cancers.
Feng ZY, Xu XH, Cen DZ, et al.miR-590-3p promotes colon cancer cell proliferation via Wnt/β-catenin signaling pathway by inhibiting WIF1 and DKK1.
Eur Rev Med Pharmacol Sci. 2017; 21(21):4844-4852 [PubMed
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OBJECTIVE: Colon cancer is one of the most common and deadly types of gastrointestinal tumor. Despite progressive treatments, the patient prognosis has not been improved effectively.
MATERIALS AND METHODS: Expression of miRNA and mRNA were tested by Realtime PCR. Cell cycle was detected by flow cytometry. Cell viability was evaluated by MTT assay. Cell spheroid formation was determined by colony assay. Wnt signaling pathway activity was evaluated by TOP/FOP ratio. Protein expression was tested using Western blot. β-catenin binding ability was detected by ChIP assay. miRNA target gene was confirmed by luciferase assay.
RESULTS: miR-590-3p was found to be overexpressed in both glioma tissues and cell lines. miR-590-3p is upregulated in colon cancer cells and tissues compared to non-tumorigenic colon cells and normal colon tissues. miR-590-3p positively regulated cell proliferation, spheroid formation, and cell cycle in LS174T cells. Conversely, inhibition of miR-590-3p reduced these effects. We confirmed that WIF1 and DKK1 are targets of miR-590-3p. Overexpression of miR-590-3p promoted TOP flash luciferase activity, enhanced nuclear β-catenin levels and increased target genes expression of Wnt signaling pathway. The results indicated that miR-590-3p activates the Wnt/β-catenin signaling pathway.
CONCLUSIONS: We demonstrate that miR-590-3p regulates colon cancer progression via WIF1 and DKK1, which suggests that miR-590-3p may be a promising candidate for therapeutic applications in colon cancer treatment.
BACKGROUND: Increasing evidence has indicated parathyroid hormone type 1 receptor (PTHR1) plays important roles for the development and progression of osteosarcoma (OS). However, its function mechanisms remain unclear. The goal of this study was to further illuminate the roles of PTHR1 in OS using microarray data.
METHODS: Microarray data were available from the Gene Expression Omnibus database under the accession number GSE46861, including six tumors from mice with PTHR1 knockdown (PTHR1.358) and six tumors from mice with control knockdown (Ren.1309). Differentially expressed genes (DEGs) between PTHR1.358 and Ren.1309 were identified using the LIMMA method, and then, protein-protein interaction (PPI) network was constructed using data from STRING database to screen crucial genes associated with PTHR1. KEGG pathway enrichment analysis was performed to investigate the underlying functions of DEGs using DAVID tool.
RESULTS: A total of 1163 genes were identified as DEGs, including 617 downregulated (Lef1, lymphoid enhancer-binding factor 1) and 546 upregulated genes (Dkk1, Dickkopf-related protein 1). KEGG enrichment analysis indicated upregulated DEGs were involved in Renin-angiotensin system (e.g., Agt, angiotensinogen) and Wnt signaling pathway (e.g., Dkk1), while downregulated DEGs participated in Basal cell carcinoma (e.g., Lef1). A PPI network (534 nodes and 2830 edges) was constructed, in which Agt gene was demonstrated to be the hub gene and its interactive genes (e.g., CCR3, CC chemokine receptor 3; and CCL9, chemokine CC chemokine ligand 9) were inflammation related.
CONCLUSIONS: Our present study preliminarily reveals the pro-malignant effects of PTHR1 in OS cells may be mediated by activating Wnt, angiogenesis, and inflammation pathways via changing the expressions of the crucial enriched genes (Dkk1, Lef1, Agt-CCR3, and Agt-CCL9).
Grinchuk OV, Yenamandra SP, Iyer R, et al.Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma.
Mol Oncol. 2018; 12(1):89-113 [PubMed
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Currently, molecular markers are not used when determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). In the present study, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT) and adjacent non-malignant tissues (AT) typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients. The workflow integrated differentially expressed gene selection, gene ontology enrichment, computational classification, survival predictions, image analysis and experimental validation methods. We developed a 24-ribosomal gene-based HCC classifier (RGC), which is prognostically significant in both PT and AT. The RGC gene overexpression in PT was associated with a poor prognosis in the training (hazard ratio = 8.2, P = 9.4 × 10
MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-κB signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGFβ and Wnt/β-catenin. Particularly, it activates Wnt/β-catenin signaling by directly targeting Wnt antagonists, including Dkk1. Importantly, Dkk1 overexpression partially rescues miR31-induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis.
