Research IndicatorsGraph generated 29 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 29 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
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: HNF4A (cancer-related)
Naghizadeh S, Mohammadi A, Baradaran B, Mansoori BOvercoming multiple drug resistance in lung cancer using siRNA targeted therapy.
Gene. 2019; 714:143972 [PubMed
] Related Publications
Among cancers, lung cancer is the most morbidity and mortality disease that is remaining the fatalist. Generally, there are multiple treatment procedures for lung cancer, such as surgery, immunotherapy, radiotherapy and chemotherapy. There is, therefore, an urgent need for more specified and efficient methods for treatment of lung cancer such as RNAi, which in combination with traditional therapies could silence genes that are involved in the drug resistance. These genes may either be motivators of apoptosis inhibition, EMT and DNA repair system promoters or a member of intracellular signaling pathways, such as JAK/STAT, RAS/RAF/MEK, PI3K/AKT, NICD, B-catenin/TCF/LEF and their stimulator receptors including IGFR, EGFR, FGFR, VEGFR, CXCR4, MET, INTEGRINS, NOTCH1 and FRIZZLED, so could be considered as appropriate targets. In current review, the results of multiple studies which have employed drug application after one specific gene silencing or more than one gene from distinct pathways also simultaneous drug and RNAi usage in vitro and in vivo in lung cancer were summarized.
BACKGROUND: As Genome-Wide Association Studies (GWAS) have been increasingly used with data from various populations, it has been observed that data from different populations reveal different sets of Single Nucleotide Polymorphisms (SNPs) that are associated with the same disease. Using Type II Diabetes (T2D) as a test case, we develop measures and methods to characterize the functional overlap of SNPs associated with the same disease across populations.
RESULTS: We introduce the notion of an Overlap Matrix as a general means of characterizing the functional overlap between different SNP sets at different genomic and functional granularities. Using SNP-to-gene mapping, functional annotation databases, and functional association networks, we assess the degree of functional overlap across nine populations from Asian and European ethnic origins. We further assess the generalizability of the method by applying it to a dataset for another complex disease - Prostate Cancer. Our results show that more overlap is captured as more functional data is incorporated as we go through the pipeline, starting from SNPs and ending at network overlap analyses. We hypothesize that these observed differences in the functional mechanisms of T2D across populations can also explain the common use of different prescription drugs in different populations. We show that this hypothesis is concordant with the literature on the functional mechanisms of prescription drugs.
CONCLUSION: Our results show that although the etiology of a complex disease can be associated with distinct processes that are affected in different populations, network-based annotations can capture more functional overlap across populations. These results support the notion that it can be useful to take ethnicity into account in making personalized treatment decisions for complex diseases.
Mehta A, Patel BMTherapeutic opportunities in colon cancer: Focus on phosphodiesterase inhibitors.
Life Sci. 2019; 230:150-161 [PubMed
] Related Publications
Despite novel technologies, colon cancer remains undiagnosed and 25% of patients are diagnosed with metastatic colon cancer. Resistant to chemotherapeutic agents is one of the major problems associated with treating colon cancer which creates the need to develop novel agents targeting towards newer targets. A phosphodiesterase is a group of isoenzyme, which, hydrolyze cyclic nucleotides and thereby lowers intracellular levels of cAMP and cGMP leading to tumorigenic effects. Many in vitro and in vivo studies have confirmed increased PDE expression in different types of cancers including colon cancer. cAMP-specific PDE inhibitors increase intracellular cAMP that leads to activation of effector molecules-cAMP-dependent protein kinase A, exchange protein activated by cAMP and cAMP gated ion channels. These molecules regulate cellular responses and exert its anticancer role through different mechanisms including apoptosis, inhibition of angiogenesis, upregulating tumor suppressor genes and suppressing oncogenes. On the other hand, cGMP specific PDE inhibitors exhibit anticancer effects through cGMP dependent protein kinase and cGMP dependent cation channels. Elevation in cGMP works through activation of caspases, suppression of Wnt/b-catenin pathway and TCF transcription leading to inhibition of CDK and survivin. These studies point out towards the fact that PDE inhibition is associated with anti-proliferative, anti-apoptotic and anti-angiogenic pathways involved in its anticancer effects in colon cancer. Thus, inhibition of PDE enzymes can be used as a novel approach to treat colon cancer. This review will focus on cAMP and cGMP signaling pathways leading to tumorigenesis and the use of PDE inhibitors in colon cancer.
