Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human SNAIL1 (SNAI1) protein encoded by SNAI1/SNA gene represses transcription of E-cadherin/CDH1 gene. Human SNAIL2 (SNAI2) protein encoded by SNAI2/SLUG gene induces the first phase of epithelial-mesenchymal transition (EMT), including desmosome dissociation, cell spreading, and initiation of cell separation. Here, we have identified human SNAIL3 (SNAI3) gene using bioinformatics. Human SNAI3 gene, consisting of at least three exons, spans around the nucleotide position 320214-328221 of human reference genomic contig NT_010404.8 in the reverse orientation. SNAI3 gene, was located between KIAA0233 gene and CBFA2T3 gene in human chromosome 16q24.3, a region affected in breast cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, and therapy-related myeloid leukemia with t(16;21)(q24;q22) translocation. Human SNAI3 gene was found to encode 292-amino-acid polypeptide with the N-terminal SNAG domain and five zinc finger domains. N-terminal SNAG domain was identified in zinc finger proteins SNAI1, SNAI2, SNAI3, SCRATCH (SCRT1), GFI1, and GFI1B. ATP/GTP binding site was identified in SCRT1, GFI1 and GFI1B, but not in SNAI1, SNAI2 and SNAI3. Phylogenetic analysis of human zinc finger proteins with SNAG domain revealed that SNAI1, SNAI2 and SNAI3 were more closely related. These results clearly indicate that SNAI1, SNAI2 and SNAI3 constitute a subfamily among SNAG zinc-finger proteins. Human SNAI3 mRNA was expressed in skin melanotic melanoma, lung epidermoid carcinoma, and germ cell tumor. Because SNAG zinc-finger proteins are transcriptional repressors implicated in carcinogenesis and embryogenesis, SNAI3 gene might be a potent target of pharmacogenomics in the field of oncology and regenerative medicine.
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PMID:Identification and characterization of human SNAIL3 (SNAI3) gene in silico. 1257 45

SNAI1, SNAI2, and SNAI3 genes, encoding transcriptional repressors implicated in epithelial mesenchymal transition (EMT), are human homologs of Drosophila snail (sna) and slug genes. SNAI1 represses transcription of CDH1 (E-cadherin) gene. SNAI2 induces the first phase of EMT, including desmosome dissociation, cell spreading, and initiation of cell separation. Because SNAI family proteins are implicated in EMT during embryogenesis and carcinogenesis, SNAI family genes are potent targets of pharmacogenomics. Here, comparative genomics analyses and comparative proteomics analyses on SNAI family orthologs were performed. Rat Snai3 gene, consisting of three exons, was identified within rat genome sequence AC111791.4. Zebrafish snai1a (NM_131066.1) was identified as SNAI1 ortholog. Chicken ChEST362l17 (CR407272.1), Xenopus slug (AF368041.1), and zebrafish zgc92564 (NM_001008581.1) were identified as SNAI2 orthologs. Chicken snail (NM_ 205142.1), Xenopus snail (BC056857.1), and zebrafish snai1b (NM_130989.1) were identified as SNAI3 orthologs. SNAI1 orthologs consisted of SNAG domain and four zinc finger (ZNF) domains, while SNAI2 and SNAI3 orthologs consisted of SNAG domain and five ZNF domains. Based on the integromics analyses, SNAI2 orthologs were found to be more conserved than SNAI1 and SNAI3 orthologs. SNAI1 mRNA was expressed in placenta, neuroblastoma, and diffuse type gastric cancer. SNAI2 mRNA was expressed in placenta, melanocyte, embryonic stem (ES) cells, leiomyosarcoma, neuroblastoma, and glioblastoma. SNAI3 mRNA was expressed in B cells. Expression of SNAI3 mRNA was repressed due to the existence of anti-sense single-exon transcript. SNAI1, functioning as E-cadherin repressor, is implicated in the malignant infiltrating phenotype of diffuse type gastric cancer through the induction of EMT or fibroblastoid transformation.
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PMID:Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs. 1614 76

