Research IndicatorsGraph generated 28 February 2015 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 27 February, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
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
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: WNT2 (cancer-related)
Farkas SA, Vymetalkova V, Vodickova L, et al.DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/β-catenin signaling pathway genes.
Epigenomics. 2014; 6(2):179-91 [PubMed
] Related Publications
AIM: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway.
MATERIAL & METHODS: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip.
RESULTS: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes.
CONCLUSION: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays.
Wang Y, Zheng TScreening of hub genes and pathways in colorectal cancer with microarray technology.
Pathol Oncol Res. 2014; 20(3):611-8 [PubMed
] Related Publications
Here we intend to identify key genes and pathways in the pathogenesis of colorectal cancer (CRC) through analyzing microarray data with bioinformatic tools. The gene expression profile dataset GSE23878 was downloaded from Gene Expression Omnibus and differentially expressed genes (DEGs) were screened out using Student's t-test. GO function and KEGG pathway enrichment analyses were performed for these DEGs with the DAVID online tool. Interaction network was constructed among the over-represented pathways based on the protein-protein interactions within the pathways. Besides, the protein interaction information obtained from HPRD database were applied to constructed protein-protein interaction networks among the DEGs and hub genes and function module were screened out. A total of 2,296 DEGs were obtained and they were enriched in 34 pathways. An interaction network was constructed among 32 pathways, in which p53 signaling pathway acted as the hub pathway as it showed the highest node degree. The protein-protein interaction network comprised 1,481 interaction relationships among 332 genes which included 40 DEGs. Further analysis revealed that theses DEGs formed 7 function modules and many genes, such as PDGFRB, MET, FZD2, CCND1, PRKCB, ARHGEF6, JUP, WNT2, WNT5A and WNT11 were key genes in the networks. The DEGs and disturbed biological functions uncovered in present study may play important roles in the development of CRC and can contribute to the understanding on molecular mechanisms of CRC. Further these DEGs we obtained can be acted as potential biomarkers for diagnosis and therapy of CRC.
BACKGROUND: Wnt-2 plays an oncogenic role in cancer, but which Frizzled receptor(s) mediates the Wnt-2 signaling pathway in lung cancer remains unclear. We sought to (1) identify and evaluate the activation of Wnt-2 signaling through Frizzled-8 in non-small cell lung cancer, and (2) test whether a novel expression construct dominant negative Wnt-2 (dnhWnt-2) reduces tumor growth in a colony formation assay and in a xenograft mouse model.
METHODS: Semi-quantitative RT-PCR was used to identify the expression of Wnt-2 and Frizzled-8 in 50 lung cancer tissues from patients. The TCF reporter assay (TOP/FOP) was used to detect the activation of the Wnt canonical pathway in vitro. A novel dnhWnt-2 construct was designed and used to inhibit activation of Wnt-2 signaling through Frizzled-8 in 293T, 293, A549 and A427 cells and in a xenograft mouse model. Statistical comparisons were made using Student's t-test.
RESULTS: Among the 50 lung cancer samples, we identified a 91% correlation between the transcriptional increase of Wnt-2 and Frizzled-8 (p<0.05). The Wnt canonical pathway was activated when both Wnt-2 and Frizzled-8 were co-expressed in 293T, 293, A549 and A427 cells. The dnhWnt-2 construct we used inhibited the activation of Wnt-2 signaling in 293T, 293, A549 and A427 cells, and reduced the colony formation of NSCLC cells when β-catenin was present (p<0.05). Inhibition of Wnt-2 activation by the dnhWnt-2 construct further reduced the size and mass of tumors in the xenograft mouse model (p<0.05). The inhibition also decreased the expression of target genes of Wnt signaling in these tumors.
CONCLUSIONS: We demonstrated an activation of Wnt-2 signaling via the Frizzled-8 receptor in NSCLC cells. A novel dnhWnt-2 construct significantly inhibits Wnt-2 signaling, reduces colony formation of NSCLC cells in vitro and tumor growth in a xenograft mouse model. The dnhWnt-2 construct may provide a new therapeutic avenue for targeting the Wnt pathway in lung cancer.
Zhang KS, Zhou Q, Wang YF, Liang LJInhibition of Wnt signaling induces cell apoptosis and suppresses cell proliferation in cholangiocarcinoma cells.
Oncol Rep. 2013; 30(3):1430-8 [PubMed
] Related Publications
The aim of the present study was to explore possible gene therapy for hilar cholangiocarcinoma by detecting the activation of the Wnt signaling pathway in 4 cholangiocarcinoma cell lines and inhibiting its expression by RNA interference (RNAi) targeting key factors of this pathway. The expression levels of the Wnt pathway-related factors, Wnt2, Wnt3, β-catenin and transcription factor 4, and its target genes, c-myc and cyclin D1, in 4 cholangiocarcinoma cell lines were detected by RT-PCR, western blotting and immunofluorescence microscopy. After transfection of siRNAs targeting Wnt2 and β-catenin into FRH0201 cells, the expression of the Wnt pathway-related factors and its target genes was again detected, and the cell cycle distribution, apoptosis and proliferation were analyzed by flow cytometry and MTT assay. Activation of the Wnt pathway and the expression of its target genes were detected in all 4 cell lines at various levels. After siRNA transfection, the expression of the target genes in the FRH0201 cells was significantly downregulated. In addition, the Wnt pathway was blocked, cell apoptosis was enhanced and cell proliferation was suppressed. In conclusion, the Wnt signaling pathway is activated in cholangiocarcinoma cells. RNAi technology targeting Wnt2 and β-catenin may be a possible gene therapy for hilar cholangiocarcinoma.
