Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Members of the inhibitor of apoptosis protein (IAP) family, including survivin, have been reported to be expressed in many tumors. However, their expression in esophageal cancer has not been clarified completely. We investigated the expression of mRNA for IAP family proteins in samples from esophageal cancers and their adjacent normal mucosa tissues by real-time quantitative RT-PCR. The survivin expression in esophageal cancer was significantly higher than that in normal mucosa (P < 0.05). Other IAP family proteins including cIAP1, cIAP2, NAIP and XIAP tended to show stronger expression in cancer tissue than normal mucosa, although the differences were not significant. As to the histological type of tumor, poorly differentiated squamous cell carcinomas exhibited significantly higher level of expression than well-differentiated carcinomas (P < 0.05). The proportion of apoptotic cells of cancer tissue inversely correlated with the intensity of survivin expression (P < 0.05). Immunohistochemical staining demonstrated cytoplasmic as well as nuclear expression of survivin in esophageal cancer, and further, in situ hybridization analysis demonstrated cytoplasmic expression of mRNA for survivin. The results suggest that the expression of IAP family proteins, especially survivin, may be associated with the biological character of esophageal cancer, such as apoptosis.
Exp Mol Pathol 2004 Jun
PMID:Expression of IAP family proteins in esophageal cancer. 1512 8

Positron emission tomography (PET) using the positron emitting glucose analogue 18F-fluorodeoxyglucose (FDG) has emerged as a useful metabolism-based wholebody imaging tool for gastro-esophageal cancer diagnosis and follow up. Most large cancer centers worldwide are now equipped for PET (or even PET-CT). Therefore, there is a growing need for a clear definition of the relative position of PET within the currently available diagnostic modalities. Significant scientific data indicate that FDG-PET adds clinically useful information to the information obtained by standard means (mainly CT and endoscopic ultrasound) throughout the different phases of clinical patient management: 1) at initial diagnosis: PET detects more frequently distant lymph node involvement and organ metastases compared to conventional diagnostics, allowing a more accurate selection of the most appropriate treatment; 2) during chemotherapy: semi-quantitative FDG-PET allows early identification of non-responding patients. Indeed, the metabolic response as measured by serial FDG-PET can be used to predict the clinical and histopathological response. Moreover, the PET-response seems to be related to overall and disease free survival; 3) after a treatment: FDG-PET allows accurate assessment of the residual tumor load; 4) in the follow up: FDG-PET allows accurate detection and restaging of recurrent disease.
Q J Nucl Med Mol Imaging 2004 Jun
PMID:Position of positron emission tomography and other imaging diagnostic modalities in esophageal cancer. 1524 7

In our previous study, the proliferation rate of esophageal squamous cell carcinoma cell lines, which poorly expressed p21Waf1, was found to be regulated by p21Waf1 gene transfection using adenovirus vector. In the present study, in order to examine the effect of p21Waf1 gene therapy in esophageal cancer, we used gene gun technology, which proved to be a powerful method to introduce the p21Waf1 gene into esophageal cancer cells. p21Waf1 transfection to KE3 and YES2 cells (weakly expressed p21Waf1 protein cells) showed a high expression of p21Waf1 protein after applying this gene gun technique. In KE3 and YES2 cells, statistical significant growth inhibition was observed after p21Waf1 transfection compared with LacZ transfection (KE3, p=0.0009; YES2, p<0.0001). In in vivo transfection experiments, on day 14, the estimated volume of KE3 tumors subjected to p21Waf1 gene transfection was 95% in comparison with the pretreatment volume on day 0, while the volume of KE3 tumors subjected to LacZ gene therapy increased to 268%. On day 14, the estimated volume of YES2 tumors subjected to either p21Waf1 or LacZ gene therapy increased to 474 and 686%, respectively. In KE3 and YES2 cells, significant growth inhibition was observed after combination therapy using p21Waf1 transfection and anticancer drug 5-fluorouracil (5Fu) compared with 5Fu alone (KE3, p<0.0001; YES2, p<0.0001). In conclusion, p21Waf1 gene therapy using the gene gun technique significantly inhibited the low basal p21Waf1 expressed esophageal cancer cell growth in vitro and in vivo. Furthermore, p21Waf1 transfection strongly enhanced the effect of 5Fu suggesting that p21Waf1 may prove beneficial in chemotherapy combined with gene therapy using gene gun technology in patients with esophageal cancer who have a low level of p21Waf1 expressed tumor.
Int J Mol Med 2004 Oct
PMID:Experimental gene therapy using p21Waf1 gene for esophageal squamous cell carcinoma by gene gun technology. 1537 80

