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Exp Mol Pathol [journal]
- Expression of GRP78 Predicts Taxane-based therapeutic resistance and recurrence of human gastric cancer. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Mar 3.
Cancer cells adapt to chronic stress in the tumor microenvironment by inducing the expression of glucose-regulated protein 78 (GRP78), a major endoplasmic reticulum chaperone with Ca(2+)-binding and antiapoptotic properties. The effect in and potential role of its expression in progression of and prognosis for gastric cancer (GC) are unclear. In the present study, we investigated the clinical value of GRP78 expression in judgment of the severity of and prognosis for GC in a retrospective cohort study of 160 patients who underwent D2 radical gastrectomy and adjuvant chemotherapy. GRP78 expression was detected using immunohistochemistry. The relationships of GRP78 expression with age, sex, differentiation, invasion depth, disease stage, lymph node metastasis, and time to recurrence (TTR) were analyzed. The GRP78 expression was higher in tumors from patients with deep tumor infiltration, with poor differentiation, at late disease stages, and with lymph node metastasis than that in tumors from patients without. Also, GRP78 positivity was associated with short TTR (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.07-4.85; P=0.041). Subgroup analysis revealed that the HR in the GRP78-high group increased significantly in patients who did not receive taxane-containing regimens (HR, 2.21; 95% CI, 1.23-7.36; P=0.038). In contrast, in the patients who received taxane-based chemotherapy, the association between GRP78 positivity and increased risk of recurrence was not statistically significant (HR, 1.16; 95% CI, 0.81-2.98; P=0.111). In the patients with GRP78 expression, those who underwent taxane-containing chemotherapy had longer median TTRs than did those who did not undergo this treatment (P=0.017). Downregulation of GRP78 expression markedly inhibited proliferation of the GC cells at the G1 phase, whereas GRP78 overexpression promoted cell-cycle progression. These findings suggest that GRP78 overexpression promotes GC cells proliferation and is an independent indicator of poor prognosis for GC.
- MicroRNA -21 is a unique signature associated with coronary plaque instability in humans by regulating matrix metalloproteinase-9 via reversion-inducing cysteine-rich protein with Kazal motifs. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Mar 1.
Coronary atherosclerotic unstable plaque is one of the leading causes of cardiovascular death. Macrophage-derived matrix metalloproteinase (MMP) 9 is considered for degrading extracellular matrix and collagen, thereby thinning the fibrous cap in plaques. MiR-21 is implicated to play an important role in progression of atherosclerosis. Nevertheless, miR-21 as the biomarker for coronary atherosclerotic unstable plaque remains unknown. We aimed to investigate the prediction role of miR-21 for unstable plaque by pathway study of miR-21 on MMPs and its inhibitor RECK in macrophages METHODS: Expression of MiR-21 in macrophages and serum miR-21 as well as MMP-9 were measured in patients with coronary non-calcified plaque, calcified plaque and controls. In vitro experiment was done in human macrophages by over-expressing miR-21 or down-regulating RECK. The regulation of RECK and MMP-9 by miR-21 was evaluated by western blotting and siRNA strategy.Patients with non-calcified coronary artery lesions had significantly higher miR-21 in macrophages and lower miR-21 serum levels compared to the control and calcified plaque patients. At the same time, the serum levels of MMP-9 were significantly elevated in non-calcified patients. Experiments in vitro indicated that over-expressing miR-21 could induce the expression and secretion of pro-MMP-9 and active-MMP-9 in human macrophages via targeting gene RECK, and knocking down RECK expression by specific siRNA can resemble that of miR-21 over-expression.MiR-21 might be a biomarker for plaque unstability by suppressing target gene RECK to promote the expression and secretion of MMP-9 in macrophages.
- Probucol via inhibition of NHE1 attenuates LPS-accelerated atherosclerosis and promotes plaque instability in vivo. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Mar 1.
Activation of Na(+)/H(+) exchanger 1 (NHE1) by lipopolysaccharide (LPS) via Ca(2+)/calpain is responsible in vascular smooth muscle cell (VSMC) apoptosis and to the process of atherosclerosis. Probucol is a lipid-lowering drug which has an anti-atherosclerosis effect. The mechanism remains poorly understood. Here we hypothesized that probucol via inhibition of NHE1 in VSMCs attenuates LPS-accelerated atherosclerosis and promotes plaque stability. Our results revealed that treatment of VSMCs with LPS increased the NHE1 activity in a time-dependent manner, associated with the increased Ca(2+)i. Probucol inhibited the LPS-induced increase of NHE1 activity in a dose-dependent manner in VSMCs for 24-hour co-incubation, as well as the change of Ca(2+)i. In addition, LPS enhanced the calpain activity. Both probucol and calcium chelation of Ca(2+) abolished the LPS-induced increase of calpain activity. Treatment of VSMCs with LPS reduced the expression of Bcl-2 without altering the mRNA level. Probucol inhibited the LPS-reduced expression of Bcl-2 protein in VSMCs. Animal studies indicated administration of probucol suppressed LPS-accelerated apoptosis, atherosclerosis and plaque instability in Apoe(-/-) mice. In conclusion, probucol via inhibition of NHE1 attenuates atherosclerosis lesion growth and promotes plaque stability.