Ovarian cancer is the leading cause of death from gynecological cancers. MicroRNAs (miRNAs) are small, non-coding RNAs that interact with the 3' untranslated region (3' UTR) of target genes to repress their expression. We have previously reported that miR-590-3p promoted ovarian cancer growth and metastasis, in part by targeting Forkhead box A (FOXA2). In this study, we further investigated the mechanisms by which miR-590-3p promotes ovarian cancer development. Using luciferase reporter assays, real-time PCR, and Western blot analyses, we demonstrated that miR-590-3p targets cyclin G2 (CCNG2) and Forkhead box class O3 (FOXO3) at their 3' UTRs. Silencing of CCNG2 or FOXO3 mimicked, while the overexpression of CCNG2 or FOXO3 reversed, the stimulatory effect of miR-590-3p on cell proliferation and invasion. In hanging drop cultures, the overexpression of mir-590 or the transient transfection of miR-590-3p mimics induced the formation of compact spheroids. Transfection of the CCNG2 or FOXO3 plasmid into the mir-590 cells resulted in the partial disruption of the compact spheroid formation. Since we have shown that CCNG2 suppressed β-catenin signaling, we investigated if miR-590-3p regulated β-catenin activity. In the TOPFlash luciferase reporter assays, mir-590 increased β-catenin/TCF transcriptional activity and the nuclear accumulation of β-catenin. Silencing of β-catenin attenuated the effect of mir-590 on the compact spheroid formation. Taken together, these results suggest that miR-590-3p promotes ovarian cancer development, in part by directly targeting CCNG2 and FOXO3.
BACKGROUND: Women with Polycystic Ovary Syndrome (PCOS) present a heterogeneous reproductive and metabolic profile with an increased lifetime risk of Type 2 Diabetes (T2D). Early biomarkers of these metabolic disturbances in PCOS women have not been identified. The abundance of circulating insulin gene promotor cell-free DNA (INS cfDNA) was shown to be valuable as a predictive biomarker of β-cell death in individuals with Type 1 diabetes (T1D) as well as with gestational diabetes. Since β-cell death is common to the development of T1D as well as in T2D, we aimed to investigate if insulin-coding DNA is more abundant in circulation of PCOS women (vs Controls) and if their levels change after 6 yr. follow-up as a potential measure to predict future T2D.
METHODS: A cohort of 40 women diagnosed with PCOS according to Rotterdam 2003 criteria and eight healthy controls were examined at baseline and 6 years follow-up. Clinical measurements for evaluation of glucose homeostasis as well as blood/serum samples were obtained at each visit. Methylated and unmethylated INS cfDNA were quantified using droplet digital PCR. Differences between groups were assessed using Kruskall-Wallis test and Wilcoxon Signed rank test.
RESULTS: At baseline, there was no detectable difference in copy number (copies/μL) of methylated (p = 0.74) or unmethylated INS cfDNA (p = 0.34) between PCOS and Control groups. At follow up, neither methylated (p = 0.50) nor unmethylated INScfDNA levels (p = 0.48) differed significantly between these groups. Likewise, when pooling the groups, there was no difference between baseline and follow up, in terms of copies of methylated or unmethylated INS cfDNA (p = 0.38 and p = 0.52, respectively). There were no significant correlations between counts of unmethylated or methylated cfDNA and the clinical measurements of β-cell function and pre-diabetes.
CONCLUSION: The circulating level of unmethylated and methylated INScfDNA is similar between PCOS and Controls and cannot be used to predict islet β-cell loss and progression to Type 2 diabetes in a 6-year follow-up.
TRIAL REGISTRATION: The Danish Data Protection Agency (REG-31-2016. Approval: 01-12-2015) and by the Danish Scientific Ethical committee of Region Zealand (Journal no. SJ-525. Approval: 13-06-2016), Clinicaltrials.gov, ( NCT03142633 , registered 1. March, 2017, Retrospectively registered).
Irgam K, Reddy BM, Annamaneni S, Rayabarapu PThe genetic susceptibility profile of the South Indian women with polycystic ovary syndrome and the universality of the lack of association of type 2 diabetes genes.