We cloned and characterized human WNT2B (WNT13) in 1996. Following our discovery of human WNT2B, others and we characterized mouse, rat, chicken and zebrafish WNT2B orthologs. Here, comparative integromics analyses on WNT2B and its clinical applications are reviewed. WNT2B-ST7L-CAPZA1 locus at human chromosome 1p13.2 and WNT2-ST7-CAPZA2 locus at human chromosome 7q31.2 are paralogous regions within the human genome. Two splicing variants occur from human WNT2B gene due to alternative promoters. WNT2B splicing variant 1 encodes secreted-type glycoprotein with WNT domain (WNT2B isoform 1), while WNT2B splicing variant 2 encodes transmembrane-type glycoprotein with WNT domain (WNT2B isoform 2). WNT2B splicing variant 2 is the evolutionarily conserved major transcript of human WNT2B gene. Mammalian WNT2B orthologs acquired the transmembrane domain and integrin-targeting RGD motif during vertebrate evolution. Human WNT2B isoform 2 and other vertebrate WNT2B orthologs are canonical WNTs to determine cell fate through the activation of beta-catenin/TCF signaling pathway and SNAIL/EMT signaling pathway. E box and CCAAT box are conserved within mammalian WNT2B promoters. WNT2B functions as the stem cell factor for neural or retinal progenitor cells during embryogenesis, and also for gastric cancer, esophageal cancer and skin basal cell carcinoma during carcinogenesis. Anti-WNT2B monoclonal antibody could be applied as selection marker of stem cells in the field of stem cell biology. Soluble WNT2B protein or small molecule WNT2B mimic compounds could be developed for stem cell expansion in the fields of tissue engineering and regenerative medicine. Anti-WNT2B monoclonal antibodies, WNT2B RNAi compounds, or small molecule WNT2B inhibitors could be developed as novel therapeutic agents for gastric cancer and esophageal cancer in the field of clinical oncology.
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PMID:WNT2B: comparative integromics and clinical applications (Review). 1627 93

Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.
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PMID:Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling. 1692 27

WNT and FGF signaling pathways cross-talk during a variety of cellular processes, such as human colorectal carcinogenesis, mouse mammary tumor virus (MMTV)-induced carcinogenesis, E2A-Pbx-induced leukemogenesis, early embryogenesis, body-axis formation, limb-bud formation, and neurogenesis. Canonical WNT signals are transduced through Frizzled receptor and LRP5/6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser 9 phosphorylation. FGF signals are transduced through FGF receptor to the FRS2-GRB2-GAB1-PI3K-AKT signaling cascade to downregulate GSK3beta activity depending on Ser 9 phosphorylation. Because GSK3beta-dependent phosphorylation of beta-catenin and SNAIL leads to FBXW1 (betaTRCP)-mediated ubiquitination and degradation, GSK3beta downregulation results in the stabilization and the nuclear accumulation of beta-catenin and SNAIL. Nuclear beta-catenin is complexed with TCF/LEF, Legless (BCL9 or BCL9L) and PYGO (PYGO1 or PYGO2) to activate transcription of CCND1, MYC, FGF18 and FGF20 genes for the cell-fate determination. Nuclear SNAIL represses transcription of CDH1 gene, encoding E-cadherin, to induce the epithelial-mesenchymal transition (EMT). Mammary carcinogenesis in MMTV-Wnt1 transgenic mice is accelerated by MMTV infection due to MMTV integration around Fgf3-Fgf4 or Fgf8 loci, and mammary carcinogenesis in MMTV-Fgf3 transgenic mice due to MMTV integration around Wnt1-Wnt10b locus. Coactivation of WNT and FGF signaling pathways in tumors leads to more malignant phenotypes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT and FGF signaling molecules could be utilized as screening method of cancer predisposition. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT and FGF signaling pathways could be developed as novel cancer-related biomarkers for diagnosis, prognosis, and therapy. Cocktail therapy using WNT and FGF inhibitors, such as small-molecule compounds and human neutralizing antibodies, should be developed to increase the efficacy of chemotherapy through the inhibition of recurrence by destructing cancer stem cells.
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PMID:Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades. 1694 Jul 50

