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Exp Mol Pathol [journal]
- Sineoculis homeobox homolog 1 protein is associated with breast cancer progression and survival outcome. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 22.
Sineoculis homeobox homolog 1 (SIX1) is one of the transcription factors that act as master regulators of development and is frequently dysregulated in cancer. This study explores the roles of SIX1 in tumor progression and as a prognostic determinant of breast cancer. Breast cancer specimens from 262 patients were selected for analysis of SIX1 protein by immunohistochemistry (IHC). The localization of SIX1 protein was detected in MDA-MB468 breast cancer cells using immunofluorescence (IF) staining. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models. SIX1 protein mainly showed cytoplasmic/perinuclear staining pattern in breast cancer using IHC in paraffin embedded breast cancer tissues and IF in MDA-MB468 cancer cells. The strongly positive rate of SIX1 protein was 61.8% (162/262) in breast cancer and 23.1% (12/52) in ductal carcinoma in situ (DCIS), which was significantly higher than adjacent normal breast tissues (6.7%, 3/45). SIX1 overexpression was positively correlated with clinical stage, lymph node metastasis, Her2 expression status, and disease-free survival (DFS) and 5-year overall survival (OS) rates of patients with breast cancer. Moreover, patients with late stage breast cancer and high SIX1 expression had poorer survival rates than those with low SIX1 expression. Further analysis using a Cox proportional hazard regression model revealed that high SIX1 expression emerged as a significant independent hazard factor for the DFS and OS rates of patients with breast cancers along with Her2 status and clinical stage. SIX1 may potentially be used as an independent biomarker for prognostic evaluation of breast cancer.
- Characteristic, polymorphism and expressing distribution of LCAT gene in Mongolian gerbil model for hyperlipidemia. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 16.
This study aims to evaluate the genetic basis and activity of lecithin cholesterol acyltransferase (LCAT) in a novel Mongolian gerbil model for hyperlipidemia. Gerbils may be susceptible to high fat and cholesterol (HF/HC) diets, which can rapidly lead to the development of hyperlipidemia. Approximately 10-30% of gerbils that are over 8months old and fed controlled diets spontaneously develop hyperlipidemia. Using the HF/HC diet model, we detected triglycerides (TG), total cholesterol (TC), HDL (high density lipoprotein)-C, LDL (low density lipoprotein)-C and LCAT in both old (>8months) and young gerbils. The TC and HDL-C levels were two times higher in old gerbils compared with young gerbils (P<0.01). However, in the old group the LCAT activity fell slightly compared with the normal lipidemia group. It is reasonable to hypothesize that this may be associated with single nucleotide polymorphisms of the LCAT gene. We cloned this gene to investigate the sensitivity of the gerbil to the HF/HC diet and spontaneous hyperlipidemia. The entire LCAT gene was cloned by splicing sequences of RACE(rapid amplification of cDNA ends) and nest-PCR products (AN:KC533867). The results showed that the 3683 base pair gene consists of six exons and five introns. The LCAT protein consists of 444 amino acid (AA) residues, which are analogous to the human LCAT gene, and includes 24 signal peptide AA and 420 mature protein AA. Expression of LCAT was detected in the kidney, spleen and adrenal tissue, apart from the liver, by immunohistochemistry. The abundance of the protein was greater in the older group compared with the control group. Polymorphisms were analyzed by PCR-SSCP(PCR-single-strand conformation polymorphism) but none were found in 444 animals of the ZCLA closed population(a Chinese cultured laboratory gerbil population).
- The Impact of TP53 and RAS Mutations on Cerebellar Glioblastomas. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 15.
Cerebellar glioblastoma (cGBM) is rare, inadequately characterized disease, without detailed information on its molecular basis. This is the first report analyzing both TP53 and RAS alterations in cGBM. TP53 mutations were detected in more than half of the samples from our cohort, mainly in hotspot codons. There were no activating mutations in hotspot codons 12/13 and 61 of KRAS and HRAS genes in cGBM samples but we detected alterations in other parts of exons 2 and 3 of these genes, including premature induction of STOP codon. This mutation was present in 3 out of 5 patients. High incidence of RAS mutations, as well as significantly longer survival of cGBM patients compared to those with supratentorial GBM suggest that cGBM may have different mechanism of occurrence. Our results suggest that inactivation of TP53 and RAS may play an important role in the progression of cerebellar GBM.