Carmona FJ, Azuara D, Berenguer-Llergo A, et al.DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer.
Cancer Prev Res (Phila). 2013; 6(7):656-65 [PubMed
] Related Publications
DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer (CRC) and precursor lesions have been extensively studied. Different panels have been reported attempting to improve current protocols in clinical practice, although no definite biomarkers have been established. In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes aiming to select the best performing candidates informative for CRC diagnosis in stool samples. Five selected markers were considered for subsequent analyses in independent biologic cohorts and in silico data sets. Among the five selected genes, three of them (AGTR1, WNT2 and SLIT2) were validated in stool DNA of affected patients with a detection sensitivity of 78% [95% confidence interval (CI), 56%-89%]. As a reference, DNA methylation of VIM and SEPT9 was evaluated in a subset of stool samples yielding sensitivities of 55% and 20%, respectively. Moreover, our panel may complement histologic and endoscopic diagnosis of inflammatory bowel disease (IBD)-associated neoplasia, as it was also efficient detecting aberrant DNA methylation in non-neoplastic tissue samples from affected patients. This novel panel of specific methylation markers can be useful for early diagnosis of CRC using stool DNA and may help in the follow-up of high-risk patients with IBD.
Lee SB, Gong YD, Park YI, Dong MS2,3,6-Trisubstituted quinoxaline derivative, a small molecule inhibitor of the Wnt/beta-catenin signaling pathway, suppresses cell proliferation and enhances radiosensitivity in A549/Wnt2 cells.
Biochem Biophys Res Commun. 2013; 431(4):746-52 [PubMed
] Related Publications
GDK-100017, a 2,3,6-trisubstituted quinoxaline derivative, reduced β-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and inhibited cell proliferation in a dose-dependent manner with an IC₅₀ value of about 10 μM in A549/Wnt2 cells. GDK-100017 down-regulated the expression of Wnt/β-catenin pathway target genes such as cyclin D1 and Dkk1 but not c-myc or survivin. GDK-100017 inhibited cell proliferation by arresting the cell cycle in the G1 phase not only in A549/wnt2 cells but also in SW480 colon cancer cells. In addition to its wnt signaling inhibitory properties, GDK-100017 also enhanced the radiosensitivity of the A549 human NSCLC line. These results suggest that GDK-100017 possesses potential anti-cancer activity by inhibiting the Wnt/β-catenin signal pathway, blocking the β-catenin-TCF/LEF interaction, and enhancing radiosensitivity.
Pituitary homeobox-2 (PITX2) plays a substantial role in the development of pituitary, heart, and brain. Although the role of PITX2 isoforms in embryonic development has been extensively studied, its possible involvement in regulating the Wnt signaling pathway has not been reported. Because the Wnt pathway is strongly involved in ovarian development and cancer, we focused on the possible association between PITX2 and Wnt pathway in ovarian carcinoma cells. Remarkably, we found that PITX2 interacts and regulates WNT2/5A/9A/6/2B genes of the canonical, noncanonical, or other pathways in the human ovarian cancer cell SKOV-3. Chromatin immunoprecipitation and promoter-reporter assays further indicated the significant association of PITX2 with WNT2 and WNT5A promoters. Detailed study further reveals that the PITX2 isoform specifically activates the canonical Wnt signaling pathway either directly or through Wnt ligands. Thus, the activated Wnt pathway subsequently enhances cell proliferation. Moreover, we found the activation of Wnt pathway reduces the expression of different FZD receptors that limit further Wnt activation, demonstrating the existence of an auto-regulatory feedback loop. In contrast, PITX2 could not activate the noncanonical pathway as the Wnt5A-specific ROR2 receptor does not express in SKOV-3 cells. Collectively, our findings demonstrated that, despite being a target of the canonical Wnt signaling pathway, PITX2 itself induces the same, thus leading to the activation of the cell cycle regulating genes as well as the proliferation of SKOV-3 cells. Collectively, we highlighted that the PITX2 and Wnt pathway exerts a positive feedback regulation, whereas frizzled receptors generate a negative feedback in this pathway. Our findings will help to understand the molecular mechanism of proliferation in ovarian cancer cells.
Hadzhieva M, Kirches E, Wilisch-Neumann A, et al.Dysregulation of iron protein expression in the G93A model of amyotrophic lateral sclerosis.
