• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4607-4611
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• 2012

Objective: Endometrial cancer (EC) is the most common gynecologic malignancy. Identification of potential biomarkers of EC would be helpful for the detection and monitoring of malignancy, improving clinical outcomes. Methods: The Weighted Gene Co-expression Network Analysis method was used to identify prognostic markers for EC in this study. Moreover, underlying molecular mechanisms were characterized by KEGG pathway enrichment and transcriptional regulation analyses. Results: Seven gene co-expression modules were obtained, but only the turquoise module was positively related with EC stage. Among the genes in the turquoise module, COL5A2 (collagen, type V, alpha 2) could be regulated by PBX (pre-B-cell leukemia homeobox 1)1/2 and HOXB1(homeobox B1) transcription factors to be involved in the focal adhesion pathway; CENP-E (centromere protein E, 312kDa) by E2F4 (E2F transcription factor 4, p107/p130-binding); MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived [avian]) by PAX5 (paired box 5); and BCL-2 (B-cell CLL/lymphoma 2) and IGFBP-6 (insulin-like growth factor binding protein 6) by GLI1. They were predicted to be associated with EC progression via Hedgehog signaling and other cancer related-pathways. Conclusions: These data on transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of EC.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3295-3300
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• 2016

Background: Different types of cancer exhibit abnormalities in cell cycle regulators. The murine double minute-2(MDM2) cell cycle regulator is a proto-oncogene that negatively regulates the P53 tumour suppressor gene. Surface epithelial tumours constitute approximately two thirds of ovarian neoplasms. Each histologic type can be classified as benign, borderline and malignant. This study aimed to examine immunohistochemical expression of the MDM2 protein in ovarian serous and mucinous epithelial tumours (benign, borderline and malignant). Materials and Methods: This study included forty five ovarian tumours, subdivided into fifteen cystadenomas (5 serous and 10 mucinous), fifteen borderline tumours (11 serous and 4 mucinous) and fifteen cystadenocarcinomas (9 serous and 6 mucinous). Paraffin sections were stained with haematoxylin and eosin for histopathologic study, and with mouse monoclonal anti-MDM2 antibody for immunohistochemistry. Results: MDM2 positivity was detected in 28.9% of the studied ovarian tumours. All benign tumours were negative and positivity was significantly higher in malignant than borderline tumours (P value of chi-square test =0.000). Significantly, all MDM2 positive mucinous tumours were malignant with no positive mucinous borderline tumours. Malignant tumours showed positive MDM2 expression in 83.3% of mucinous type and in 55.6% of serous type. Borderline serous tumours showed negative MDM2 in 72.7% of cases (P value of Z test =0.04). Conclusions: Alterations in the expression of the cell cycle regulator (MDM2) occur early in the process of tumourigenesis in serous and mucinous ovarian tumours. We suggest that MDM2 may be used in those tumours as a marker for risk stratification and identification of cases with cancer development and progression. We recommend further studies on MDM2 immunohistochemistry, in conjunction with adjuvant methods as DNA ploidy and FISH gene amplification, focusing on the mucinous tumours and differentiating between the three tumour categories, benign, borderline and malignant.

• The Journal of Korean Medicine
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• v.25 no.2
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• pp.127-137
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• 2004

Objectives : The purpose of this investigation was to evaluate the effects of Sohaphyang-won (SH) on the alteration in gene expression in a hypoxia model using cultured rat cortical cells. Methods : E18 rat cortical cells were grown in neurobasal medium containing B27 supplement. On 12 DIV, SH was added ($20\mu\textrm{g}/ml$) to the culture media for 24 hrs. On 14 DIV, cells were given a hypoxic insult (2% O2/5% CO2, $37^{\circ}C$, 3 hrs), returned to normoxia and cultured for another 24 hrs. Total RNA was prepared from SH-untreated (control) and -treated cultures and alteration in gene expression was analyzed by microarray using rat 5K-TwinChips. Results : Effects on some of the genes whose functions are implicated in neural viability are as follows: 1) For most of the genes altered in expression, the global M values were between -05 to +0.5, Among these, 1517 genes were increased in their expression by more than global M +0.1, while 1480 genes were decreased by more than global M -0.1. 2) The expression of apoptosis-related genes such as Bad (global M =0.35), tumor protein p53 (T53) (global M =0.28) were increased, while v-akt murine thymoma viral oncogene homolog 1 (Akt1) was decreased. 3) The expression of hemoglobin alpha 1 (probably neuroglobin) was increased by about 3.2-fold (global M =1.7). 4) The expression of antioxidation-related catalase gene was increased (global M =0.26). 5) The expression of PKCzeta (prkcz), an upstream kinase of MAPK, was increased (global M =0.29). 6) The expression of retinoic acid receptor alpha (RAR), which may regulate transcription in hypoxic stress, was increased (global M =10.27). Conclusions : In summary, the microarray data suggest that SH doesn't increase the expression of oxygen capture-, anti-oxidation- and 'response to stress' -related genes but decreases some anti-apoptosis genes which would help protect the hypoxic cells from apoptosis.

