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)

WNT signaling pathway plays a key role in carcinogenesis and embryogenesis. We have cloned and characterized the human WNT5B. Overlapping WNT5B cDNAs, containing 1080-bp ORF, were isolated. WNT5B encoded a 359-amino-acid polypeptide with the N-terminal signal peptide, four N-linked glycosylation sites, and consensus amino-acid residues conserved among the WNT family. WNT5B showed 80.5% total-amino-acid identity with WNT5A. Comparison between nucleotide sequence of WNT5B cDNA and human genome draft sequences revealed that the WNT5B gene, consisting of 4 exons, was located on human chromosome 12p13.3 region. Northern blot analyses with W5B2 probe detected the 2.8- and 2.4-kb WNT5B mRNAs. WNT5B was moderately expressed in adult prostate and fetal brain, and weakly expressed in fetal lung, kidney, adult liver, ovary, and small intestine. Among human cancer cell lines, WNT5B was expressed in gastric cancer cell lines MKN7, MKN45, KATO-III, and a teratocarcinoma cell line NT2. WNT5B might be implicated in human carcinogenesis through activation of the WNT-beta-catenin-TCF signaling pathway, just like Wnt5a.
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PMID:Molecular cloning and characterization of human WNT5B on chromosome 12p13.3 region. 1144 50

WNT signaling pathway is implicated in carcinogenesis. Here, we cloned and characterized human WNT11, which showed three amino-acid substitutions (Ala121Thr, Gly156Arg, and Ser271Trp) compared with human WNT11 cDNA previously isolated by another group. WNT11 encoded a 354 amino-acid polypeptide with five N-glycosylation sites. Gly156 of human WNT11 was conserved in other members of the human WNT family, such as WNT2B1, WNT2B2, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT10A, and WNT14. The Ala121-Gly156-Ser271 WNT11 allele isolated in this study was also identified in human genome draft sequence AC069055. Expression profile of WNT11 was next investigated. The 4.3-kb WNT11 mRNA was expressed in fetal lung, kidney, adult heart, liver, skeletal muscle, and pancreas. WNT11 mRNA was significantly up-regulated in a gastric cancer cell line MKN45 and a cervical cancer cell line SKG-IIIa. Among various types of human primary tumors, WNT11 mRNA was up-regulated in four cases of colorectal adenocarcinoma, and a case of renal cell carcinoma. Up-regulation of WNT11 mRNA might play an important role in human carcinogenesis through activation of the WNT signaling pathway.
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PMID:Molecular cloning and characterization of human WNT11. 1171 81

WNT10A and WNT10B genes are human orthologues of mouse proto-oncogene Wnt-10b. We have previously cloned and characterized WNT10A, and demonstrated up-regulation of WNT10A by tumor necrosis factor alpha (TNFalpha) in gastric cancer. Here, we cloned and characterized human WNT10B, which showed Gly60Asp amino-acid substitution compared with human WNT10B previously reported by another group. Gly60 WNT10B allele was identified in 2 human genome draft sequences and 7 human ESTs, while Asp60 WNT10B allele was not identified in any human genome draft sequences or ESTs. The Gly60-type WNT10B cDNA isolated in this study might be derived from more common WNT10B allele. WNT10B was most homologous to WNT10A (64.5% total amino-acid identity) among human WNTs. Variable region in the WNT core domain of WNT10B and WNT10A were longer than that of other WNTs, such as WNT2B1, WNT2B2, WNT3, WNT3A, WNT5B, WNT7B, WNT8A, WNT11, WNT14, and WNT14B/WNT15. We next investigated expression of WNT10B in human gastric cancer. WNT10B was moderately expressed in MKN45 and MKN74 cells, and weakly expressed in Okajima, TMK1, MKN7, MKN28, and KATO-III cells. Because interferon gamma (IFNgamma) and TNFalpha were frequently elevated in gastric mucosa with Helicobacter pylori infection, effects of IFNgamma and TNFalpha on WNT10B expression in MKN45 cells were investigated. TNFalpha induced transient up-regulation of WNT10B mRNA in MKN45 cells. Up-regulation of WNT10B in human gastric mucosa might lead to gastric carcinogenesis through activation of the beta-catenin - TCF signaling pathway, just like up-regulation of Wnt-10b in mouse mammary gland leads to mammary carcinogenesis.
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PMID:Proto-oncogene WNT10B is up-regulated by tumor necrosis factor alpha in human gastric cancer cell line MKN45. 1171 88