- KRAS insertions in colorectal cancer: What do we know about unusual KRAS mutations? [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Mar 1.
KRAS mutations are negative predictors of the response to anti-EGFR therapy in colorectal carcinomas (CRCs). Point mutations in codons 12, 13, and 61 are the most common KRAS mutations in CRC. There are few reports on insertions in KRAS, and little is known about its ability to activate the RAS pathway. The scarcity of data regarding insertion frequencies and nucleotide additions in KRAS impedes the management of patients with such mutations. We present data on KRAS insertions in CRC and discuss a case.Pyrosequencing and Sanger sequencing were performed to identify KRAS and BRAF mutations in paraffin-embedded samples of CRC. Expression of mismatch repair proteins was examined by immunohistochemistry.We detected a GGT insertion between codons 12 and 13 (c.36_37insGGT;p.G12_G13insG) in a CRC patient. We found that insertions in KRAS constitute less than 1% of mutations in CRC and that the most frequent type of insertion is c.36_37insGGT.KRAS gene insertions represents a diagnostic and clinical challenge due to the difficult and unusual pyrosequencing findings and the lack of information regarding its clinical impact.
- The PAS positive material in gastric cancer cells of signet ring type is not mucin. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Feb 28.
To assess the exocrine and neuroendocrine properties of tumour cells in diffuse gastric cancer with signet ring cell differentiation.Mucin mRNA and protein expressions (MUC1, 2, 3, 4, 5AC, 6 and MUC13) were assessed by immunohistochemistry and in situ hybridization. The neuroendocrine properties were evaluated by protein and mRNA expression of the general neuroendocrine markers chromogranin A and synaptophysin.No MUC expression was observed in signet ring tumour cells including the amorphous substance in any of the nine cases. All cases showed immunoreactivity to synaptophysin, and seven out of nine cases immunoreactivity to chromogranin A in signet ring and non-signet ring tumour cells. Chromogranin A mRNA expression was observed in tumour cells in all samples with retained mRNA.The lack of MUC protein and mRNA in signet ring tumour cells suggests the amorphous substance is not mucin. The lack of MUC mRNA expression in non-signet ring tumour cells questions exocrine differentiation in this tumour group. The abundant protein expression of the general neuroendocrine markers CgA and synaptophysin, and mRNA expression in tumour cells strengthens the hypothesis that this tumour group may be of neuroendocrine origin.
- Gene Expression Profiling and Bioinformatics Analysis of Gastric Carcinoma. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Feb 28.
Gastric cancer remains one of the major health problems worldwide, and it is one of the most common cancers and the leading cause of cancer-related deaths in China. This study was to analyze the expression profiles of genes in gastric carcinoma, and predict potential regulating factors. The gene expression profile data GSE13911 was downloaded from Gene Expression Omnibus and the differentially expressed genes (DEGs) were identified by t-test. Gene modules were constructed using hierarchical clustering in R based on average linkage and Pearson's correlation coefficient and functional analysis for these genes were performed with DAVID. Genes in each module with Pearson's correlation coefficient >0.3 were obtained to construct co-expression network. Protein-protein interactions (PPI) were identified by comparing protein-protein interaction (PPI) network with co-expression networks. In addition, the potential regulatory microRNAs and the transcription factors for each module were screened out. In this study, six modules associated with protein degradation, cell cycle, protein trafficking and immunoreaction etc. were identified. COPS5 (COP9 Subunit 5) was the core protein in the largest PPI network of module 1. The transcription factors MYC and MAZ (Myc-associated zinc-finger protein) were enriched in module 1. A total of 9 MicroRNA-target bi-clusters were identified and module 1 enriched 20 genes targeting to miR-17-92 gene cluster(miR-17/20ab)and miR-106b-25 gene cluster (miR-106b/93). In conclusion, we constructed 6 gene modules and screened out some genes, transcriptional factors and microRNAs that may be used as potential molecular biomarkers for gastric carcinoma.