- Annexin A3 plays a role in cytoplasmic calcium oscillation by extracellular calcium in the human promyelocytic leukaemia HL-60 cells differentiated by phorbol-12-myristate-13-acetate. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 15.
The roles of annexin A3 (ANXA3) in macrophages are not fully understood. In contrast to C5a, we have demonstrated that C-terminal ribosomal protein S19 (RP S19)-tagged S-tagged C5a (S-tagged C5a/RP S19) raises an alternative cytoplasmic calcium oscillation by extracellular calcium during macrophage migration into apoptotic cells. We here differentiated human promyelocytic leukaemia HL-60 cells bearing with either control sense RNA and shRNA for ANXA3 mRNA or a vector cDNA with or without ANXA3 cDNA into macrophage-like cells by phorbol-12-myristate-13-acetate and found that a fluorescence ratio (340nm/380nm) upon the S-tagged C5a/RP S19-induced alternative cytoplasmic calcium oscillation by extracellular calcium was an equilateral association with a dose of ANXA3. Moreover, the ANXA3-dependent modification was partially reflected upon the S-tagged C5a-induced classical cytoplasmic calcium oscillation by both intracellular and extracellular calcium. ANXA3 seems to extend the C5aR-mediated cytoplasmic calcium oscillation by extracellular calcium at least in the HL-60 macrophage-like cells.
- Decreased expression and prognostic role of cytoplasmic BRSK1 in human breast carcinoma: correlation with Jab1 stability and PI3K/Akt pathway. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 15.
Jun activation domain-binding protein 1 (Jab1) was overexpressed in breast cancer, which involved in degradation of the cyclin-dependent kinase inhibitor p27(Kip1). The objective of this study was to examine the effect of Brain specific kinases 1 (BRSK1) expression on Jab1 over-expression and related signaling pathway in breast cancer.Immunohistochemical analysis was performed in 95 human breast carcinoma samples and the data were correlated with clinicopathologic features. Furthermore, Western blot analysis was performed for BRSK1 and Jab1 in breast carcinoma samples and cell lines to evaluate their protein levels and molecular interaction.We found that the cytoplasmic BRSK1 expression was inversely associated with Jab1 expression (P<0.01) and correlated significantly with histologic grade (P=0.006), however nuclear BRSK1 expression couldn't obtain similar results. Kaplan-Meier analysis revealed that survival curves of low versus high expressers of cytoplasmic BRSK1 and Jab1 showed a highly significant separation in breast cancer (P<0.01). While in vitro, following release of breast cancer cell lines from serum starvation, the expression of Jab1, phosphor-Akt (p-Akt) were up-regulated, whereas BRSK1 and p27(Kip1) were decreased. Treatment of phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 could diminish Jab1 expression but increase BRSK1 expression. In addition, we employed siRNA technique to knock down Jab1 and/or BRSK1 expression and observed their effects on MDA-MB-231 cells growth.BRSK1 is a novel tumor suppressor in breast cancer which inversely correlated with Jab1 expression, may involve in the restoring Jab1-induced suppression of p27kip1 and may regulate cell cycle through PI3K⁄Akt pathway.
- FTY720 attenuates hypoxia-reoxygenation-induced apoptosis in cardiomyocytes. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 14.
- Associated changes in the transcription levels of IL-17A and tight junction-associated genes in the duodenal mucosa of rhesus macaques repeatedly exposed to simian/human immunodeficiency virus. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 14.