Neuroscience. 2013; 230:94-101 [PubMed
] Related Publications
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by selective loss of motor neurons which leads to progressive paralysis and death by respiratory failure. Although the cause of sporadic ALS is still unknown, oxidative stress is suggested to play a major role in the pathogenesis of this disease and of the rare familial form, which often exhibits mutations of the superoxide dismutase 1 (SOD1) gene. Since enhanced iron levels are discussed to participate in oxidative stress and neuronal death, we analyzed the expression levels of Fe-related mRNAs in a cell culture ALS model with the G93A mutation of SOD1. We observed an increased total iron content in G93A-SOD1 SH-SY5Y neuroblastoma cells compared to wild-type (WT)-SOD1 cells. mRNA expression for transferrin receptor 1 (TfR1) and divalent metal transporter 1 was increased in G93A-SOD1 cells, which was in accordance with higher iron uptake. Experiments with the iron chelator deferoxamine revealed a normal reaction of WT and mutant cells to cytoplasmic iron depletion, i.e. TfR1 upregulation, suggesting a basically conserved function of the iron-responsive element/iron regulatory protein (IRE/IRP) pathway, designed to adapt gene expression to iron levels. Expression levels of mitoferrin 1 and 2, frataxin, and iron-sulfur cluster scaffold protein were also significantly increased in G93A-SOD1 cells, suggesting higher mitochondrial iron import and utilization in biosynthetic pathways within the mitochondria. Moreover, expression of these transcripts was further enhanced, if G93A-SOD1 cells were differentiated by retinoic acid (RA). Since RA treatment increased cytoplasmic reactive oxygen species (ROS) levels in these cells, an IRE/IRP independent, ROS-mediated mechanism may account for dysregulation of iron-related genes.
Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs. Expression of WNT2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 (also known as TAK1) kinase. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases. Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer.
Chen W, Wang GM, Guo JM, et al.NGF/γ-IFN inhibits androgen-independent prostate cancer and reverses androgen receptor function through downregulation of FGFR2 and decrease in cancer stem cells.
Stem Cells Dev. 2012; 21(18):3372-80 [PubMed
] Related Publications
Androgen-independent prostate cancer (AIPC) is difficult to treat. Present study is to explore the inhibitory effect of a cytokine environment on AIPC and its mechanism. We utilized nerve growth factor (NGF)/γ-interferon (γ-IFN) to change the cytokine environment. Animal models and 2 androgen receptor (AR)-negative prostate cancer cell lines were used to evaluate the effect of NGF/γ-IFN. Flow cytometry, immunocytochemistry, western blotting, Tunel assay, colony formation efficiency, gene microarray, and in vivo bioluminescence were used to discern the mechanisms within NGF/γ-IFN that effect the environment. In vitro, NGF/γ-IFN effectively inhibited the proliferation of AIPC cell lines and promoted the apoptosis of the cancer cells. In vivo, NGF/γ-IFN suppressed the growth and metastasis of a tumor mass that arose from the AIPC cell line. After NGF/γ-IFN treatment, the AR-negative cell lines re-expressed AR and were then able to respond to the androgen. Contrary to expectations, the proliferation of cells was inhibited after dihydrotestosterone was added, and the results indicated that NGF/γ-IFN decreased the proportion of cancer stem cells. NGF/γ-IFN worked mainly through the downregulation of fibroblast growth factor receptor 2.
Recent studies demonstrated that cancer stem cells (CSCs) have higher tumorigenesis properties than those of differentiated cancer cells and that transcriptional factor-SOX2 plays a vital role in maintaining the unique properties of CSCs; however, the function and underlying mechanism of SOX2 in carcinogenesis of lung cancer are still elusive. This study applied immunohistochemistry to analyze the expression of SOX2 in human lung tissues of normal individuals as well as patients with adenocarcinoma, squamous cell carcinoma, and large cell and small cell carcinoma and demonstrated specific overexpression of SOX2 in all types of lung cancer tissues. This finding supports the notion that SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1 was detected in side population (SP) cells than in non-side population (NSP) cells of human lung adenocarcinoma cell line-A549, revealing a possible mechanism for the tenacious tumorigenic potential of CSCs. To further elucidate the function of SOX2 in tumorigenesis of cancer cells, A549 cells were established with expression of luciferase and doxycycline-inducible shRNA targeting SOX2. We found silencing of SOX2 gene reduces the tumorigenic property of A549 cells with attenuated expression of c-MYC, WNT1, WNT2, and NOTCH1 in xenografted NOD/SCID mice. By using the RNA-Seq method, an additional 246 target cancer genes of SOX2 were revealed. These results present evidence that SOX2 may regulate the expression of oncogenes in CSCs to promote the development of human lung cancer.
Siar CH, Nagatsuka H, Han PP, et al.Differential expression of canonical and non-canonical Wnt ligands in ameloblastoma.
J Oral Pathol Med. 2012; 41(4):332-9 [PubMed
] Related Publications
BACKGROUND: Canonical and non-canonical Wnt signaling pathways modulate diverse cellular processes during embryogenesis and post-natally. Their deregulations have been implicated in cancer development and progression. Wnt signaling is essential for odontogenesis. The ameloblastoma is an odontogenic epithelial neoplasm of enamel organ origin. Altered expressions of Wnts-1, -2, -5a, and -10a are detected in this tumor. The activity of other Wnt members remains unclarified.
