| 1. |
- Chung, C M, et al.
(författare)
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Amplification and overexpression of Aurora kinase A (AURKA) in immortalized human ovarian epithelial (HOSE) cells
- 2005
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 1098-2744 .- 0899-1987. ; 43:3, s. 165-174
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Tidskriftsartikel (refereegranskat)abstract
- Immortalization is an early and essential step of human carcinogenesis. Amplification of chromosome 20q has been shown to be a common event in immortalized cells and cancers. We have previously reported that gain and amplification of chromosome 20q is a non-random and common event in immortalized human ovarian surface epithelial (HOSE) cells. The chromosome 20q harbors genes including TGIF2 (20q11.2-q12), AIB1 (20q12), PTPN1 (20q13.1), ZNF217 (20q13.2), and AURKA (20q13.2-q13.3), which were previously reported to be amplified and overexpressed in ovarian cancers. Some of these genes may be involved in immortalization of HOSE cells and represent crucial premalignant changes in ovarian surface epithelium. Investigation of the involvement of these genes was examined in four pairs of pre-crisis (preimmortalized) and post-crisis (immortalized) HOSE cells. Overexpression of AURKA (Aurora kinase A), also known as BTAK and STK15, by both real time-quantitative polymerase chain reaction (RT-QPCR) and Western blotting was detected in all the four immortalized HOSE cells examined while overexpression of AIB1 and ZNF217 was observed in two of four immortalized HOSE cells examined. Overexpression of TGIF2 and PTPN1 was not significant in our immortalized HOSE cell systems. The degree of overexpression of AURKA was shown to be closely associated with the amplification of chromosome 20q in immortalized HOSE cells. Fluorescence in situ hybridization (FISH) with labeled Pi artificial clone (PAC) confirmed the amplification of the chromosomal region (20q13.2-13.3) where AURKA resides. DNA amplification of AURKA was also confirmed using semi-quantitative PCR. Our study showed that amplification and overexpression of AURKA is a common and significant event during immortalization of HOSE cells and may represent an important premalignant change in ovarian carcinogenesis.
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| 2. |
- Elander, Nils, et al.
(författare)
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Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer
- 2009
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 48:5, s. 401-407
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Tidskriftsartikel (refereegranskat)abstract
- Bioactive metabolites downstream of cyclooxygenase-2 (COX-2) generated prostaglandin H-2 (PGH(2)), in particular prostaglandin E-2 (PGE(2)), are thought to play critical roles during the development of colorectal tumors. Previous reports reveal that defects of the tumor suppressor adenomatosis polyposis coli (APC) contribute to COX-2 upregulation in colon tumor cells. We investigated whether a similar relation was present between APC functional status and the expression of microsomal prostaglandin E synthase-1 (mPGES-1), which acts downstream of COX-2 and catalyses the terminal conversion of PGH(2) into PGE(2). Surprisingly, mPGES-1 mRNA and protein levels were upregulated upon induction of a wild type-APC carrying vector in HT29 colon cancer cells, and downregulated following siRNA silencing of APC in HCT-116 cells. mPGES-1 was overall enhanced in human colorectal tumor specimens versus corresponding non-tumor mucosa and, in accordance with data on HT29 and HCT116 cells, higher levels of mPGES-1 were observed among tumors carrying wild type versus mutant APC. RNAi silencing of beta-catenin and luciferase assays regarding the mPGES-1 promoter region did not reveal a role for APC or beta-catenin/Tcf in controlling mPGES-1 gene transcription. However, RNA degradation assays in HT29 cells revealed a suppressed degradation of mPGES-1 in the presence of wild type APC, implying that mPGES-1 mRNA is stabilized in the APC wild type state. Collectively, we demonstrate a novel association between APC functional status and mPGFS-1 expression in colorectal tumor cells, being most likely related to reduced mPGES-1 mRNA degradation rate in the APC wild type state.
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| 3. |
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| 4. |
- Fransén, Karin, 1973-, et al.
(författare)
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Association between ulcerative growth and hypoxia inducible factor-1alpha polymorphisms in colorectal cancer patients
- 2006
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Ingår i: Molecular Carcinogenesis. - : John Wiley & Sons. - 0899-1987 .- 1098-2744. ; 45:11, s. 833-840
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Tidskriftsartikel (refereegranskat)abstract
- The hypoxia inducible factor-1alpha (HIF-1alpha) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1alpha is hydroxylated at normoxia and rapidly degraded via the von Hippel-Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1alpha gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26-21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58-26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1alpha C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33-13.08; P = 0.004). These results suggest that the HIF-1alpha polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1alpha allele may therefore be of importance in the selection of treatment strategies of CRC.