The aryl hydrocarbon receptor (AhR) has roles in cell proliferation, differentiation and organ homeostasis, including the liver. AhR depletion induces undifferentiation and pluripotency in normal and transformed cells. Here, AhR-null mice (AhR-/-) were used to explore whether AhR controls liver regeneration and carcinogenesis by restricting the expansion of stem-like cells and the expression of pluripotency genes. Short-term CCl
Sakabe T, Azumi J, Umekita Y, et al.Expression of Cancer Stem Cell-associated
Anticancer Res. 2017; 37(9):4881-4888 [PubMed
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BACKGROUND/AIM: Cancer stem cells (CSCs) are associated with prognosis of hepatocellular carcinoma (HCC). In our previous study, we created cDNA microarray databases on the CSC population of human HuH7 cells. In the present study, we identified genes that might serve as prognostic markers of HCC by employing existing databases.
MATERIALS AND METHODS: Expressions of glutathione S-transferase pi 1 (GSTP1), lysozyme (LYZ), C-X-C motif chemokine ligand 5 (CXCL5), interleukin-8 (IL8) and dickkopf WNT signaling pathway inhibitor 1 (DKK1), the five most highly expressed genes in the CSC cDNA microarray databases, were examined in 99 patients with HCC by real-time polymerase chain reaction (qRT-PCR), and their clinical significance was analyzed.
RESULTS: The Kaplan-Meier analysis showed that both overall and cancer-specific survival were significantly longer in patients with low DKK1 expression than in those with high DKK1 expression. The multivariate analysis revealed that overall survival was negatively associated with albumin and positively associated with alkaline phosphatase (ALP), serosal invasion and stage, and cancer-specific survival was positively associated with ALP, portal vein invasion and DKK1 mRNA.
CONCLUSION: Expression of CSC-associated DKK1 mRNA might be an unfavorable prognostic marker for patients with HCC.
Duan H, Yan Z, Chen W, et al.TET1 inhibits EMT of ovarian cancer cells through activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2.
Gynecol Oncol. 2017; 147(2):408-417 [PubMed
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OBJECTIVE: Epithelial ovarian cancer (EOC) is the deadliest type of ovarian cancer, but the mechanisms contributing to its tumorigenesis are not well understood. Herein, we will elucidate the role of Ten-eleven translocation 1 (TET1) in EOC development.
METHODS: The expression of TET1 in EOC cell lines and primary samples was examined by western blot and immunohistochemistry. The biological role of ectopic TET1 overexpression was revealed by a series of in vitro functional studies. Its downstream signaling pathway was predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of microarray data. The methylation level and expression of Wnt/β-catenin signaling inhibitors Dikkopf 1 (DKK1) and secreted Fzd receptor protein 2 (SFRP2) were examined by Chromatin immunoprecipitation (ChIP) assay, Epimark™ 5hmC and 5mC level analysis and quantitative RT-PCR. Small interference RNA (siRNA) technology was used to investigate the biological roles of DKK1 and SFRP2.
RESULTS: TET1 expression was inversely correlated with clinical stage in patients with EOC by tissue microarray (TMA). TET1 expression was undetected in 6 types of EOC cell lines. Ectopic expression of TET1 inhibited colony formation, cell migration and invasion in SKOV3 and OVCAR3 cells. Furthermore, TET1 overexpression reversed the epithelial-mesenchymal transition (EMT) process of SKOV3 cells. Mechanistically, TET1 potently inhibited canonical Wnt/β-catenin signaling by demethylating and upregulating two upstream antagonists of this pathway, SFRP2 and DKK1, which was associated with inhibition of EMT and cancer cell metastasis.
CONCLUSION: This study uncovers that TET1 has potent tumor-suppressive effects in EOC by activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2.
Jiang C, Yu M, Xie X, et al.miR-217 targeting DKK1 promotes cancer stem cell properties via activation of the Wnt signaling pathway in hepatocellular carcinoma.
Oncol Rep. 2017; 38(4):2351-2359 [PubMed
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Hepatocellular carcinoma (HCC) is one of the most common malignancies and exhibits heterogeneity in terms of clinical outcomes and biological activities. Emerging evidence has demonstrated that cancer stem cells (CSCs) play important roles in the tumorigenesis and progression of HCC. However, the molecular mechanisms underlying the stemness maintenance of CSCs remain largely unknown. In the present study, through real-time PCR, western blotting, luciferase assays, RNA immunoprecipitation, and in vitro and in vivo assays, we demonstrated that miR-217 expression was markedly increased in HCC tissues and cells. Overexpression of miR-217 promoted, while silencing miR-217 suppressed, the fraction of the side population and the expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further demonstrated that miR-217 promoted the CSC-like phenotype via dickkopf-1 (DKK1) targeting, resulting in constitutive activation of Wnt signaling. Moreover, the stimulatory effects of miR-217 on stem cell properties and Wnt signaling were antagonized by the upregulation of DKK1 in miR-217-overexpressing cells. Conversely, the inhibitory effects of silencing miR-217 on stem cell properties and Wnt signaling were reversed by the downregulation of DKK1 in miR-217-downregulated cells. Therefore, our results indicate that miR-217 plays a vital role in the CSC-like phenotypes of HCC cells and may be used as a potential therapeutic target against HCC.