MATERIALS AND METHODS: Canonical (Wnts-1, -2, -3, -8a, -8b, -10a, and -10b), non-canonical (Wnts-4, -5a, -5b, -6, 7a, -7b, and -11), and indeterminate groups (Wnts-2b and -9b) were examined immunohistochemically in 72 cases of ameloblastoma (19 unicystic [UA], 35 solid/multicystic [SMA], eight desmoplastic [DA], and 10 recurrent [RA]).
RESULTS: Canonical Wnt proteins (except Wnt-10b) were heterogeneously expressed in ameloblastoma. Their distribution patterns were distinctive with some overlap. Protein localization was mainly membranous and/or cytoplasmic. Overexpression of Wnt-1 in most subsets (UA = 19/19; SMA = 35/35; DA = 5/8; RA = 7/10) (P < 0.05), Wnt-3 in granular cell variant (n = 3/3), and Wnt-8b in DA (n = 8/8) was key observations. Wnts-8a and -10a demonstrated enhanced expression in tumoral buddings and acanthomatous areas. Non-canonical and indeterminate Wnts were absent except for limited Wnt-7b immunoreactivity in UA (n = 1/19) and SMA (n = 1/35). Stromal components expressed variable Wnt positivity.
CONCLUSION: Differential expression of Wnt ligands in different ameloblastoma subtypes suggests that the canonical and non-canonical Wnt pathways are selectively activated or repressed depending on the tumor cell differentiation status. Canonical Wnt pathway is most likely the main transduction pathway while Wnt-1 might be the key signaling molecule involved in ameloblastoma tumorigenesis.
Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron-sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance.
Huang L, Zheng M, Zhou QM, et al.Identification of a gene-expression signature for predicting lymph node metastasis in patients with early stage cervical carcinoma.
Cancer. 2011; 117(15):3363-73 [PubMed
] Related Publications
BACKGROUND: Pelvic lymph node metastasis (PLNM) is an important prognostic factor for patients with cervical carcinoma. The objective of this study was to identify a gene-expression signature that could predict PLNM in cervical carcinoma.
METHODS: Eighty-eight women with cervical carcinoma with PLNM (n = 23) and without PLNM (n = 65) were divided randomly into a training group and a test group. An oligonucleotide microarray that contained probes for 1440 human cancer-related genes was fabricated in-house and was used to detect the gene expression profile of cervical carcinoma. The gene expression levels detected in the microarray were verified by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).
RESULTS: A gene-expression signature for predicting PLNM was developed in patients from the training group, including 11 genes: ribosomal protein L35 (RPL35); thymosin β 10 (TMSB10); tyrosine 3-mono-oxytenase/tryptophan 5-mono-oxygenase activation protein, ζ polypeptide (YWHAZ); biotinidase (BTD); lactate dehydrogenase A (LDHA); glucuronidase β (GUSB); superoxide dismutase 2 (SOD2); nuclear receptor subfamily 3, group C, member 2 (NR3C2); fructosamine 3 kinase (FN3K); x-ray repair cross-complementing 4 (XRCC4); and wingless-type mouse mammary tumor virus integration site family member 2 (WNT2). In the test group, the signature's accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 91%, 90.9%, 93.9%, 83.3%, and 96.9%, respectively, for predicting PLNM. The expression levels of 5 genes in the signature were confirmed by qRT-PCR. A multivariate analysis demonstrated that patients with 11-gene high-risk scores were had a 33-fold increased risk for PLNM compared with patients who had low-risk scores. The 5-year overall and disease-free survival rates for patients who had 11-gene high-risk scores were marginally significantly lower than the rates for patients who had 11-gene low-risk scores (P = .087 and P = .174, respectively).
CONCLUSIONS: In this study, 11-gene signature for predicting PLNM in cervical carcinoma was identified that may help clinicians in planning therapy for patients with cervical carcinoma.
Mochmann LH, Bock J, Ortiz-Tánchez J, et al.Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG.
Oncogene. 2011; 30(17):2044-56 [PubMed
] Related Publications
E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were co-expressed in 80% of AML (n=30) and 40% in T-ALL (n=30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were co-stimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.
Zhang H, Li W, Nan F, et al.MicroRNA expression profile of colon cancer stem-like cells in HT29 adenocarcinoma cell line.