Gene. 2019; 701:113-120 [PubMed
] Related Publications
We explored genetic susceptibility profile of the South Indian women with a large set of SNPs and tested if the lack of association of type 2 diabetes genes with PCOS, recently observed in a number of studies, holds true for this Indian population and suggest probable universality of this phenomenon. A prioritized set of 92 SNPs that belong to important reproductive and metabolic pathway genes were genotyped on 250 PCOS cases and 299 ethnically matched controls, representing the southern Indian population of Hyderabad, using SEQUENOM MassARRAY iPLEX™ platform. These data were analyzed both for individual SNP association patterns as well as for gene-gene interactions, besides obtaining cumulative risk score and the ROC curve with the help of appropriate statistical packages such as PLINK, SNPAssoc of R-program, Haploview, GMDR and SPSS. The analysis of 72 of the 92 SNPs, after excluding 20 of those that showed either minor allele frequency < 1% and/or deviated from Hardy Weinberg Equilibrium (p < .001), suggested that only 13 were associated with PCOS at p ≤ .05, but none after correction for multiple testing. Further, neither any of the diabetic genes nor the interactions between diabetic and reproductive pathway genes were found to be significant even at p ≤ .05.The lack of association of any of the SNPs with PCOS and/or the gene-gene interactions among them may be because of the minor effects of each of them on the phenotype(OR < 2). Further, that none of the type 2 diabetes genes were associated with PCOS in the present study as well as in the earlier studies from different ethnic groups may indicate probable universality of this pattern. It is possible that there are still other genetic variants, novel as well as already known, which may confer greater risk than the ones considered in this study and further studies are warranted to ascertain this both in the present population as well as in other ethnic and/or geographic groups of the Indian subcontinent.
Fetisov TI, Lesovaya EA, Yakubovskaya MG, et al.Alterations in WNT Signaling in Leukemias.
Biochemistry (Mosc). 2018; 83(12):1448-1458 [PubMed
] Related Publications
The WNT/β-catenin signaling pathway plays an important role in the differentiation and proliferation of hematopoietic cells. In recent years, special attention has been paid to the role of impairments in the WNT signaling pathway in pathogenesis of malignant neoplasms of the hematopoietic system. Disorders in the WNT/β-catenin signaling in leukemias identified to date include hypersensitivity to the WNT ligands, epigenetic repression of WNT antagonists, overexpression of WNT ligands, impaired β-catenin degradation in the cytoplasm, and changes in the activity of the TCF/Lef transcription factors. At the molecular level, these impairments involve overexpression of the FZD protein, hypermethylation of the SFRP, DKK, WiF, Sox, and CXXC gene promoters, overexpression of Lef1 and plakoglobin, mutations in GSK3β, and β-catenin phosphorylation by the BCR-ABL kinase. This review is devoted to the systematization of these data.
The microbiome research is going through an evolutionary transition from focusing on the characterization of reference microbiomes associated with different environments/hosts to the translational applications, including using microbiome for disease diagnosis, improving the effcacy of cancer treatments, and prevention of diseases (e.g., using probiotics). Microbial markers have been identified from microbiome data derived from cohorts of patients with different diseases, treatment responsiveness, etc, and often predictors based on these markers were built for predicting host phenotype given a microbiome dataset (e.g., to predict if a person has type 2 diabetes given his or her microbiome data). Unfortunately, these microbial markers and predictors are often not published so are not reusable by others. In this paper, we report the curation of a repository of microbial marker genes and predictors built from these markers for microbiome-based prediction of host phenotype, and a computational pipeline called Mi2P (from Microbiome to Phenotype) for using the repository. As an initial effort, we focus on microbial marker genes related to two diseases, type 2 diabetes and liver cirrhosis, and immunotherapy efficacy for two types of cancer, non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC). We characterized the marker genes from metagenomic data using our recently developed subtractive assembly approach. We showed that predictors built from these microbial marker genes can provide fast and reasonably accurate prediction of host phenotype given microbiome data. As understanding and making use of microbiome data (our second genome) is becoming vital as we move forward in this age of precision health and precision medicine, we believe that such a repository will be useful for enabling translational applications of microbiome data.
Gao H, Yin FF, Guan DX, et al.Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of β-catenin/TCF/LEF signalling.
Cell Prolif. 2019; 52(3):e12583 [PubMed
] Related Publications
OBJECTIVES: Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive.
MATERIALS AND METHODS: The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting.
RESULTS: The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of β-catenin to the nucleus by activating glycogen synthase kinase-3β (GSK3β). Moreover, constitutively active β-catenin blocked the suppressive effects of WISP3 on HCC.
CONCLUSIONS: Our study showed that WISP3 suppressed the progression of HCC by negative regulation of β-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.