WNTs are a family of secreted-type glycoproteins implicated in embryogenesis and carcinogenesis. We have previously cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14, and WNT14B/WNT15. WNT14B gene is clustered with WNT3 gene in human chromosome 17q21, and mRNA expression of WNT14B is significantly up-regulated by retinoic acid during the early phase of neuronal differentiation in human NT2 cells. Here, we identified mouse Wnt14b gene fragments in mouse genome draft sequence AL596108.5 by using bioinformatics, and isolated mouse Wnt14b cDNAs by using cDNA-PCR. Mouse Wnt14b was found to encode a 359-amino-acid WNT family protein with the N-terminal signal peptide, an N-linked glycosylation site, and 24 conserved cysteine residues. Mouse Wnt14b showed 92.5% total-amino-acid identity with human WNT14B, and 64.2% total-amino-acid identity with human WNT14. Mouse Wnt14b gene, consisting of 4 exons, was clustered with mouse Wnt3 gene in mouse chromosome 11. Mouse Wnt14b mRNA was relatively highly expressed in 17-day embryo, and also expressed in adult brain, kidney, liver, 7-day embryo, and 11-day embryo. This is the first report on molecular cloning and characterization of mouse Wnt14b.
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PMID:Molecular cloning and characterization of mouse Wnt14b, clustered with mouse Wnt3 in mouse chromosome 11. 1178 23

We have previously cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT10A, WNT10B, WNT11, WNT14, and WNT14B/WNT15 by using bioinformatics, cDNA-library screening, cDNA-PCR, and RACE. WNT3 and WNT3A genes are two human paralogues of mouse proto-oncogene Wnt3, which induces carcinogenesis through activation of the beta-catenin - TCF signaling pathway. Here, regulation of WNT3 and WNT3A mRNAs in human cancer cell lines was investigated. WNT3 and WNT3A mRNAs were co-expressed in an embryonal carcinoma cell line NT2, which is reported to differentiate into postmitotic CNS neurons by treatment with retinoic acid for two weeks. Expression level of WNT3 mRNA in NT2 cells was not changed during 72 h after retinoic acid treatment, while expression of WNT3A mRNA was down-regulated in NT2 cells by retinoic acid. WNT3 and WNT3A mRNAs were also co-expressed in a breast cancer cell line MCF-7, and were down-regulated together by beta-estradiol in MCF-7 cells. Expression of WNT3 mRNA in a gastric cancer cell line MKN45 was not changed after treatment with tumor necrosis factor alpha (TNFalpha) or interferon gamma (IFNgamma), and that of WNT3A mRNA was undetectable before and after treatment with TNFalpha or IFNgamma. WNT3A, down-regulated by retinoic acid in NT2 cells, might play key roles in the maintenance of NT2 cells in the undifferentiated proliferation stage through activation of the beta-catenin - TCF signaling pathway.
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PMID:Regulation of WNT3 and WNT3A mRNAs in human cancer cell lines NT2, MCF-7, and MKN45. 1178 4

WNT signaling pathway plays key roles in carcinogenesis and embryogenesis, and WNT signaling molecules are potent targets for diagnosis, prevention and treatment of cancer as well as for regenerative medicine or tissue engineering. We have so far cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14 and WNT14B/WNT15 using bioinformatics and cDNA-PCR. We have also reported frequent up-regulation of WNT2 and WNT5A in primary gastric cancer, which is probably due to cancer-stromal interaction. Here, expression and regulation of WNT5A and WNT5B in human cancer were investigated. WNT5A was relatively highly expressed in TE6 and TE10 among 12 esophageal cancer cell lines, and WNT5B was expressed in the majority of esophageal cancer cell lines. Among 7 pancreatic cancer cell lines, WNT5A was up-regulated in Hs700T, and WNT5B in PANC-1. WNT5A, but not WNT5B, was up-regulated by TNFalpha in MKN45 cells derived from gastric cancer. WNT5B, but not WNT5A, was up-regulated by beta-estradiol in MCF-7 cells derived from breast cancer. WNT5A and WNT5B were expressed together in 5 embryonal tumor cell lines, and were slightly down-regulated by all-trans retinoic acid in NT2 cells. Up-regulation of WNT5A and WNT5B in several types of human cancer expressing FZD5 might lead to more malignant phenotype through activation of the beta-catenin - TCF pathway.
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PMID:Expression and regulation of WNT5A and WNT5B in human cancer: up-regulation of WNT5A by TNFalpha in MKN45 cells and up-regulation of WNT5B by beta-estradiol in MCF-7 cells. 1216 12