Biochem Biophys Res Commun. 2011; 404(1):273-8 [PubMed
] Related Publications
Increasing evidence has suggested cancer stem cells (CSCs) are considered to be responsible for cancer formation, recurrence, and metastasis. Recently, many studies have also revealed that microRNAs (miRNAs) strongly implicate in regulating self renewal and tumorigenicity of CSCs in human cancers. However, with respect to colon cancer, the role of miRNAs in stemness maintenance and tumorigenicity of CSCs still remains to be unknown. In the present study, we isolated a population of colon CSCs expressing a CD133 surface phenotype from human HT29 colonic adenocarcinoma cell line by Flow Cytometry Cell Sorting. The CD133(+) cells possess a greater tumor sphere-forming efficiency in vitro and higher tumorigenic potential in vivo. Furthermore, the CD133(+) cells are endowed with stem/progenitor cells-like property including expression of "stemness" genes involved in Wnt2, BMI1, Oct3/4, Notch1, C-myc and other genes as well as self-renewal and differentiation capacity. Moreover, we investigated the miRNA expression profile of colon CSCs using miRNA array. Consequently, we identified a colon CSCs miRNA signature comprising 11 overexpressed and 8 underexpressed miRNAs, such as miR-429, miR-155, and miR-320d, some of which may be involved in regulation of stem cell differentiation. Our results suggest that miRNAs might play important roles in stemness maintenance of colon CSCs, and analysis of specific miRNA expression signatures may contribute to potential cancer therapy.
Rhabdomyosarcoma is a primitive neoplasm with a poorly understood etiology that exhibits features of fetal skeletal muscle. It represents the most frequent malignant soft tissue sarcoma affecting the pediatric population and is often treated very aggressively. Embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma constitute the two major subtypes and exhibit different molecular features. We investigated one potential molecular basis for ERMS by using cells derived from tumors produced in p53(-/-)/c-fos(-/-) mice. This model closely recapitulates the timing, location, molecular markers, and histology seen in human ERMS. A combined chromatin immunoprecipitation/promoter microarray approach was used to identify promoters bound by the c-Jun-containing AP-1 complex in the tumor-derived cells that lacked c-Fos. Identification of the Wnt2 gene and its overexpression in ERMS cells was confirmed in human rhabdomyosarcoma cell lines and prompted further analysis of the Wnt signaling pathway. Contrary to our expectations, the canonical Wnt/β-catenin signaling pathway was down-regulated in ERMS cells compared with normal myoblasts, and activating this pathway promoted myogenic differentiation. Furthermore, the identification of both survivin and sfrp2 through promoter and expression analyses suggested that increased resistance to apoptosis was associated with the inhibition of the Wnt signaling pathway. These results suggest that altered AP-1 activity that leads to the down-regulation of the Wnt pathway may contribute to the inhibition of myogenic differentiation and resistance to apoptosis in ERMS cases.
Iron regulatory proteins, IRP1 and IRP2, bind to mRNAs harboring iron responsive elements and control their expression. IRPs may also perform additional functions. Thus, IRP1 exhibited apparent tumor suppressor properties in a tumor xenograft model. Here we examined the effects of IRP2 in a similar setting. Human H1299 lung cancer cells or clones engineered for tetracycline-inducible expression of wild type IRP2, or the deletion mutant IRP2(Delta73) (lacking a specific insert of 73 amino acids), were injected subcutaneously into nude mice. The induction of IRP2 profoundly stimulated the growth of tumor xenografts, and this response was blunted by addition of tetracycline in the drinking water of the animals, to turnoff the IRP2 transgene. Interestingly, IRP2(Delta73) failed to promote tumor growth above control levels. As expected, xenografts expressing the IRP2 transgene exhibited high levels of transferrin receptor 1 (TfR1); however, the expression of other known IRP targets was not affected. Moreover, these xenografts manifested increased c-MYC levels and ERK1/2 phosphorylation. A microarray analysis identified distinct gene expression patterns between control and tumors containing IRP2 or IRP1 transgenes. By contrast, gene expression profiles of control and IRP2(Delta73)-related tumors were more similar, consistently with their growth phenotype. Collectively, these data demonstrate an apparent pro-oncogenic activity of IRP2 that depends on its specific 73 amino acids insert, and provide further evidence for a link between IRPs and cancer biology.
Terzoudi GI, Hatzi VI, Barszczewska K, et al.G2-checkpoint abrogation in irradiated lymphocytes: A new cytogenetic approach to assess individual radiosensitivity and predisposition to cancer.
Int J Oncol. 2009; 35(5):1223-30 [PubMed
] Related Publications
Increased yield of chromatid breaks, following in vitro G2-phase lymphocyte irradiation, can be a marker of individual radiosensitivity and cancer predisposing genes whose role is to respond to DNA damage. Mutations or polymorphisms of genes encoding DNA repair pathways may underlie the increased chromosomal radiosensitivity. However, genes that facilitate DNA damage recognition, using signal transduction pathways to activate cell cycle arrest and preserve genomic integrity, are perhaps the most important determinant. Based on the latter hypothesis, an individual radiosensitivity parameter (IRP) is introduced, which expresses, at individual level, the G2-checkpoint potential to facilitate DNA damage recognition and repair of radiation-induced chromosomal damage during G2 to M-phase transition. Based on this parameter a new methodology for assessment of individual radiosensitivity is proposed, which involves G2-checkpoint abrogation by caffeine to obtain the IRP values. To evaluate the proposed methodology, blood samples from 52 healthy donors were taken for inter-individual radiosensitivity analysis using both the conventional G2 chromosomal radiosensitivity assay as well as the new approach using caffeine-induced G2-checkpoint abrogation. The two assays were compared in experiments using samples from 5 hypersensitive patients, 3 AT-homozygotes, 3 AT-heterozygotes, and the GM15786, GM03188A, GM09899, HCC1937 and MCF-7 cell lines. Using the G2 chromosomal radiosensitivity assay, donors are predicted as G2 radiosensitive or normal, while according to the new approach, individuals can be classified as highly radiosensitive, radiosensitive, normal, radioresistant and highly radioresistant. Overall, the new approach provides better individual radiosensitivity discrimination and intra-experimental reproducibility. Therefore, the proposed methodology using IRP values may provide a clinically applicable predictive assay for individual radiosensitivity and predisposition to cancer.
