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Esophageal cancer is a significant worldwide health problem because of its poor prognosis and high incidence in certain parts of the world. Tobacco smoke and alcohol consumption are significant risk factors for esophageal squamous cell carcinoma, whereas frequent gastroesophageal reflux and subsequent inflammatory reactions play a role in causing the adenocarcinoma. Esophageal carcinogenesis involves multiple genetic alterations. A large body of knowledge has been generated regarding molecular alterations associated with esophageal carcinogenesis. These alterations include aberrant cell cycle control, DNA repair, cellular enzymes, growth factor receptors, and nuclear receptors. This chapter reviews the most frequent gene alterations and their correlation with risk factors as well as the prevention strategies in esophageal cancer.
Methods Mol Biol 2009
PMID:Risk factors and gene expression in esophageal cancer. 1910 88

Angiogenesis is critical for cancer development and metastasis. Here we have employed a functional antibody library-based proteomic screen to identify proteins that participate in and might be used as therapeutic targets for tumor-related angiogenesis. Mice were immunized with human esophageal cancer endothelial cells (HECEC). The antibody library was established with the mouse spleen cells the serum of which had most anti-angiogenic effect. Monoclonal antibodies were subjected to an immunoreactive and functional screen and monoclonal antibodies that reacted strongly with cell surface antigens of HECECs and influenced their behavior were selected. Antigens that recognized by the antibodies were obtained by immunoprecipitation and then identified by mass spectrometry analysis. Migration-stimulating factor (MSF), the antigen of 1D2 antibody was identified using this approach. Further studies demonstrated that the 1D2 antibody suppressed MSF-effected migration and adhesion of HECECs on fibronectin matrix. Biodistribution assay showed that MSF targeting antibody 1D2 could specifically home to the xenograft with humanized blood vessel. Targeting treatment with 1D2 antibody significantly suppressed tumor growth through inhibition of human tumor-related angiogenesis. These results indicate that the functional antibody library-based proteomic screen can successfully identify proteins that involved in tumor-related angiogenesis and MSF may be a target for the anti-angiogenic treatment of the esophageal cancer.
Mol Cell Proteomics 2009 Apr
PMID:Antibody library-based tumor endothelial cells surface proteomic functional screen reveals migration-stimulating factor as an anti-angiogenic target. 1911 29

The Akt-Mdm2 pathway plays an important role in carcinogenesis in a variety of malignant tumors. However, the Akt-Mdm2 pathway in esophageal squamous cell carcinoma (ESCC) has not been fully studied. We investigated the proteins and mRNA expression of Akt and Mdm2 to elucidate the roles of these proteins in ESCC. We also examined the effect of Akt knockdown on Mdm2 expression in ESCC cells. ESCC tissue samples were obtained from 23 individuals who underwent surgical resection with no preoperative treatment. Akt1-3 and Mdm2 gene and protein expression were analyzed. The effect of siRNA-mediated Akt knockdown on Mdm2 expression was also studied, using ESCC cell lines. Akt1 and Mdm2 immunoreactivity was detected in 77.8 and 66.7% of tumor specimen from ESCC patients, respectively. Akt1 and Mdm2 mRNA expressions were correlated and significantly elevated in tumor tissue (p<0.0001 and p<0.05, respectively). The siRNA-targeted reduction of each Akt isoform reduced Mdm2 protein expression. The overexpression of Akt1 and Mdm2 may be related to esophageal carcinogenesis. Furthermore, Akt expression regulates Mdm2 expression, which may in turn regulate the function of wild-type p53. These results may provide the basis for future preventative or clinical therapies for esophageal cancer.
Exp Mol Pathol 2009 Aug
PMID:Expression of Akt and Mdm2 in human esophageal squamous cell carcinoma. 1912 15

Esophageal cancer, although uncommon in the United States, has been increasing in frequency, and despite advances in therapy, the diagnosis still carries a poor prognosis. Many patients present with locally advanced disease and receive multimodality therapy with combined chemoradiation before surgery. Imaging plays an important role in the initial selection of patients for tri-modality therapy and in evaluating responses to neoadjuvant chemoradiation prior to surgery. There is increasing use of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in management of esophageal cancer to identify distant metastasis at presentation and to assess response to therapy. Standardized imaging protocols with semiquantitative analysis may also provide prognostic information and be used to individualize patient therapy. This review will discuss the role of imaging studies in the management of esophageal cancer patients, with particular attention to FDG-PET/CT.
Q J Nucl Med Mol Imaging 2009 Apr
PMID:The evolving role of PET-CT in the management of esophageal cancer. 1929 68