WNT family of secreted-type glycoproteins play key roles in carcinogenesis and embryogenesis. We have cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14 and WNT14B/WNT15 using bioinformatics and cDNA-PCR, and also reported frequent up-regulation of WNT2 in primary gastric cancer. Here, expression and regulation of WNT1 in human cancer were investigated using cDNA-PCR. WNT1 mRNA was relatively highly expressed in OKAJIMA cells (gastric cancer) and BxPC-3 cells (pancreatic cancer). Expression of WNT1 mRNA was up-regulated in 5 out of 10 cases of primary gastric cancer. Effects of beta-estradiol on expression of human WNT1 in MCF-7 cells (breast cancer) was next investigated, because mouse Wnt-1 induces mammary carcinogenesis even in estrogen receptor alpha (ERalpha) knockout mice. Expression of WNT1 mRNA was significantly up-regulated by beta-estradiol in MCF-7 cells. WNT1 was found to be one of estrogen target genes in human MCF-7 cells, which in part explains Wnt1-induced mammary carcinogenesis in ERalpha knockout mice.
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PMID:Expression and regulation of WNT1 in human cancer: up-regulation of WNT1 by beta-estradiol in MCF-7 cells. 1246 6

Canonical WNTs (WNT2, WNT2B, etc) activate the beta-catenin-TCF pathway to induce carcinogenesis, while non-canonical WNTs (WNT5A, WNT11, etc) activate the planar cell polarity (PCP) pathway to induce cell motility and metastasis. WNT5A gene at chromosome 3p14.3 and WNT5B gene at chromosome 12p13.33 are paralogs within the human genome. Here, we identified and characterized rat Wnt5a and Wnt5b genes by using bioinformatics. Rat Wnt5a and Wnt5b genes, consisting of five exons, were identified within AC095764.5 and AC112027.3 genome sequences, respectively. Rat Wnt5a (380 aa) and Wnt5b (359 aa) were secreted proteins with 24 conserved Cys residues and four Asn-linked glycosylation sites, which showed 75.8% total-amino-acid identity. Nucleotide position 182586-183836 of AC095764.5 genome sequence and nucleotide position 161044-159886 of AC121764.2 genome sequence were identified as evolutionarily conserved rat Wnt5a and human WNT5A promoters, respectively. Nucleotide identity between rat Wnt5a and human WNT5A promoters was 72.5%. E47 and NKX2-5-binding sites were evolutionarily conserved among rat Wnt5a, mouse Wnt5a, and human WNT5A promoters. On the other hand, rodent Wnt5b promoters and human WNT5B promoter were significantly divergent. Up-regulation of Wnt5b during rodent adipocytic differentiation does not simply indicate the implication of WNT5B in human adipogenesis. Real susceptibility gene for type 2 diabetes, associated with SNP within intron 3 of human WNT5B gene (IMS-JST024404), remains to be identified. This is the first report on rat Wnt5a and Wnt5b genes as well as on comparative genomics for Wnt5a and Wnt5b orthologs.
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PMID:Comparative genomics on Wnt5a and Wnt5b genes. 1575 42