The histopathological diagnosis of melanoma can be challenging. No currently used molecular markers accurately distinguish between nevus and melanoma. Recent transcriptome analyses have shown the differential expression of several genes in melanoma progression. Here, we describe a multi-marker diagnostic assay using 5 markers (ARPC2, FN1, RGS1, SPP1, and WNT2) overexpressed in melanomas. Immunohistochemical marker expression was analyzed in 693 melanocytic neoplasms comprising a training set (tissue microarray of 534 melanomas and nevi), and 4 independent validation sets: tissue sections of melanoma arising in a nevus; dysplastic nevi; Spitz nevi; and misdiagnosed melanocytic neoplasms. Both intensity and pattern of expression were scored for each marker. Based on the differential expression of these 5 markers between nevi and melanomas in the training set, a diagnostic algorithm was obtained. Using this algorithm, the lesions in the validation sets were diagnosed as nevus or melanoma, and the results were compared with the known histological diagnoses. Both the intensity and pattern of expression of each marker were significantly different in melanomas compared to nevi. The diagnostic algorithm exploiting these differences achieved a specificity of 95% and a sensitivity of 91% in the training set. In the validation sets, the multi-marker assay correctly diagnosed a high percentage of melanomas arising in a nevus, Spitz nevi, dysplastic nevi, and misdiagnosed lesions. The multi-marker assay described here can aid in the diagnosis of melanoma.
Park JK, Song JH, He TC, et al.Overexpression of Wnt-2 in colorectal cancers.
Neoplasma. 2009; 56(2):119-23 [PubMed
] Related Publications
UNLABELLED: The binding of the Wnt ligand to its receptor Frizzled, activates the Wnt canonical signaling pathway in carcinogenesis as well as many cellular processes, including cellular proliferation and differentiation. Wnt-2, one of 19 members of the Wnt gene family, is frequently overexpressed in malignant tissues. Here, in order to investigate the role of Wnt-2 in colorectal carcinogenesis, we examined the expression of the Wnt-2 protein in 120 colorectal cancers by immunohistochemistry. Wnt-2 protein was expressed in the cell membrane and cytoplasm and up-regulated in 74 (61.7%) of 120 colorectal cancers. Statistically, overexpression of Wnt-2 protein was not associated with the clinical and pathological parameters studied, including tumor location, tumor size, clinical stage, lymph node metastasis, and 5-year survival (P > 0.05). These results indicate that up-regulation of the Wnt-2 protein might play a role in the development of colorectal cancers, as an early event of carcinogenesis.
KEYWORDS: Wnt-2 protein, expression, immunohistochemistry, tissue microarray, colon cancer.
Ellsworth RE, Seebach J, Field LA, et al.A gene expression signature that defines breast cancer metastases.
Clin Exp Metastasis. 2009; 26(3):205-13 [PubMed
] Related Publications
The most important predictor of prognosis in breast cancer is lymph node status, yet little is known about molecular changes associated with lymph node metastasis. Here, gene expression analysis was performed on primary breast (PBT) and corresponding metastatic lymph node (MLN) tumors to identify molecular signatures associated with nodal metastasis. RNA was isolated after laser microdissection from frozen PBT and MLN from 20 patients with positive lymph nodes and hybridized to the microarray chips. Differential expression was determined using Mann-Whitney testing; Bonferroni corrected P values of 0.05 and 0.001 were calculated. Results were validated using TaqMan assays. Fifty-one genes were differentially expressed (P < 1 x 10(-5), less than twofold differences) between the PBT and paired MLN; 13 with significantly higher expression in the MLN and 38 in the PBT. qRT-PCR validated the differential expression of 40/51 genes. Of the 40 validated genes, NTS and PAX5 were found to have >100-fold higher expression in MLT while COL11A1, KRT14, MMP13, TAC1 and WNT2 had >100-fold higher expression in PBT. Gene expression differences between PBT and MLN suggests that expression of a unique set of genes is required for successful lymph node colonization. Genes expressed at higher levels in PBT are involved in degradation of the extracellular matrix, enabling cells with metastatic potential to disseminate, while genes expressed at higher levels in metastases are involved in transcription, signal transduction and immune response, providing cells with proliferation and survival advantages. These data improve our understanding of the biological processes involved in successful metastatis and provide new targets to arrest tumor cell dissemination and metastatic colonization.