To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently, B-cell lymphoma 3 (BCL-3; a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be overexpressed in a subset of colorectal cancers (CRCs), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood. Despite evidence in the literature that BCL-3 may interact with β-catenin, it is perhaps surprising, given the importance of deregulated Wnt/β-catenin/T-cell factor (TCF) signalling in colorectal carcinogenesis, that the functional significance of this interaction is not known. Here, we show for the first time that BCL-3 acts as a co-activator of β-catenin/TCF-mediated transcriptional activity in CRC cell lines and that this interaction is important for Wnt-regulated intestinal stem cell gene expression. We demonstrate that targeting BCL-3 expression (using RNA interference) reduced β-catenin/TCF-dependent transcription and the expression of intestinal stem cell genes
Jiang J, Yang X, He X, et al.MicroRNA-449b-5p suppresses the growth and invasion of breast cancer cells via inhibiting CREPT-mediated Wnt/β-catenin signaling.
Chem Biol Interact. 2019; 302:74-82 [PubMed
] Related Publications
Accumulating evidence has suggested that microRNA-449b-5p (miR-449b-5p) plays an important role in the development and progression of multiple cancers. However, little is known about the role of miR-449b-5p in breast cancer. In this study, we aimed to investigate the expression level, biological function and underlying mechanism of miR-449b-5p in breast cancer. Our results showed that miR-449b-5p expression was frequently down-regulated in breast cancer cell lines and tissues. The overexpression of miR-449b-5p significantly inhibited growth and invasion, and induced the cell cycle arrest of breast cancer cells. In contrast, the inhibition of miR-449b-5p showed the opposite effect. Interestingly, bioinformatic analysis predicted that cell cycle-related and expression-elevated protein in tumor (CREPT), an important oncogene in breast cancer, was a potential target gene of miR-449b-5p. The overexpression of miR-449b-5p decreased CREPT expression while miR-449b-5p inhibition promoted CREPT expression in breast cancer cells. Restoration of CREPT expression in miR-449b-5p mimics transfected cells partially reversed the suppressive effect of miR-449b-5p on breast cancer cell growth and invasion. Notably, our results showed that miR-449b-5p overexpression decreased the expression of β-catenin and suppressed the activation of Wnt/β-catenin/TCF-4 signaling via targeting CREPT. In addition, blocking Wnt/β-catenin partially reversed the promotion effect of miR-449b-5p inhibition on breast cancer cell growth and invasion. Overall, these results reveal a tumor suppressive role of miR-449b-5p that restricts the growth and invasion of breast cancer cells through targeting CREPT and inhibiting CREPT-mediated activation of Wnt/β-catenin signaling. Our study suggests that the miR-449b-5p/CREPT/Wnt/β-catenin axis may play an important role in the pathogenesis of breast cancer and miR-449-5p may serve as a potential therapeutic target for breast cancer.
BACKGROUND: Zinc-finger protein-326 (ZNF326) was initially found in the NIH3T3 cell line to regulate cell growth, however, the expression and underlying role of ZNF326 in human tumours, especially in glioma, is not fully understood.
METHODS: Immunohistochemistry was applied to detect the expression of ZNF326 in glioma tissues, and statistical analysis was used to analyse the relationship between ZNF326 expression and clinicopathological factors. The effect of ZNF326 on glioma cells proliferation and invasion was conducted by functional experiments both in vivo and in vitro. Chromatin immunoprecipitation and dual-luciferase assays were performed to demonstrate that histone deacetylase enzyme-7 (HDAC7) is the target gene of ZNF326. Immunoblotting, real-time PCR, GST-pulldown and co-immunoprecipitation assays were used to clarify the underlying role of ZNF326 on Wnt pathway activation.
RESULTS: High nuclear expression of ZNF326 was observed in glioma cell lines and tissues, and closely related with advanced tumour grade in the patients. Moreover, ectopic ZNF326 expression promoted the proliferation and invasiveness of glioma cells. Mechanistically, ZNF326 could activate HDAC7 transcription by binding to a specific promoter region via its transcriptional activation domain and zinc-finger structures. The interaction of the up-regulated HDAC7 with β-catenin led to a decrease in β-catenin acetylation level at Lys-49, followed by a decrease in β-catenin phosphorylation level at Ser-45. These changes in β-catenin posttranscriptional modification levels promoted its redistribution and import into the nucleus. Additionally, ZNF326 directly associated with β-catenin in the nucleus, and enhanced the binding of β-catenin to TCF-4, serving as a co-activator in stimulating Wnt pathway.