• Toxicological Research
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• v.8 no.2
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• pp.343-357
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• 1992

Tumor necrosis factor-${\alpha}$(TNF), a polypeptide hormone secreted primarily by activated macrophages, was originally identified on the basis of its ability to cause hemorrhagic necrosis and tumor regression in vivo. Subsequently, TNF has been shown to be an important component of the host responses to infection and cancer and may mediate the wasting syndrome known as cachexia. These systemic actions of TNF are reflected in its diverse effects on target cells in vitro. TNF initiates its diverse cellular actions by binding to specific cell surface receptors. Although TNF receptors have been identified on most of animal cells, regulation of these receptors and the mechanisms which transduce TNF receptor binding into cellular responses are not well understood. Therefore, in the present study, the mechanisms how TNF receptors are being regulated and how TNF receptor binding is being transduced into cellular responses were investigated in rat liver plasma membranes (PM) and ME-180 human cervical carcinoma cell lines. $^{125}I$-TNF bound to high ($K_d=1.51{\pm}0.35nM$)affinity receptors in rat liver PM. Solubilization of PM with 1% Triton X-100 increased both high affinity (from $0.33{\pm}0.04\;to\;1.67{\pm}0.05$ pmoles/mg protein) and low affinity (from $1.92{\pm}0.16\;to\;7.57{\pm}0.50$ pmoles/mg protein) TNF binding without affecting the affinities for TNF, suggesting the presence of a large latent pool of TNF receptors. Affinity labeling of receptors whether from PM or solubilized PM resulted in cross-linking of $^{125}I$-TNF into $M_r$ 130 kDa, 90 kDa and 66kDa complexes. Thus, the properties of the latent TNF receptors were similar to those initially accessible to TNF. To determine if exposure of latent receptors is regulated by TNF, $^{125}I$-TNF binding to control and TNF-pretreated membranes were assayed. Specific binding was increased by pretreatment with TNF (P<0.05), demonstrating that hepatic PM contains latent TNF receptors whose exposure is promoted by TNF. Homologous up-regulation of TNF receptors may, in part, be responsible for sustained hepatic responsiveness during chronic exposure to TNF. As a next step, the post-receptor events induced by TNF were examined. Although the signal transduction pathways for TNF have not been delineated clearly, the actions of many other hormones are mediated by the reversible phosphorylation of specific enzymes or target proteins. The present study demonstrated that TNF induces phosphorylation of 28 kDa protein (p28). Two dimensional soidum dodecyl sulfate-polyacrylamide gel electrophoresis(SDS-PAGE) resolved the 28kDa phosphoprotein into two isoforms having pIs of 6.2 and 6.1. The pIs and relative molecular weight of p28 were consistent with those of a previously characterized mRNA cap binding protein. mRNA cap binding proteins are a class of translation initiation factors that recognize the 7-methylguanosine cap structure found on the 5' end of eukaryotic mRNAs. In vitro, these proteins are defined by their specific elution from affinity columns composed of 7-methylguanosine 5'-triphosphate($m^7$GTP)-Sepharose. Affinity purification of mRNA cap binding proteins from control and TNF treated ME-180 cells proved that TNF rapidly stimulates phosphorylation of an mRNA cap binding protein. Phosphorylation occurred in several cell types that are important in vitro models of TNF action. The mRNA cap binding protein phosphorylated in response to TNF treatment was purifice, sequenced, and identified as the proto-oncogene product eukaryotic initiation factor-4E(eIF-4E). These data show that phosphorylation of a key component of the cellular translational machinery is a common early event in the diverse cellular actions of TNF.