WNT signaling pathway networks with Hedgehog and Notch signaling pathways during carcinogenesis and embryogenesis. FZD7 is up-regulated in gastric cancer, esophageal cancer, and hepatocellular carcinoma (HCC). Here we identified and characterized rat Fzd7 gene by using bioinformatics. Rat Fzd7 gene was identified within AC136379.2 genome sequence. The 5'-flanking region and exonic region were well conserved among mammalian Fzd7 orthologs. Nucleotide position 153000-152216 of AC136379.2 genome sequence was identified as the evolutionarily conserved promoter region of rat Fzd7 gene, and nucleotide position 2273-3046 of AC069148.6 genome sequence as the evolutionarily conserved promoter region of human FZD7 gene. Match program revealed that PAX4-binding site was conserved among rat Fzd7, mouse Fzd7 and human FZD7 promoters. Rat Fzd7 (572 aa) was a seven-transmembrane-type Wnt receptor, which showed 99.3, 96.9, 87.4, 85.5, 79.5 and 79.0% total-amino-acid identity with mouse Fzd7, human FZD7, chicken fzd7, Xenopus fzd7, zebrafish fzd7a and fzd7b, respectively. Frizzled (Fz) domain within the N-terminal extracellular region, Leucine zipper motif around the fifth transmembrane (TM5) region, Dishevelled (Dvl)- and Magi3-binding motifs within the C-terminal cytoplasmic region were conserved among vertebrate Fzd7 orthologs. Leucine zipper motif around the TM5 region of Fzd7 orthologs was disrupted in FzE3 aberrant cDNA due to multiple cloning artifacts or sequencing errors. These facts indicate that experimental data obtained by using FzE3 cDNA do not always reflect the functions of Fzd7 orthologs.
Int J Mol Med 2005 Jun
PMID:Comparative genomics on Fzd7 orthologs. 1587 Sep 13

Chemosensitivity is affected by molecular biological factors, including factors related to the induction of apoptosis and the activity of proliferation. We analyzed immunohistochemically the expression of p53, Bcl-2, and Ki-67 in various types of cancers and assessed the correlation between this expression and chemosensitivity. Moreover, we investigated whether the expression of these factors could be a useful predictor for the clinical response to chemotherapy. Study subjects comprised 63 preoperative patients with untreated malignant tumors (9 with esophageal cancer, 12 with stomach cancer, 12 with colon cancer, 16 with liver cancer, and 14 with breast cancer). Immunohistochemical staining (the labeled streptavidin biotin technique: LSAB method) was used to assess expression of p53 protein, Bcl-2 protein, and Ki-67. A chemosensitivity test was carried out with the histoculture drug response assay method using four drugs: mitomycin C, 5-fluorouracil, doxorubicin hydrochloride (ADM), and cisplatin (CDDP). Immunohistochemical studies for p53 were found to be useful for predicting chemosensitivity.
Methods Mol Med 2005
PMID:Immunohistochemistry of p53, Bcl-2, and Ki-67 as predictors of chemosensitivity. 1590 38

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.
Int J Mol Med 2005 Dec
PMID:WNT2B: comparative integromics and clinical applications (Review). 1627 93