Lung carcinogenesis is a complex process requiring the acquisition of genetic mutations that confer the malignant phenotype as well as epigenetic alterations that may be manipulated in the course of therapy. Inflammatory signals in the lung cancer microenvironment can promote apoptosis resistance, proliferation, invasion, metastasis, and secretion of proangiogenic and immunosuppressive factors. Here, we discuss several prototypical inflammatory mediators controlling the malignant phenotype in lung cancer. Investigation into the detailed molecular mechanisms underlying the tumor-promoting effects of inflammation in lung cancer has revealed novel potential drug targets. Cytokines, growth factors and small-molecule inflammatory mediators released in the developing tumor microenvironment pave the way for epithelial-mesenchymal transition, the shift from a polarized, epithelial phenotype to a highly motile mesenchymal phenotype that becomes dysregulated during tumor invasion. Inflammatory mediators within the tumor microenvironment are derived from neoplastic cells as well as stromal and inflammatory cells; thus, lung cancer develops in a host environment in which the deregulated inflammatory response promotes tumor progression. Inflammation-related metabolic and catabolic enzymes (prostaglandin E(2) synthase, prostaglandin I(2) synthase and 15-hydroxyprostaglandin dehydrogenase), cell-surface receptors (E-type prostaglandin receptors) and transcription factors (ZEB1, SNAIL, PPARs, STATs and NF-kappaB) are differentially expressed in lung cancer cells compared with normal lung epithelial cells and, thus, may contribute to tumor initiation and progression. These newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapy and prevention in lung cancer.
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PMID:Inflammation and lung carcinogenesis: applying findings in prevention and treatment. 1794 66

Lysyl oxidase-like 2 (Loxl2) interacts with and stabilizes Snai1 transcription factor, promoting epithelial-mesenchymal transition. Either Loxl2 or Snai1 knock-down blocks tumor growth and induces differentiation, but the specific role of each factor in tumor progression is still unknown. Comparison of the gene expression profiles of the squamous cell carcinoma cell line HaCa4 after knocking-down Loxl2 or Snai1 revealed that a subset of epidermal differentiation genes was specifically up-regulated in Loxl2-silenced cells. In agreement, although both Loxl2- and Snai1-knockdown cells showed reduced in vivo invasion, only Loxl2-silenced cells exhibited a skin-like epidermal differentiation program. In addition, we show that expression of Loxl2 and Snai1 correlates with malignant progression in a two-stage mouse skin carcinogenesis model. Furthermore, we found that increased expression of both LOXL2 and SNAI1 correlates with local recurrence in a cohort of 256 human laryngeal squamous cell carcinomas. We describe for the first time that high levels of LOXL2 are associated with decreased overall and disease-free survival in laryngeal squamous cell carcinomas, lung squamous cell carcinoma, and lymph node-negative (N(0)) breast adenocarcinomas. Altogether, our results show that LOXL2 can be used as a new poor prognosis indicator in human squamous cell carcinomas promoting malignant transformation by both SNAI1-dependent and SNAI1-independent pathways.
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PMID:Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas. 1855 98

SHH, IHH, and DHH are lipid-modified secreted proteins binding to Patched receptors, and CDON, BOC or GAS1 co-receptors. In the absence of Hedgehog signaling, GLI1 is transcriptionally repressed, GLI2 is phosphorylated by GSK3 and CK1 for the FBXW11 (betaTRCP2)-mediated degradation, and GLI3 is processed to a cleaved repressor. In the presence of Hedgehog signaling, Smoothened is relieved from Patched-mediated suppression due to the Hedgehog-dependent internalization of Patched, which leads to MAP3K10 (MST) activation and SUFU inactivation for the stabilization and nuclear accumulation of GLI family members. GLI activators then upregulate CCND1, CCND2 for cell cycle acceleration, FOXA2, FOXC2, FOXE1, FOXF1, FOXL1, FOXP3, POU3F1, RUNX2, SOX13, TBX2 for cell fate determination, JAG2, INHBC, and INHBE for stem cell signaling regulation. Hedgehog signals also upregulate SFRP1 in mesenchymal cells for WNT signaling regulation. Epithelial-to-mesenchymal transition (EMT) during embryogenesis, adult tissue homeostasis and carcinogenesis is characterized by class switch from E-cadherin to N-cadherin. SNAI1 (Snail), SNAI2 (Slug), SNAI3, ZEB1, ZEB2 (SIP1), KLF8, TWIST1, and TWIST2 are EMT regulators repressing CDH1 gene encoding E-cadherin. Hedgehog signals induce JAG2 upregulation for Notch-CSL-mediated SNAI1 upregulation, and also induce TGFbeta1 secretion for ZEB1 and ZEB2 upregulation via TGFbeta receptor and NF-kappaB. TGFbeta-mediated downregulation of miR-141, miR-200a, miR-200b, miR-200c, miR-205, and miR-429 results in upregulation of ZEB1 and ZEB2 proteins. Hedgehog signaling activation indirectly leads to EMT through FGF, Notch, TGFbeta signaling cascades, and miRNA regulatory networks. miRNAs targeted to stem cell signaling components or EMT regulators are potent drug targets; however, off-target effects should be strictly controlled before clinical application of synthetic miRNA. Peptide mimetic and RNA aptamer could also be utilized as Hedgehog signaling inhibitors or EMT suppressors.
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PMID:Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). 1869 84

