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| 33. |
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| 34. |
- Packer, Leisl, et al.
(författare)
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Osteopontin is a downstream effector of the PI3-kinase pathway in melanomas that is inversely correlated with functional PTEN
- 2006
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 27:9, s. 1778-1786
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Tidskriftsartikel (refereegranskat)abstract
- The tumor suppressor PTEN antagonizes phosphatidylinositol 3-kinase (PI3K), which contributes to tumorigenesis in many cancer types. While PTEN mutations occur in some melanomas, their precise mechanistic consequences have yet to be elucidated. We sought to identify novel downstream effectors of PI3K using a combination of genomic and functional tests. Microarray analysis of 53 melanoma cell lines identified 610 genes differentially expressed (P < 0.05) between wild-type lines and those with PTEN aberrations. Many of these genes are known to be involved in the PI3K pathway and other signaling pathways influenced by PTEN. Validation of differential gene expression by qRT-PCR was performed in the original 53 cell lines and an independent set of 18 melanoma lines with known PTEN status. Osteopontin (OPN), a secreted glycophosphoprotein that contributes to tumor progression, was more abundant at both the mRNA and protein level in PTEN mutants. The inverse correlation between OPN and PTEN expression was validated (P < 0.02) by immunohistochemistry using melanoma tissue microarrays. Finally, treatment of cell lines with the PI3K inhibitor LY294002 caused a reduction in expression of OPN. These data indicate that OPN acts downstream of PI3K in melanoma and provides insight into how PTEN loss contributes to melanoma development.
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| 35. |
- Parhamifar, Ladan, et al.
(författare)
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Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells.
- 2005
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 26:Jun 23, s. 1988-1998
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Tidskriftsartikel (refereegranskat)abstract
- It is well documented that prolonged inflammatory conditions, particularly those relating to the colon, have been shown to induce cancer. We have previously demonstrated that the pro-inflammatory mediator leukotriene D-4 (LTD4) induces survival and proliferation in intestinal cells and that its receptor, CysLT(1), is upregulated in human colon cancer tissue. Here we demonstrate, for the first time that in both Int 407 (a non-transformed human intestinal epithelial cell line) and Caco-2 cells (a human colorectal carcinoma cell line), cytosolic phospholipase A(2)alpha (cPLA(2)alpha) is activated and translocates to the nucleus upon LTD4 stimulation via a calcium-dependent mechanism that involves activation of protein kinase C (PKC), and the mitogen-activated protein kinases ERK1/2 and p38. We also show with a cPLA(2)alpha promoter luciferase assay, that LTD4 induces an increase in the transcriptional activity of cPLA(2)alpha via activation of cPLA(2)alpha and the transcription factor NF kappa B. Interestingly we demonstrate here that both the basal and the LTD4-induced cPLA(2)alpha activity is elevated similar to 3-fold in Caco-2 colon cancer cells compared with Int 407 cells. The difference in basal activity was confirmed in human colon tumor samples by the finding of a similar increase in cPLA(2)alpha activity when compared with normal colon tissue. A functional role of the increased cPLA(2)alpha activity in tumor cells was revealed by our findings that inhibition of this enzyme reduced both basal and LTD4-induced proliferation, the effects being most pronounced in Caco-2 tumor cells. The present data reveal that cPLA(2)alpha, an important intracellular signal activated by inflammatory mediators, is an important regulator of colon tumor growth.
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| 36. |
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| 37. |
- Pfeifer, Daniella, et al.
(författare)
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Polymorphism of the p73 gene in relation to colorectal cancer risk and survival
- 2005
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 26:1, s. 103-107
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Tidskriftsartikel (refereegranskat)abstract
- The results regarding a GC/AT polymorphism in the p73 gene in relation to cancer risk are inconsistent, and the significance of loss of heterozygosity (LOH) of the gene is unclear. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. 179 patients with colorectal cancer and 260 healthy controls were genotyped for the polymorphism by PCR-restriction fragment length polymorphism (RFLP). Fifty informative cases were examined for LOH in tumours. Immunohistochemistry was performed on distant (n = 42) and adjacent normal mucosa (n = 33), primary tumour (n = 6 9) and lymph node metastasis (n = 12). The frequencies of the genotypes were 63% for wild-type (GC/GC), 30% for heterozygotes (GC/AT) and 7% for variants (AT/AT) in patients, and 62, 36 and 2% in controls, respectively. The frequencies of the genotypes in the patients and controls were significantly different (P = 0.02). The patients carrying the AT allele had a better prognosis than those with the GC/GC genotype (OR = 0.42, 95% CI = 1.15-5.02, P = 0.02). No LOH was observed at the p73 locus. Expression of p73 protein was increased from normal mucosa to primary tumours (P = 0.02), but was not significantly changed between primary tumours and metastases (P = 1.0). In conclusion, the AT/AT homozygotes may have a greater risk of developing colorectal cancer, while the patients who carried the AT allele had a better prognosis.
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| 38. |
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| 39. |
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| 40. |
- Sonestedt, Emily, et al.
(författare)
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Plant foods and estrogen receptor {alpha} and {beta} defined breast cancer: observations from the Malmo Diet and Cancer cohort.
- 2008
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 29:11, s. 2203-2209
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Tidskriftsartikel (refereegranskat)abstract
- The associations between plant foods and breast cancer incidence are inconsistent. The objective of this study was to examine prospectively the association between dietary fibre, plant foods and breast cancer, especially the association between plant food intake and estrogen receptor (ER) alpha and beta defined breast cancer. Among women without prevalent cancer from the population-based prospective Malmö Diet and Cancer cohort (n = 15,773, 46-75 years at baseline), 544 women were diagnosed with incident invasive breast cancer during a mean follow-up of 10.3 years. Information on dietary habits was collected by a modified diet history method. ER status of the tumours was determined by immunohistochemistry using tissue microarray. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer associated with fibre and 11 plant food groups. High-fibre bread was significantly associated with a decreased breast cancer incidence (HR, 0.75, 95 % CI, 0.57-0.98, for highest compared to lowest quintile). The other plant food groups were not significantly associated with breast cancer incidence. There was a tendency for a negative association for high-fibre bread among ERalpha (+) breast cancer (p for trend = 0.06) and ERbeta (+) breast cancer (p for trend = 0.06). Fried potatoes were statistically significantly associated with increased risk of ERbeta (-) breast cancer (p = 0.01). This study suggests that different plant foods may be differently associated with breast cancer, with fibre-rich bread showing an inverse association. We did not observe strong evidence for differences in incidence according to the ER alpha and beta status of breast cancer.
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