Mucosal barrier dysfunction might play a key role in HIV/AIDS, yet the early effects of HIV-1 on intestinal mucosal barrier, especially tight junctions (TJ) have not been well addressed.To investigate the effects of acute HIV-1 infection on the expression of intestinal IL-17A and TJ-associated genes using an NHP-AIDS model.TaqMan probe real-time RT-PCR methods were established and claudin-1, claudin-3, occludin and zonula occluden-1 (ZO-1) mRNA levels in the duodenal biopsies of rhesus macaques collected before and after rectal exposures to SHIV-SF162P4 were examined and compared with that of IL-17A, IL-6, TGF-β, RORγt, T-bet, Foxp3 and GATA-3.The mRNA levels of TJ-associated genes were statistically significantly reduced soon after viral exposures and the mRNA levels of claudin-1, occludin and ZO-1 in viral positive tissues (from Group I) were lower than that in viral negative tissues (from Group II) after viral exposure. IL-17A mRNA levels were also decreased and positively correlated with the mRNA levels of the TJ-associated genes after viral exposure or infection, although the levels of IL-6, TGF-β and RORγt mRNA showed no statistical difference. The levels of GATA-3 mRNA in tissues collected before viral exposure were statistically different between Group I and Group II animals. The balance between T-bet and GATA-3 mRNA levels in Group II was markedly altered and statistically significantly different from that in Group I.Acute SHIV, and by extension HIV infection could affect the expression of TJ-associated genes, probably through IL-17A and other immune alterations.
- Exposure of breast cancer cells to a subcytotoxic dose of apigenin causes growth inhibition, oxidative stress, and hypophosphorylation of Akt. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 12.
Epidemiological studies show that fruit- and vegetable-rich diets are associated with a reduced risk of developing certain forms of cancer, including breast cancer. In this study we demonstrate that a subcytotoxic concentration of apigenin, which is a flavone found at high concentrations in parsley, onions, grapefruit, oranges, and chamomile tea, inhibited DNA synthesis in a panel of human breast cancer cell lines (MDA-MB-231, MBA-MB-468, MCF-7, SK-BR-3). Decreased proliferation of MDA-MB-468 cells in the presence of apigenin was associated with G2/M phase cell cycle arrest and the production of reactive oxygen species. Apigenin-treated MDA-MB-468 cells also showed reduced phosphorylation of Akt (protein kinase B), which is an essential effector serine/threonine kinase in the phosphatidylinositide 3-kinase pathway that promotes tumor growth and progression. However, exposure to the antioxidant reduced glutathione failed to reverse apigenin-mediated inhibition of Akt phosphorylation and cell proliferation, indicating that these effects were not due to oxidative stress. Taken together, these findings suggest that low-dose apigenin has the potential to slow or prevent breast cancer progression.
- Dengue Fever and Bone Marrow Myelofibrosis. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 9.
Myelofibrosis is characterized by reticulin and/or collagen fibrosis in the bone marrow stroma resulting in secondary cytopenia. In addition to clonal hematologic neoplasms, myelofibrosis may also develop in association with other clinical conditions, including hematological disorders, solid malignancies, Down syndrome, autoimmune diseases and others. We report the first case to our knowledge of myelofibrosis associated with dengue fever. We briefly describe dengue infections and hypothesize the causes of myelofibrosis in this condition.
- Ac-SDKP suppresses epithelial-mesenchymal transition in A549 cells via HSP27 signaling. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Jul 3.
The synthetic tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has been shown to be a modulator of molecular aspects of the fibrosis pathway. This study reveals that Ac-SDKP exerts an anti-fibrotic effect on human type II alveolar epithelial cells (A549), which are a source of myofibroblasts once exposed to TGF-β1, by decreasing the expression of heat shock protein 27 (HSP27). We used A549 cells in vitro to detect morphological evidence of epithelial-mesenchymal transition (EMT) by phase-contrast microscopy. Immunocytochemical and western blot analysis determined the distributions of cytokeratin 8 (CK8), α-smooth muscle actin (α-SMA), and SNAI1. Confocal laser scanning microscopy revealed a colocalization of HSP27 and SNAI1 on TGF-β1-induced A549 cells. These results also demonstrated that A549 cells became spindle-like when exposed to TGF-β1. Coincident with these morphological changes, expression levels of CK8 and E-cad decreased, while those of vimentin and α-SMA increased. This process was accompanied by increases in levels of HSP27, SNAI1, and type I and type III collagen. In vitro transfection experiments demonstrated that the inhibition of HSP27 in cultured A549 cells could decrease the expression of SNAI1 and α-SMA while increasing the expression of E-cad. A noticeable reduction in collagen types I and III was also evident. Our results found that Ac-SDKP inhibited the transition of cultured A549 cells to myofibroblasts and attenuated collagen synthesis through modulating the expression of HSP27.