CONCLUSIONS: Our findings elucidated ZNF326 promotes the malignant phenotype of human glioma via ZNF326-HDAC7-β-catenin signalling. This study reveals the vital role and mechanism of ZNF326 in the malignant progression of glioma, and provides the reference for finding biomarkers and therapeutic targets for glioma.
Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose-starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m-chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.
Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards 'normal' liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.
The catalytic subunit p110δ of phosphoinositide 3-kinase (PI3K) encoded by PIK3CD has been implicated in some human solid tumors. However, its roles in colorectal cancer (CRC) remain largely unknown. Here we found that PIK3CD was overexpressed in colon cancer tissues and CRC cell lines and was an independent predictor for overall survival (OS) of patients with colon cancer. The ectopic overexpression of PIK3CD significantly promoted CRC cell growth, migration and invasion in vitro and tumor growth in vivo. In contrast, inhibition of PIK3CD by specific small-interfering RNA or idelalisib dramatically suppressed CRC cell growth, migration and invasion in vitro and tumor growth in vivo. Moreover, PIK3CD overexpression increased AKT activity, nuclear translocation of β-catenin and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activity and decreased glycogen synthase kinase 3β (GSK-3β) activity, whereas PIK3CD inhibition exhibited the opposite effects. Furthermore, PIK3CD-mediated cell growth, migration and invasion were reversed by blockade of AKT signaling or depletion of β-catenin. In addition, PIK3CD expression in colon cancer tissues positively correlated with β-catenin abnormal expression, which was an independent predictor for OS of colon cancer patients. Taken together, our findings demonstrate that PIK3CD is an independent prognostic factor in CRC and that PIK3CD induces CRC cell growth, migration and invasion by activating AKT/GSK-3β/β-catenin signaling, suggesting that PIK3CD might be a novel prognostic biomarker and a potential therapeutic target for CRC.
BACKGROUND Essential thrombocythemia (ET) is one of the BCR-ABL gene fusion negative chronic myeloproliferative disorders (MPDs), which also include polycythemia vera (PV), and myelofibrosis. Few clinical cases have reported the progression of ET to chronic myelogenous leukemia (CML) with the expression of the BCR-ABL gene. This report describes such a case and includes a review of other reported cases of CML co-occurring with BCR-ABL-negative chronic MPDs. CASE REPORT A 49-year-old woman was diagnosed with ET in 2007. Cytogenetic testing was negative for expression of the JAK2 or BCR-ABL1 genes. Eight years later, in January 2015, she presented with excessive fatigue, poor appetite, unintentional weight loss, a white blood cell (WBC) count of 24,700 per mL, hemoglobin of 9.9 g/dl, and a platelet count of 557,000 per mL, with blasts and basophils in the blood film. Cytogenetic analysis with fluorescent in situ hybridization (FISH) confirmed a 9: 22 chromosomal translocation (Philadelphia chromosome), and quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected the expression of the BCR-ABL gene, confirming a diagnosis of CML. In February 2015, first-line therapy commenced with nilotinib, which was changed to imatinib after three months. During the following nine months, qRT-PCR confirmed a trend to deep molecular remission (MR5). However, she developed early myelofibrosis, and myelosuppressive therapy was resumed. CONCLUSIONS This rare case highlights the importance of cytogenetic testing in cases of CMPD that transform to CML, not only to confirm the diagnosis but to plan treatment, as Philadelphia chromosome-positive and -negative cases differ in their management.
Ezzidi I, Mtiraoui N, Mohmmed Ali ME, et al.Impact of variants on type-2 diabetes risk genes identified through genomewide association studies in polycystic ovary syndrome: a case-control study.
J Genet. 2018; 97(5):1213-1223 [PubMed
] Related Publications
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females, and is associated with altered metabolic processes in particular insulin resistance and diabetes mellitus. PCOS shares with type-2 diabetes (T2D) a number of features, including beta cell dysfunction, impaired glucose tolerance and dyslipidaemia. Recently, genomewide association studies (GWAS) have reported a number of genes with reproducible associations and susceptibilities to T2D. To address this, we examined the association between the T2D GWAS candidate genes (
BACKGROUND: Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/β-catenin signaling has previously been shown to support MLL-AF9-driven leukemogenesis, the mechanism underlying this relationship remains unclear.
METHODS: We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs).
FINDINGS: We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/β-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML.