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| 5. |
- Fransén, Karin, 1973-, et al.
(författare)
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Association between ulcerative growth and hypoxia inducible factor-1α polymorphisms in colorectal cancer patients
- 2006
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 45:11, s. 833-840
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Tidskriftsartikel (refereegranskat)abstract
- The hypoxia inducible factor-1α (HIF-1α) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1α is hydroxylated at normoxia and rapidly degraded via the von Hippel–Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1α gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26–21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58–26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1α C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33–13.08; P = 0.004). These results suggest that the HIF-1α polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1α allele may therefore be of importance in the selection of treatment strategies of CRC.
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| 6. |
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| 7. |
- Mukherjee, Sudeshna, et al.
(författare)
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Differential Alterations in Metabolic Pattern of the Spliceosomal Uridylic Acid-Rich Small Nuclear RNAs (UsnRNAs) During Malignant Transformation of 20-Methylcholanthrene-induced Mouse CNCI-PM-20 Embryonic Fibroblasts
- 2009
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 1098-2744 .- 0899-1987. ; 48:9, s. 773-778
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Tidskriftsartikel (refereegranskat)abstract
- Differential alterations of the spliceosomal Uridylic acid rich small nuclear RNAs (UsnRNAs) (U1, U2, U4, US, and U6) are reported to be associated with cellular proliferation and development, but definitive information is scarce and also elusive. An attempt is made in this study to analyze the metabolic patterns of major spliceosomal UsnRNAs, during tumor development, in an in vitro carcinogenesis model of 20-methylcholanthrene (MCA)-transformed Swiss Mouse Embryonic Fibroblast (MEF), designated as CNCI-PM-20. MEF cells, after treatment with 20-MCA, progressed through a sequence of passages with distinct and heritable changes, finally becoming neoplastic at passage-42 (P42). A differential expression pattern of major UsnRNAs was observed during this process. The abundance of U1 was 20% below control (P1) at passage-20 (P20), followed by a gradual increase up until P42 (similar to 12% above the P1 value). The abundance of U2 was more or less constant during the cellular transformation. U4 showed a trend of increase, with above 30% abundance than control at P20, followed by a significant increase at P36 and P42 (1.5- and 2-fold, respectively, P-value <0.01). US also followed an identical pattern, with an increase of 70% compared to control (P-value <0.05) at P42. Interestingly, U6 gradually decreased from P20 onwards up until P42, with 22% at P20 and 67% at P42 (P-value <0.01). An overall significant quantitative alteration in abundance of U4, US, and U6, observed in our study, contributes to the understanding of the fact that, the metabolism of major spliceosomal UsnRNAs is differentially regulated during the process of neoplastic transformation. (C) 2009 Wiley-Liss, inc.
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| 9. |
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| 10. |
- Samuelson, Emma, 1974, et al.
(författare)
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Absence of Ras mutations in rat DMBA-induced mammary tumors.
- 2009
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Ingår i: Molecular carcinogenesis. - : Wiley. - 1098-2744 .- 0899-1987. ; 48:2, s. 150-5
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Tidskriftsartikel (refereegranskat)abstract
- Animal cancer models reduce genetic background heterogeneity and thus, may facilitate identification and analysis of specific genetic aberrations in tumor cells. Rat and human mammary glands have high similarity in physiology and show comparable hormone responsiveness. Thus, spontaneous and carcinogen (e.g., NMU and DMBA)-induced rat mammary models are valuable tools for genetic studies of breast cancer. In NMU-induced rat mammary tumors, activating mutations in Hras codon 12 have frequently been reported and are supposed to contribute to the mammary carcinogenic process. Involvement of Ras mutations in DMBA-induced tumors is less clear. In the present study we investigated the mutation status of the three Ras genes, Hras, Kras, and Nras, in DMBA-induced rat mammary tumors. We examined codons 12, 13, and 61 of all three genes for mutations in 71 tumors using direct sequencing method that in experimental conditions is sensitive enough to detect single nucleotide mutations even when present in only 25% of the test sample. No activating Ras gene mutation was found. Thus, in contrast to NMU-induced rat mammary tumor, tumorigenesis in DMBA-induced rat mammary tumors seems to be independent on activating mutations in the Ras genes. Our finding suggests that the genetic pathways selected in mammary tumor development are influenced by and perhaps dependent on the identity of the inducing agent, again emphasizing the importance of tumor etiology on the genetic changes in the tumor cells.
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