WNT/planar cell polarity (PCP) signaling pathway controls tissue polarity and cell movement through the activation of RHOA, c-Jun N-terminal kinase (JNK), and nemo-like kinase (NLK) signaling cascades. PCP is induced in Drosophila by the asymmetrical localization of Frizzled-Dishevelled-Diego-Starry night (Flamingo) complex and Van Gogh (Strabismus)-Prickle complex. Here, WNT/PCP signaling pathway implicated in human carcinogenesis is reviewed. Human WNT5A, WNT5B, and WNT11 are representative non-canonical WNTs transducing PCP signals through FZD3 or FZD6 receptors, and ROR1, ROR2 or PTK7 co-receptors. Human VANGL1, VANGL2 (Van Gogh homologs), CELSR1, CELSR2, CELSR3 (Starry night homologs), DVL1, DVL2, DVL3 (Dishevelled homologs), PRICKLE1, PRICKLE2 (Prickle homologs), and ANKRD6 (Diego homolog) are core PCP signaling molecules. MAGI3 assembles FZD, VANGL, PTEN, and adhesion molecules. Dishevelled-dependent WNT/PCP signals are transduced to the RHOA signaling cascade through Formin homology proteins DAAM1 and DAAM2, and to the JNK signaling cascade through MAPKKKs and MAPKK4/7. Dishevelled-independent WNT/ PCP signals are transduced to the NLK signaling cascade through MAP3K7 (TAK1). ANKRD6, NKD1 and NKD2 induce class switch from the WNT/GSK3beta signaling pathway to the WNT/PCP signaling pathway. WNT5A is up-regulated in various types of human cancer, such as gastric cancer, lung cancer, and melanoma. FZD3/FZD6 receptor and ROR2 co-receptor transduce WNT5A signal in gastric cancer. Aberrant activation of WNT/PCP signaling pathway in human cancer leads to more malignant phenotypes, such as abnormal tissue polarity, invasion, and metastasis. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT/PCP signaling pathway could be developed as novel cancer prognostics. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT/PCP signaling molecules mentioned above are suitable for use in screening of cancer predisposition, especially for gastric cancer. Antibody, RNAi, or small molecule compounds to regulate the function of WNT/PCP signaling molecules mentioned above are good candidates for development as novel cancer therapeutics.
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PMID:WNT/PCP signaling pathway and human cancer (review). 1627 60

Non-canonical WNT and planar cell polarity (PCP) are overlapping but distinct signaling pathways, which control convergent extension, neural tube closure, orientation of cilia and sensory hair cells, axon guidance, and cell motility. Non-canonical WNT signals, regulated by the interaction of WNT, WNT antagonist, Frizzled and ROR2, are transduced to JNK, ROCK, PKC, MAP3K7, and NFAT signaling cascades. PCP signals, regulated by the interaction of VANGL-PRICKLE complex, CELSR and Frizzled-DVL complex, are transduced to JNK, ROCK, and other uncharacterized signaling cascades. PTK7 signaling, regulated by SEMA6 and Plexin-A family members, affects PCP pathway through VANGL. Here, integrative genomic analyses on WNT5A, WNT5B, WNT11, FZD3, FZD6, ROR1, ROR2, RYK, CELSR1, CELSR2, CELSR3, VANGL1, VANGL2, PRICKLE1, PRICKLE2, PTK7, SEMA6A, SEMA6B, SEMA6C and SEMA6D were carried out. PTK7 and SEMA6A were expressed in undifferentiated embryonic stem (ES) cells, SEMA6A in endodermal progenitors, CELSR1, VANGL1 and PTK7 in gastrointestinal tumors. CELSR2, PRICKLE2 and SEMA6C were expressed in fetal brain, CELSR2, PRICKLE1 and SEMA6A in adult brain, WNT5A and CELSR3 in adult brain tumors. These facts indicate class switches of non-canonical WNT or PCP signaling molecules during embryogenesis and carcinogenesis. TCF/LEF-, SP1-, and 5 bHLH-binding sites within human PTK7 promoter were conserved in chimpanzee, rhesus monkey, mouse, and rat PTK7 orthologs, which explained the mechanism of PTK7 upregulation in colorectal cancer. NANOG-, SOX2-, and POU5F1 (OCT3/OCT4)-binding sites within intron 1 of the human SEMA6A gene were conserved in chimpanzee, rhesus monkey, mouse, and rat SEMA6A orthologs, which explained the mechanism of SEMA6A upregulation in undifferentiated ES cells. Most of non-canonical WNT or PCP signaling molecules, except PTK7 and SEMA6A, were not frequently expressed in undifferentiated human ES cells. Non-canonical WNT or PCP signaling pathway, activated to orchestrate gastrulation and neurulation, was relatively downregulated in undifferentiated ES cells derived from inner cell mass of blastocysts.
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PMID:Comparative integromics on non-canonical WNT or planar cell polarity signaling molecules: transcriptional mechanism of PTK7 in colorectal cancer and that of SEMA6A in undifferentiated ES cells. 1767 48


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