INTERPRETATION: By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/β-catenin-dependent growth of LICs. Small molecules disrupting WNT/β-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.
Zeng CX, Fu SB, Feng WS, et al.TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway.
Neoplasma. 2019; 66(1):46-53 [PubMed
] Related Publications
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies because of its complexity, high metastasis, recurrence and limited treatment options. Reports state that transcription factor 19 (TCF19) is related to the susceptibility to chronic HBV infection and that it strongly increases the risk of HCC occurrence, but its molecular mechanisms remain unknown. This study analyzed the datasets and confirmed that TCF19 is significantly increased in HCC cell lines and tissues. MTT and colony formation assay revealed that TCF19 over-expression enhances cell proliferation and tumorigenesis. Flow cytometry assay then determined that TCF over-expression helps HCC cell G1/S phase transition, and further research showed that TCF19 up-regulation inhibits p57Kip2, p21Cip1 and p27Kip1 cell cycle suppressors, enhances the expression of cyclin D1 expression and simulates retinoblastoma (Rb), FOXO1 and AKT phosphorylation. In addition, AKT and FOXO1 inhibitors suppress the TCF19 effect on cell proliferation. This demonstrates that AKT/FOXO1 signaling is essential for TCF19 influence on HCC progression, and our combined results suggest that crucial links between TCF19 and HCC can provide a novel target for hepatocellular carcinoma treatment.
Ye L, Xiang T, Zhu J, et al.Interferon Consensus Sequence-Binding Protein 8, a Tumor Suppressor, Suppresses Tumor Growth and Invasion of Non-Small Cell Lung Cancer by Interacting with the Wnt/β-Catenin Pathway.
Cell Physiol Biochem. 2018; 51(2):961-978 [PubMed
] Related Publications
BACKGROUND/AIMS: Interferon consensus sequence-binding protein 8 (IRF8) belongs to a family of interferon (IFN) regulatory factors that modulates various important physiological processes including carcinogenesis. As reported by others and our group, IRF8 expression is silenced by DNA methylation in both human solid tumors and hematological malignancies. However, the role of IRF8 in lung carcinoma remains elusive. In this study, we determined IRF8 epigenetic regulation, biological functions, and the signaling pathway involved in non-small cell lung cancer (NSCLC).
METHODS: IRF8 expression were determined by Q- PCR. MSP and A+T determined promotor methylation. MTS, clonogenic, Transwell assay, Flow cytometry, three-dimensional culture and AO/EB stain verified cell function. In vivo tumorigenesis examed the in vivo effects. By Chip-QPCR, RT-PCR, Western blot and Immunofluorescence staining, the mechanisms were studied.
RESULTS: IRF8 was significantly downregulated in lung tumor tissues compared with adjacent non-cancerous tissues. Furthermore, methylation-specific PCR analyses revealed that IRF8 methylation in NSCLC was a common event, and demethylation reagent treatment proved that downregulation of IRF8 was due to its promoter CpG hypermethylation. Clinical data showed that the IRF8 methylation was associated with tumor stage, lymph node metastasis status, patient outcome, and tumor histology. Exogenous expression of IRF8 in the silenced or downregulated lung cancer cell lines A549 and H1299 at least partially restored the sensitivity of lung cancer cells to apoptosis, and arrested cells at the G0/G1 phase. Cell viability, clonogenicity, and cell migration and invasive abilities were strongly inhibited by restored expression of IRF8. A three-dimensional culture system demonstrated that IRF8 changed the cells to a more spherical phenotype. Moreover, ectopic expression of IRF8 enhanced NSCLC chemosensitivity to cisplatin. Furthermore, as verified by Chip-qPCR, immunofluorescence staining, and western blotting, IRF8 bound to the T-cell factor/lymphoid enhancer factor (TCF /LEF) promoter, thus repressing β-catenin nuclear translocation and its activation. IRF8 significantly disrupted the effects of Wnt agonist, bml284, further suggesting its involvement in the Wnt/β-catenin pathway.
CONCLUSION: IRF8 acted as a tumor suppressor gene through the transcriptional repression of β-catenin-TCF/LEF in NSCLC. IRF8 methylation may serve as a potential biomarker in NSCLC prognosis.
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with limited treatment options. Mutation of β-catenin is one of the most frequent genetic events along hepatocarcinogenesis. β-catenin mutations can be in the form of point mutation or large N-terminal deletion. Studies suggested that different β-catenin mutations might have distinct oncogenic potential.