We evaluated the clinical utility of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) on the precise localization of pathologic foci and exclusion of normal variants in the imaging evaluation of patients with esophageal carcinoma. Combined PET/CT scans were performed in 60 patients (50 males, 10 females, age range 47-84 years) with history of esophageal carcinoma either at the time of initial diagnosis (group I, n=14) or for surveillance and/or detection of recurrent and metastatic disease (group II, n=46). Prior treatments included esophagectomy with gastric pull-up (n=23), surgery and chemotherapy (n=3), surgery and chemoradiation therapy (n=10), chemotherapy alone (n=5), radiation therapy alone (n=2), and chemoradiation without surgery (n=3). Diagnostic validation was by tissue sampling in three patients and clinical/radiological follow-up for up to 1.5 years in the remaining patients. In group I, discordant abnormalities were noted in seven patients. PET demonstrated hypermetabolism in normal-size lymph nodes on CT in three patients that were considered likely true positive in view of concurrent existence of other adjacent enlarged hypermetabolic lymph nodes in the same nodal basin. Hypometabolic incidental CT abnormalities of up to 1-cm lung nodules were noted in three patients and pleural effusion in one patient, which were considered true negative in view of no change on follow-up PET/CT studies. In group II, both PET and CT showed concordant abnormalities in 23 patients. The precise image fusion of hypermetabolism in a liver lesion allowed a diagnostic CT-guided biopsy in one patient. PET demonstrated true positive hypermetabolic abnormalities in four patients that localized to structures, which were normal by noncontrast CT criteria, and true negative in one patient with hepatic fatty deposits. PET showed decline in metabolic activity of the primary lesion in one patient after chemotherapy, while the corresponding CT abnormality remained unchanged. PET/CT image fusion provided relevant complementary diagnostic information in 14 patients with discordant findings (23% of total) that resulted in biopsy in three cases, institution of chemotherapy in four cases, and a wait-and-watch strategy in seven cases. In conclusion, our findings add to the current body of literature that suggests that FDG-PET/CT scanning may improve the imaging evaluation of patients with esophageal cancer by providing complementary structural-metabolic information. In particular, our findings support the notion that PET/CT may be the most appropriate imaging modality in the evaluation of patients of esophageal cancer that may impact patient management.
Mol Imaging Biol
PMID:2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography/computed tomography imaging evaluation of esophageal cancer. 1656 10

AREG (Amphiregulin), BTC (beta-cellulin), EGF, EPGN (Epigen), EREG (Epiregulin), HBEGF, NRG1, NRG2, NRG3, NRG4 and TGFA (TGFalpha) constitute EGF family ligands for ERBB family receptors. Cetuximab (Erbitux), Pertuzumab (Omnitarg) and Trastuzumab (Herceptin) are anti-cancer drugs targeted to EGF family ligands, while Gefitinib (Iressa), Erlotinib (Tarceva) and Lapatinib (GW572016) are anti-cancer drugs targeted to ERBB family receptors. AREG and TGFA are biomarkers for Gefitinib non-responders. The TCF/LEF binding sites within the promoter region of human EGF family members were searched for by using bioinformatics and human intelligence (Humint). Because three TCF/LEF-binding sites were identified within the 5'-promoter region of human AREG gene, comparative genomics analyses on AREG orthologs were further performed. The EPGN-EREG-AREG-BTC cluster at human chromosome 4q13.3 was linked to the PPBP-CXCL segmental duplicons. AREG was the paralog of HBEGF at human chromosome 5q31.2. Chimpanzee AREG gene, consisting of six exons, was located within NW_105918.1 genome sequence. Chimpanzee AREG was a type I transmembrane protein showing 98.0% and 71.4% total amino-acid identity with human AREG and mouse Areg, respectively. Three TCF/LEF-binding sites within human AREG promoter were conserved in chimpanzee AREG promoter, but not in rodent Areg promoters. Primate AREG promoters were significantly divergent from rodent Areg promoters. AREG mRNA was expressed in a variety of human tumors, such as colorectal cancer, liver cancer, gastric cancer, breast cancer, prostate cancer, esophageal cancer and myeloma. Because human AREG was characterized as potent target gene of WNT/beta-catenin signaling pathway, WNT signaling activation could lead to Gefitinib resistance through AREG upregulation. AREG is a target of systems medicine in the field of oncology.
Int J Mol Med 2006 Jun
PMID:Canonical WNT signaling pathway and human AREG. 1668 31