Although early growth response-1 (EGR-1) has been shown as a key transcription factor in controlling cell growth, proliferation, differentiation, and angiogenesis, its role in the development of esophageal cancer is poorly understood despite the high frequency of this disease in many parts of the world. Here, immunohistochemistry showed that EGR-1 is overexpressed in 80% of esophageal tumor tissues examined. Furthermore, EGR-1 is constitutively expressed in all esophageal cancer cell lines analyzed. Esophageal squamous carcinoma WHCO1 cells stably transfected with EGR-1 short hairpin RNA displayed a 55% reduction in EGR-1 protein levels, 50% reduction in cell proliferation, a 50% reduction in cyclin-dependent kinase 4 levels, and a 2-fold induction in p27(Kip1) levels associated with a G(2)-M cell cycle arrest. EGR-1 knockdown also caused a marked induction in IkappaBalpha expression, an effect also observed in GRObeta RNA interference-expressing WHCO1 cells, because EGR-1 lies downstream of GRO/CXCR2 signaling. Furthermore, p65 mRNA levels were also reduced in cells treated with either short hairpin RNA EGR-1 or small interfering RNA EGR-1. Immunohistochemical analysis indicated that p65 is elevated in 78% (n = 61) of esophageal tumor sections analyzed. Moreover, nuclear factor-kappaB inhibition with either sodium salicylate or p65 RNA interference led to a significant reduction in GROalpha and GRObeta expression. These results indicate that EGR-1 and nuclear factor-kappaB mediate GRO/CXCR2 proliferative signaling in esophageal cancer and may represent potential target molecules for therapeutic intervention.
Mol Cancer Res 2009 May
PMID:A key role for early growth response-1 and nuclear factor-kappaB in mediating and maintaining GRO/CXCR2 proliferative signaling in esophageal cancer. 1943 11

To develop novel therapeutic and diagnostic methods for esophageal cancer, it is important to understand the precise biological mechanism. Micro-RNAs (miRNAs) seem to be crucial factors in diverse regulation pathways. In this study, we analyzed the expression of mature miRNAs in esophageal squamous cell carcinoma (ESCC). The expression of 73 miRNAs was quantified by qRT-PCR in 30 primary ESCC specimens. We examined the correlation between miRNA expressions and the clinicopathological factors and prognosis of ESCC. The Kaplan-Meier survival curves showed that the high expression levels of 6 of the 72 miRNAs correlated with significantly lower patient survival rates. The overexpression of miR-129 was identified as a significant and independent prognostic factor (P = 0.031) in surgically treated ESCC patients. The hazard ratio for the prediction of early death was 18.11 for high versus low expression levels of miR-129. Similar results were obtained from an analysis performed on an additional 19 patients (test cohort) (P = 0.0057, for training cohort; P = 0.011, for test cohort; log-rank test). This experiment supports the notion that the high miR-129 expression levels, as observed in this study, might play a important role in the development of esophageal cancer.
Med Mol Morphol 2009 Jun
PMID:Expression profiling of micro-RNAs in human esophageal squamous cell carcinoma using RT-PCR. 1953 17