METHODS: We tested the oncogenic activity of β-cateninS45Y, one of the most frequent point mutations of β-catenin, and ∆N90-β-catenin, a form of β-catenin with a large N-terminal deletion, in promoting HCC development in mice. Thus, we co-expressed β-cateninS45Y or ∆N90-β-catenin together with c-Met into the mouse liver using hydrodynamic injection.
RESULTS: We found that both β-catenin mutations were able to induce HCC formation in combination with c-Met at the same latency and efficiency. Tumors showed similar histological features and proliferation rates. However, immunohistochemistry showed predominantly nuclear staining of β-catenin in c-Met/∆N90-β-catenin HCC, but membrane immunoreactivity in c-Met/β-cateninS45Y HCC. qRT-PCR analysis demonstrated that both ∆N90-β-catenin and β-cateninS45Y induced the same effectors, although at somewhat different levels. In cultured cells, both ∆N90-β-catenin and β-cateninS45Y were capable of inducing TCF/LEF reporter expression, promoting proliferation, and inhibiting apoptosis.
CONCLUSIONS: Our study suggests that β-cateninS45Y and ∆N90-β-catenin, in combination with the c-Met proto-oncogene, have similar oncogenic potential. Furthermore, nuclear staining of β-catenin does not always characterize β-catenin activity.
Muñoz-Bello JO, Olmedo-Nieva L, Castro-Muñoz LJ, et al.HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor.
Int J Mol Sci. 2018; 19(10) [PubMed
] Free Access to Full Article Related Publications
The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of
Chong PSY, Zhou J, Chooi JY, et al.Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia.
Oncogene. 2019; 38(9):1508-1519 [PubMed
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Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation.
BACKGROUND: Aberrant activation of Wnt/β-catenin signaling pathway is considered to be an important issue in progression and metastasis of various human cancers, especially in colorectal cancer (CRC). MiR-452 could activate of Wnt/β-catenin signaling. But the mechanism remains unclear.
METHODS: The expression of miR-452 in CRC and normal tissues was detected by real-time quantitative PCR. The effect of miR-452 on CRC growth and invasion was conducted by functional experiments in vitro and in vivo. Bioinformatics and cell luciferase function studies verified the direct regulation of miR-452 on the 3'-UTR of the GSK3β, which leads to the activation of Wnt/β-catenin signaling.
RESULTS: MiR-452 was upregulated in CRC compared with normal tissues and was correlated with clinical significance. The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3'-UTR of the GSK3β, which activate the Wnt/β-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3β and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3β and attenuated Wnt/β-catenin-mediated cell metastasis and proliferation. More important, T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, which are crucial downstream molecules of the Wnt/β-catenin signaling pathway was verified as a valid transcription factor of miR-452's promoter.
CONCLUSIONS: Our findings first demonstrate that miR-452-GSK3β-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration.
Yan H, Wang Q, Shen Q, et al.Identification of potential transcription factors, long noncoding RNAs, and microRNAs associated with hepatocellular carcinoma.
J Cancer Res Ther. 2018; 14(Supplement):S622-S627 [PubMed
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Aim: This study aimed to investigate the key transcription factors (TFs), long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) associated with hepatocellular carcinoma (HCC).
Materials and Methods: The datasets GSE31383 and GSE54238 were downloaded from Gene Expression Omnibus data repository. GSE31383 was used to screen differentially expressed miRNAs, and GSE54238 was used to screen differentially expressed messenger RNAs (mRNAs) and lncRNAs. ChipBase was used to identify TF-miRNA pairs. StarBase was selected to identify miRNA-mRNA and lncRNA-miRNA interactions. Kyoto Encyclopedia of Genes and Genomes pathway analysis was also conducted using Database for Annotation, Visualization, and Integrated Discovery tool.
Results: A total of 2065 mRNAs, 1050 lncRNAs, and 26 miRNAs were identified to be divergently expressed in HCC compared with normal tissues. There were 338 miRNA-mRNA and 65 lncRNA-miRNA pairs with reverse expression trend. Besides 249 TF-miRNA relationships including differentially expressed miRNA were isolated. Among them, 11 TF-miRNA had the same expression trend. Furthermore, lncRNA-miRNA-mRNA and TF-miRNA-mRNA regulatory networks were constructed. hsa-miR-497, hsa-miR-195, and hsa-miR-424 were identified as hub nodes in these two networks. Hub TFs, such as TATA box binding protein-associated factor 1 (TAF1) and hepatocyte nuclear factor 4, alpha (HNF4α), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were also screened out in the network.