Esophageal cancer tissues and adjacent normal mucosae in 13 patients with primary esophageal cancer were examined for quantitative differences in DNA-dependent protein kinase (DNA-PK) activity and for expressions of Ku70, Ku80 and DNA-PKcs proteins by Western blotting and immunohistochemistry. The tumor tissues showed higher DNA-PK activity than the normal mucosae. Protein levels of Ku70, Ku80 and DNA-PKcs correlated with DNA-PK activities in the tumor tissues. Immunohistochemical analysis revealed that Ku70, Ku80 and DNA-PKcs located predominantly in the nuclei in both the tumor tissues and normal mucosae. In the normal epithelium, Ku70, Ku80 and DNA-PKcs were expressed only in the nuclei of the basal cell layers and not in those of the lumenal cell layers. In the tumor tissues, the expressions of DNA-PK proteins showed intratumoral heterogeneity. The different portions in the same tumor showed different expression levels of DNA-PK proteins, and even each tumor cell showed different expression levels. These results suggest that cell differentiation and tumor progression affect cellular DNA-PK protein levels and its activity. Furthermore, the intratumoral heterogeneity of DNA-PK protein expression in esophageal cancer cells/ tissues also suggests the difficulty in prediction of radio- or chemo-sensitivity of the tumor through estimation of DNA-PK activity/protein levels in tumor specimens.
Int J Mol Med 2006 Sep
PMID:Heterogeneous expression of DNA-dependent protein kinase in esophageal cancer and normal epithelium. 1686 28

WNT5A, WNT5B, WNT11, FZD3, FZD6, VANGL1, VANGL2, DVL1, DVL2, DVL3, PRICKLE1, PRICKLE2, ANKRD6, NKD1, NKD2, DAAM1, DAAM2, CELSR1, CELSR2, CELSR3, ROR1 and ROR2 are planar cell polarity (PCP) signaling molecules implicated in the regulation of cellular polarity, convergent extension, and invasion. FAT1, FAT2, FAT3 and FAT4 are Cadherin superfamily members homologous to Drosophila Fat, functioning as a positive regulator of PCP in the Drosophila wing. Complete coding sequence (CDS) for human FAT1 (NM_005245.3) and FAT2 (NM_001447.1) are available, while artificial CDS for human FAT3 (XM_926199 and XM_936538) and partial CDS for FAT4 (NM_024582.2). Here, complete CDS of human FAT3 and FAT4 were determined by using bioinformatics and human intelligence (Humint). FAT3 gene, consisting of 26 exons, encoded a 4557-aa protein with extracellular 33 Cadherin repeats, one Laminin G (LamG) domain and two EGF domains. FAT4 gene encoded a 4924-aa protein with extracellular 34 Cadherin repeats, two LamG domains and three EGF domains. Cytoplasmic VCSVxPxLP and SDYxS motifs were identified as novel motifs conserved among FAT1, FAT2 and FAT3 orthologs. Domain architecture comparison and phylogenetic analysis revealed that FAT1, FAT2 and FAR3 were divergent from FAT4. FAT1-MTNR1A locus at 4q35.2 and FAT3-MTNR1B locus at 11q14.3-q21 were paralogous regions within the human genome. FAT1 mRNA was expressed in embryonic stem (ES) cells, neural tissues, gastric cancer, pancreatic cancer, colorectal cancer, breast cancer, lung cancer and brain tumors. FAT2 mRNA was expressed in infant brain, cerebellum, gastric cancer, pancreatic cancer, ovarian cancer, esophageal cancer, skin squamous cell carcinoma, head and neck cancer. FAT3 mRNA was expressed in ES cells, primitive neuroectoderm, fetal brain, infant brain, adult neural tissues and prostate. FAT4 mRNA was expressed in fetal brain, infant brain, brain tumor and colorectal cancer. FAT family members were revealed to be targets of systems medicine in the fields of oncology and neurology.
Int J Mol Med 2006 Sep
PMID:Comparative integromics on FAT1, FAT2, FAT3 and FAT4. 1686 40


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