We and others previously cloned and characterized vertebrate WNT11 orthologs, which are involved in gastrulation, neurulation, cardiogenesis, nephrogenesis, and chondrogenesis during fetal development. WNT11 orthologs activate both canonical and non-canonical WNT signaling cascades depending on the expression profile of WNT receptors, such as Frizzled family members, LRP6, ROR2, and RYK. Human WNT11 is expressed in breast cancer, gastric cancer, esophageal cancer, colorectal cancer, neuroblastoma, Ewing sarcoma, and prostate cancer. Canonical WNT signals and GATA family members are involved in WNT11 transcription during embryogenesis of model animals; however, precise mechanisms of WNT11 expression remain unclear. Here, refined integrative genomic analyses of WNT11 are carried out to elucidate the mechanisms of WNT11 transcription. The WNT11 gene was found to encode two isoforms by using alternative first exons. WNT11 isoform A (NM_004626.2 RefSeq) consists of exons 2, 3, 4, 5 and 6, whereas WNT11 isoform B consists of exons 1, 2, 3, 4, 5 and 6. We identified double TCF/LEF-binding sites within the proximal promoter regions -48-bp position from the TSS of human WNT11 isoform B and -43-bp position from the TSS of human WNT11 isoform A), and also double GATA-binding sites within intron 2 of human WNT11 gene (+933-bp and +5001-bp positions from TSS of human WNT11 isoform A). Double TCF/LEF- and double GATA-binding sites within the regulatory regions of human WNT11 gene were conserved in other mammalian WNT11 orthologs. These facts indicate that canonical WNT signals and GATA family members directly upregulate WNT11 transcription. Canonical WNT-induced WNT11 activates non-canonical WNT signaling cascades to induce cellular movement, and also activates the Ca2+-MAP3K7-NLK signaling cascade to break the canonical WNT signaling. Canonical WNT-to-WNT11 signaling loop is involved in cellular migration during embryogenesis as well as tumor invasion during carcinogenesis.
Int J Mol Med 2009 Aug
PMID:Integrative genomic analyses of WNT11: transcriptional mechanisms based on canonical WNT signals and GATA transcription factors signaling. 1957 97

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in cancer etiology. The -765G>C and 8473T>C polymorphisms have been implicated in cancer risk. However, the results on the association between the two COX-2 polymorphisms and cancer risk are conflicting. To derive a more precise estimation of the association between them, we performed a meta-analysis of 8,090 cancer cases and 11,010 controls concerning -765G>C polymorphism and 14,283 cancer cases and 15,489 controls concerning 8473T>C polymorphism from 33 case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, individuals with the -765GC or GC/CC genotypes were associated with higher cancer risk than those with the -765GG genotype and in the stratified analysis this effect maintained in colorectal carcinoma or esophageal cancer of Asian descents. Overall, no significant cancer risk of 8473T>C polymorphism was found. Stratified by cancer types, the variant 8473CC was associated with a decreased risk in breast cancer, compared with the TT or TC/TT genotypes and in lung cancer subgroup after sensitive analysis, there was a decreased risk in CC versus TT, TC versus TT and the dominant models. Moreover, a decreased risk of lung cancer was observed among smokers in the dominant model. In summary, this meta-analysis suggesting that -765G>C may cause an increased risk of colorectal carcinoma and esophageal cancer in Asian descents while 8473T>C polymorphism may cause a decreased risk of breast and lung cancer.
Mol Biol Rep 2010 Jan
PMID:-765G>C and 8473T>C polymorphisms of COX-2 and cancer risk: a meta-analysis based on 33 case-control studies. 1966 67

Esophageal cancer is the eighth most common malignancy, and one of the leading causes of cancer-related deaths worldwide. The overall 5-year survival rate of patients with esophageal cancer remains low at 10% to 40% due to late diagnosis, metastasis, and resistance of the tumor to radiotherapy and chemotherapy. NF-kappaB is involved in the regulation of cell growth, survival, and motility, but little is known about the role of this signaling pathway in the tumorigenesis of human esophageal squamous cell carcinoma (ESCC), the most common form of esophageal cancer. This study aims to explore the functions of NF-kappaB in human ESCC progression and to determine whether targeting the NF-kappaB signaling pathway might be of therapeutic value against ESCC. Our results from human ESCC cell lines and ESCC tissue indicated that NF-kappaB is constitutively active in ESCC. Exposure of ESCC cells to two NF-kappaB inhibitors, Bay11-7082 and sulfasalazine, not only reduced cancer cell proliferation, but also induced apoptosis and enhanced sensitivity to chemotherapeutic drugs, 5-fluorouracil, and cisplatin. In addition, Bay11-7082 and sulfasalazine suppressed the migration and invasive potential of ESCC cells. More importantly, the results from tumor xenograft and experimental metastasis models showed that Bay11-7082 had significant antitumor effects on ESCC xenografts in nude mice by promoting apoptosis, and inhibiting proliferation and angiogenesis, as well as reduced the metastasis of ESCC cells to the lungs without significant toxic effects. In summary, our data suggest that NF-kappaB inhibitors may be potentially useful as therapeutic agents for patients with esophageal cancer.
Mol Cancer Ther 2009 Sep
PMID:Targeting NF-kappaB signaling pathway suppresses tumor growth, angiogenesis, and metastasis of human esophageal cancer. 1972 87

Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy.
Curr Mol Med 2009 Sep
PMID:Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. 1986 Jun 66


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