Lakhal S, Talbot NP, Crosby A, et al.Regulation of growth differentiation factor 15 expression by intracellular iron.
Blood. 2009; 113(7):1555-63 [PubMed
] Related Publications
Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-beta superfamily and has been identified in different contexts as a hypoxia-inducible gene product and as a molecule involved in hepcidin regulation. The biology of iron and oxygen is closely related, and known regulatory pathways involving hypoxia-inducible factor (HIF) and iron-regulatory proteins (IRPs) are responsive to both these stimuli. We therefore sought to characterize the regulation of GDF15 by iron and oxygen and to define the involvement or otherwise of HIF and IRP pathways. Here we show that GDF15 is strongly up-regulated by stimuli that deplete cells of iron and that this response is specifically antagonized by the reprovision of iron. GDF15 exhibits greater sensitivity to iron depletion than hypoxia, and responses to hypoxia and iron depletion are independent of HIF and IRP activation, suggesting a novel mechanism of regulation. We also report significant induction of serum GDF15 in iron-deficient subjects and after administration of an iron chelator to normal subjects. These findings indicate that GDF15 can be induced by pathophysiologic changes in iron availability, raising important questions about the mechanism of regulation and its role in iron homeostasis.
Rydzanicz M, Giefing M, Ziolkowski A, et al.Nonrandom DNA copy number changes related to lymph node metastases in squamous cell carcinoma of the lung.
Neoplasma. 2008; 55(6):493-500 [PubMed
] Related Publications
Lung cancer is one of the most common malignancies and cancer-related death worldwide. Lymph node metastasis is the main cause of treatment failure. Although many studies were performed to evaluate genetic events associated with development and progression of lung cancer, molecular mechanism still remains poorly defined. In the present study, using comparative genomic hybridization (CGH) technique, we described the pattern of DNA copy number changes in a cohort of 42 primary squamous cell carcinomas (SCC) of the lung. A direct comparison of nonmetastatic (TxN0M0) and metastatic (TxN1-2M0) tumors was performed to define chromosomal imbalances related to lymph node metastases. Some genetic alterations were observed more frequently in metastatic than in non-metastatic tumors, including losses at 11q, 16p, 16q, 19p and gains at 4q, 7q, 12p, 13q, 18p. The gain at 7q with the smallest common altered region 7q31.2-q32, was found to be directly associated with lymph node involvement (p=0.0407). We suggest that the established chromosomal region harbors two putative tumor suppressor genes WNT2 and c-Met. An overexpresion of these genes seems to be involved in inducing the invasive growth and metastatic potential of SCC of the lung.
Pu P, Zhang Z, Kang C, et al.Downregulation of Wnt2 and beta-catenin by siRNA suppresses malignant glioma cell growth.
Cancer Gene Ther. 2009; 16(4):351-61 [PubMed
] Related Publications
Increasing evidence suggests that aberrant activation of Wnt signaling is involved in tumor development and progression. Our earlier study on gene expression profile in human gliomas by microarray found that some members of Wnt family were overexpressed. To further investigate the involvement of Wnt signaling in gliomas, the expression of core components of Wnt signaling cascade in 45 astrocytic glioma specimens with different tumor grades was examined by reverse transcription-PCR and immunohistochemistry. Wnt2, Wnt5a, frizzled2 and beta-catenin were overexpressed in gliomas. Knockdown of Wnt2 and its key mediator beta-catenin in the canonical Wnt pathway by siRNA in human U251 glioma cells inhibited cell proliferation and invasive ability, and induced apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous U251 gliomas with siRNA targeting Wnt2 and beta-catenin intratumorally also delayed the tumor growth. In both in vitro and in vivo studies, downregulation of Wnt2 and beta-catenin was associated with the decrease of PI3K/p-AKT expression, indicating the interplay between Wnt/beta-catenin and PI3K/AKT signaling cascades. In conclusion, the canonical Wnt pathway is of critical importance in the gliomagenesis and intervention of this pathway may provide a new therapeutic approach for malignant gliomas.
Jonmarker S, Glaessgen A, Culp WD, et al.Expression of PDX-1 in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic tissue.
APMIS. 2008; 116(6):491-8 [PubMed
] Related Publications
Pancreatic duodenal homeobox 1 (PDX-1), a Hox type transcription factor, is necessary for differentiation of exocrine and endocrine pancreas, and regulates insulin gene transcription. PDX-1 expression was studied by immunohistochemistry on a tissue microarray (TMA) of 289 primary prostate cancers (PCa) from radical prostatectomy (RP) specimens with median follow-up of 48.9 months. We separately arrayed benign prostatic tissue, atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa from 40 men and also 17 lymph node metastases. Intensity and extent of immunoreactivity and their product (IRp) were evaluated by two independent observers. PDX-1 was overexpressed in cancer vs benign tissue (p<0.001), but also in atrophy and HGPIN vs cancer (p<0.001 and p=0.022, respectively). PDX-1 expression did not correlate with biochemical recurrence, but decreased with higher Gleason pattern (p<0.001) and in metastases vs primary PCa (p<0.001). Weighted kappa for interobserver agreement of intensity, extent and IRp was 0.65, 0.13 and 0.54, respectively. Presence of PDX-1 protein in benign and malignant prostatic tissue was confirmed by Western blot. In view of recent attention to the role of insulin systems in men with PCa, this protein is of interest in the pathogenesis of PCa.