Conclusions: Our findings highlight the regulatory networks among TFs, lncRNAs, miRNAs, and mRNAs in HCC. Several key molecules, such as hsa-miR-195, lncRNA MALAT1 and TFs TAF1 and HNF4α, may contribute to the progression of HCC.
Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4γ was increased in liver-specific
Hepatocellular carcinoma (HCC) accounts for a large proportion of liver cancer cases and has an extremely poor prognosis. Therefore, novel innovative therapies for HCC are strongly desired. As gene therapy tools for HCC, 2 hepatic transcription factors (TF), HNF4A and HNF1A, have been used to suppress proliferation and to extinguish cancer-specific characteristics of target cells. However, our present data demonstrated that single transduction of HNF4A or HNF1A had only a limited effect on suppression of HCC cell proliferation. Thus, in this study, we examined whether combinations of TF could show more effective antitumor activity, and found that combinatorial transduction of 3 hepatic TF, HNF4A, HNF1A and FOXA3, suppressed HCC cell proliferation more stably than single transduction of these TF. The combinatorial transduction also suppressed cancer-specific phenotypes, such as anchorage-independent growth in culture and tumorigenicity after transplantation into mice. HCC cell lines transduced with the 3 TF did not recover their proliferative property after withdrawal of anticancer drugs, indicating that combinatorial expression of the 3 TF suppressed the growth of all cell subtypes within the HCC cell lines, including cancer stem-like cells. Transcriptome analyses revealed that the expression levels of a specific gene set involved in cell proliferation were only decreased in HCC cells overexpressing all 3 TF. Moreover, combined transduction of the 3 TF could facilitate hepatic differentiation of HCC cell lines. Our strategy for inducing stable inhibition and functional differentiation of tumor cells using a defined set of TF will become an effective therapeutic strategy for various types of cancers.
Cao Z, Hao Z, Xin M, et al.Endogenous and exogenous galectin-3 promote the adhesion of tumor cells with low expression of MUC1 to HUVECs through upregulation of N-cadherin and CD44.
Lab Invest. 2018; 98(12):1642-1656 [PubMed
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Tumor cell-endothelial adhesion is one of the key steps in tumor cell haematogenous dissemination in metastasis and was previously shown to be mediated by interaction of galectin-3 with the transmembrane mucin protein MUC1. In this study, the effect of exogenous as well as endogenous galectin-3 on adhesion of two cell lines (low MUC1-expressing human prostate cancer PC-3M cells and non-small-cell lung cancer A549 cells) to monolayer of umbilical vein endothelial cells (HUVECs) was investigated. We found that suppression of endogenous galectin-3 expression reduced tumor cell adhesion to HUVECs and also decreased cell invasion and migration. Exogenous galectin-3 promoted tumor cell adhesion to HUVECs by entering cells. Both exogenous and endogenous galectin-3 upregulated the expression of β-catenin and increased β-catenin nuclear accumulation, and subsequently upregulated the expression of N-cadherin and CD44. We deduced that both exogenous as well as endogenous galectin-3 promoted low MUC1-expressing cancer cell adhesion to HUVECs by increasing the expression of N-cadherin and CD44 via an increase of nuclear β-catenin accumulation. These results were confirmed further by using a β-catenin/TCF transcriptional activity inhibitor, N-cadherin or CD44 siRNAs. Taken together, our results suggest a new molecular mechanism of galectin-3-mediated cell adhesion in cancer metastasis.
Stumm J, Vallecillo-García P, Vom Hofe-Schneider S, et al.Odd skipped-related 1 (Osr1) identifies muscle-interstitial fibro-adipogenic progenitors (FAPs) activated by acute injury.
Stem Cell Res. 2018; 32:8-16 [PubMed
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Fibro-adipogenic progenitors (FAPs) are resident mesenchymal progenitors in adult skeletal muscle that support muscle repair, but also give rise to fibrous and adipose infiltration in response to disease and chronic injury. FAPs are identified using cell surface markers that do not distinguish between quiescent FAPs and FAPs actively engaged in the regenerative process. We have shown previously that FAPs are derived from cells that express the transcription factor Osr1 during development. Here we show that adult FAPs express Osr1 at low levels and frequency, however upon acute injury FAPs reactivate Osr1 expression in the injured tissue. Osr1