Epithelial-mesenchymal transition (EMT) and hypoxia are considered as crucial events favouring invasion and metastasis of many cancer cells. In this study, different human neoplastic cell lines of epithelial origin were exposed to hypoxic conditions in order to investigate whether hypoxia per se may trigger EMT programme as well as to mechanistically elucidate signal transduction mechanisms involved. The following human cancer cell lines were used: HepG2 (from human hepatoblastoma), PANC-1 (from pancreatic carcinoma), HT-29 (from colon carcinoma) and MCF-7 (from breast carcinoma). Cancer cells were exposed to carefully controlled hypoxic conditions and investigated for EMT changes and signal transduction by using morphological, cell and molecular biology techniques. All cancer cells responded to hypoxia within 72 h by classic EMT changes (fibroblastoid phenotype, SNAIL and beta-catenin nuclear translocation and changes in E-cadherin) and by increased migration and invasiveness. This was involving very early inhibition of glycogen synthase kinase-3beta (GSK-3beta), early SNAIL translocation as well as later and long-lasting activation of Wnt/beta-catenin-signalling machinery. Experimental manipulation, including silencing of hypoxia-inducible factor (HIF)-1alpha and the specific inhibition of mitochondrial generation of reactive oxygen species (ROS), revealed that early EMT-related events induced by hypoxia (GSK-3beta inhibition and SNAIL translocation) were dependent on transient intracellular increased generation of ROS whereas late migration and invasiveness were sustained by HIF-1alpha- and vascular endothelial growth factor (VEGF)-dependent mechanisms. These findings indicate that in cancer cells, early redox mechanisms can switch on hypoxia-dependent EMT programme whereas increased invasiveness is sustained by late and HIF-1alpha-dependent release of VEGF.
Carcinogenesis 2008 Dec
PMID:Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. 1879 Nov 99

Epithelial-to-mesenchymal transition (EMT) is defined as phenotypic change of epithelial cells into mesenchymal cells. EMT, allowing cellular dissociation from epithelial tissues, plays a key role in invasion and metastasis during carcinogenesis as well as in gastrulation and neurulation during embryogenesis. SNAI1/Snail, SNAI2/Slug, ZEB1/deltaEF1/ZFHX1A, ZEB2/SIP1/ZFHX1B, TWIST1/TWIST, and TWIST2/DERMO1 are representative EMT regulators. ZEB2 represses transcription of CDH1, CLDN4, CCND1, TERT, SFRP1, ALPL and miR-200b-200a-429 primary miRNA, and upregulates transcription of mesenchymal markers. ZEB2 is relatively highly expressed in brain corpus callosum and monocytes. ZEB2 is expressed in various types of human tumors, such as breast cancer, gastric cancer, and pancreatic cancer. TGFbeta, TNFalpha, IL1, AKT and hypoxia signals are involved in ZEB2 upregulation and EMT induction; however precise mechanisms of ZEB2 transcription remained unclear. Here, refined integrative genomic analyses of ZEB2 gene were carried out. ZEB2 was co-expressed with POU3F2 (BRN2) and POU3F3 (BRN1) in brain corpus callosum, spinal cord, and fetal brain, whereas ZEB2 was co-expressed with POU2F2 (OCT2) in monocytes. Ets-Smad-binding CGGAGAC motif, bHLH-binding site, and POU/OCT-binding site within proximal promoter region, and NF-kappaB-binding site within intron 2 were completely conserved in human ZEB2, chimpanzee ZEB2, cow ZEB2, mouse Zeb2, rat Zeb2, and chicken zeb2 genes. In addition, HIF1alpha-binding site within proximal promoter region was conserved in mammalian ZEB2 orthologs. Consensus binding site for Hedgehog effector GLI was not identified within or adjacent to the 7-kb regions of human ZEB2 gene. TGFbeta, TNFalpha, IL1, and hypoxia signals directly upregulate ZEB2 to induce EMT, growth arrest, and senescence, whereas Hedgehog signals indirectly upregulate ZEB2 via TGFbeta. Together these facts indicate that ZEB2, occupying the crossroads of inflammation, aging and carcinogenesis, is an important target for drug discovery.
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PMID:Integrative genomic analyses of ZEB2: Transcriptional regulation of ZEB2 based on SMADs, ETS1, HIF1alpha, POU/OCT, and NF-kappaB. 1942 92


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