Ma XR, Edmund Sim UH, Pauline B, et al.Overexpression of WNT2 and TSG101 genes in colorectal carcinoma.
Trop Biomed. 2008; 25(1):46-57 [PubMed
] Related Publications
Colorectal carcinoma (CRC) arises as a result of mutational activation of oncogenes coupled with inactivation of tumour suppressor genes. Mutations in APC, K-ras and p53 have been commonly reported. In a previous study by our group, the tumour susceptibility gene 101 (TSG101) were found to be persistently upregulated in CRC cases. TSG101 was reported to be closely related to cancers of the breast, brain and colon, and its overexpression in human papillary thyroid carcinomas and ovarian carcinomas had previously been reported. The wingless-type MMTV integration site family member 2 (WNT2) is potentially important in the Wnt/beta-catenin pathway and upregulation of WNT2 is not uncommon in human cancers. In this study, we report the investigation for mutation(s) and expression pattern(s) of WNT2 and TSG101, in an effort to further understand their role(s) in CRC tumourigenesis. Our results revealed no mutation in these genes, despite their persistent upregulation in CRC cases studied.
Han JC, Zhang KL, Chen XY, et al.Expression of seven gastric cancer-associated genes and its relevance for Wnt, NF-kappaB and Stat3 signaling.
APMIS. 2007; 115(12):1331-43 [PubMed
] Related Publications
The aim of the current study was to profile c-Myc, standard CD44 (CD44s), CD44v6, cyclin D1, survivin, MMP-7 and VEGF expression patterns in different gastric samples and to elucidate their relevance for Wnt, NF-kappaB and/or Stat3 activation using multiple experimental approaches. The results revealed that 87.1% (27/31) of gastric cancers and 8.7% (2/23) of noncancerous lesions (chronic gastritis and intestinal metaplasia) showed Wnt activation (Wnt(+)) that was closely related to the expression of the seven genes. Some Wnt(-) noncancerous lesions also expressed the above-mentioned genes, higher frequencies of survivin (7/8), VEGF (7/8), cyclin D1 (6/8) and c-Myc (5/8) but not CD44s (2/8), CD44v6 (3/8) and MMP-7 (2/8) being detected in the NF-kappaB(+) samples. Stat3 was activated in 37/54 gastric tissues, and in 3/4 VEGF, 4/6 c-Myc, 4/8 survivin, 2/4 MMP-7, 1/2 CD44v6, and 4/9 cyclin D1(+) but Wnt(-)/NF-kappaB(-) samples. These findings showed a close correlation in GCs between Wnt, NF-kappaB and Stat3 signaling and expression of the seven genes, the importance of NF-kappaB and Stat3 activation in regulating c-Myc, survivin, cyclin D1 and VEGF in noncancerous lesions, and the potential coordinative effects of these three signalings on GC formation presumably by promoting the transcription of their common target genes.
Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. We present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, we show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/beta-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, we illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Our results provide mechanistic insights regarding the cell of origin of MFH, establish what we believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas.
You XJ, Bryant PJ, Jurnak F, Holcombe RFExpression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease.
Oncol Rep. 2007; 18(3):691-4 [PubMed
] Related Publications
Mutations in apc which lead to activation of the Wnt signaling pathway are a hallmark of sporadic colon cancers but occur infrequently in colon cancers arising in patients with inflammatory bowel disease (IBD). There is evidence, however, that other components of the Wnt pathway may be altered in IBD-related colon cancer. In this study, we examined the expression the Wnt pathway components frizzled (Fz), the cell surface receptor, and disheveled (DVL), a family of cytoplasmic signal transduction molecules, in IBD and IBD-related colon cancer. Paraffin sections of normal and malignant colon tissues were obtained from patients with a history of ulcerative colitis and from controls with sporadic colon cancer. Tissue sections were stained with antibodies directed against Fz1/2 receptors and DVL1, DVL2 and DVL3 and antigen expression visualized by immunohistochemistry. Fz1/2 receptors were minimally expressed in normal IBD mucosa, were not expressed in IBD colon cancer, but exhibited strong expression in dysplastic tissues adjacent to the cancers. DVL1 was not expressed in IBD normal mucosa or normal mucosa from non-IBD patients, but was expressed in all cancers. DVL2 and DVL3 were expressed in all normal mucosa samples tested, and in sporadic colon cancer, but were not expressed in colon cancers arising in IBD patients. The characteristics of Fz and DVL expression in IBD tissues reported herein provides evidence of the importance of Wnt signaling in IBD and IBD-related colon cancer and, specifically, the significance of non-APC components of this pathway. Fz may serve as a marker for dyspasia in IBD patients and DVL1 is a potential therapeutic target for IBD-related colon cancer.