- Do mast cells play a pathogenetic role in neurofibromatosis type 1 and ulcerative colitis? [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Feb 26.
Concurrent association of neurofibromatosis type I and ulcerative colitis has been reported in one clinical case (Tavakkoli et al., 2009). Although this association may represent a casual finding, a common pathophysiology is postulated. Mast cells have been implicated in the pathogenesis of both neurofibromatosis type 1 and ulcerative colitis (He, 2004; Yoshida et al., 2010). Mast cells are typically present in neurofibromas microenvironment where they appear to contribute to tumor initiation, progression and angiogenesis (Staser et al., 2010, 2013). Moreover, interaction of mast cells with nerves throughout the gastrointestinal tract has been correlated with progression and maintenance of ulcerative colitis (Stoyanova and Gulubova, 2002). We describe a 14year-old male with history of neurofibromatosis type 1 and new onset of ulcerative colitis diagnosed on clinical and histological findings. On gross examination the entire colonic mucosa appeared edematous showing a peculiar granular pattern, with focal erythema, shallow ulcers and multiple sessile polyps. Hematoxylin and eosin stained tissue biopsies from the colonic mucosa showed chronic inflammatory bowel disease, severe activity, consistent with chronic ulcerative colitis. Immunohistochemistry stain of the intestinal lesions revealed high expression of Neuron Specific Enolase (NSE) and S100 highlighting the presence of a Schwann cell component. In addition, c-kit/CD117 positive stain indicated a marked increase of mast cells in the lamina propria. This pattern of cellularity in the lamina propria showing increased mast cells and augmented Schwann cell component was absent in the colonic mucosa of a normal control or a patient with ulcerative colitis alone. Our observation supports the evidence of a pathogenetic role of the mast cell in ulcerative colitis associated with neurofibromatosis type 1. Further investigations are warranted to confirm the significance of this correlation as it may impact therapeutic approaches of these pathologies.
- Growth and differentiation factor-5 (GDF-5) in the human intervertebral annulus cells and its modulation by IL-1ß and TNF-α in vitro. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Feb 25.
Growth and differentiation factor-5 (GDF-5) is a member of the TGF-ß superfamily which regulates cell division and differentiation. GDF-5 attracted high interest because of its role in skeletal development, especially in cartilaginous sites. Little is known, however, about the role of GFD-5 in disc cell biology. The present work demonstrated the immunohistologic presence of GDF-5 in human outer and inner annulus tissue. Microarray analysis of annulus cells showed significant upregulation of GDF-5 expression in herniated vs. non-herniated lumbar discs (2.14-fold change, p=0.021). In vitro three-dimensional culture studies challenged human annulus cells with IL-1ß and TNF-α, two proinflammatory cytokines known to be elevated in the human degenerating disc. Exposure resulted in significant downregulation of GDF-5 during both TNF-α exposure (5.83-fold change, p=0.044) and IL-1ß exposure (3.38-fold change, p=0.015). In vitro findings suggest that the degenerating disc milieu, with high proinflammatory cytokine levels, may limit expression of GDF-5, resulting in limited regenerative capacity of the intact disc.
- The single nucleotide polymorphisms in Smad-interacting protein 1 gene contribute to its ectopic expression and susceptibility in Hirschsprung's disease. [JOURNAL ARTICLE]
- Exp Mol Pathol 2014 Feb 24.
Hirschsprung's disease (HSCR) is the third most common congenital disorder of the gastrointestinal tract. It is an anomalous enteric nervous system (ENS) characterized by the absence of ganglion cells in the myenteric and submucosal plexuses. It has been reported that the Smad-interacting protein 1(SIP1) is critical in embryonic development of ENS for its regulation on neural crest cells. In the present study, we analyzed 3 polymorphisms of the SIP1 gene rs41292293 (exon5), rs34961586 (exon6) and rs13017697 (exon8) to determine their potential contributions to the susceptibility of HSCR. Allele frequencies and genotype distributions were analyzed by sequence analysis in 107 HSCR patients and 107 normal controls. The SIP1 expression was carried out by using real-time PCR, western blot and immunohistochemistry. Polymorphic analysis indicated that the genotype distributions and allele frequencies in SIP1 gene rs41292293, rs34961586 and rs13017697 were statistically different between HSCR and normal controls. The expression analysis revealed that SIP1 was ectopically expressed in the aganglionic segments; neither the mRNA nor the protein levels demonstrated that the difference compared with those was in the normal segments. In conclusion, the single nucleotide polymorphisms in SIP1 gene rs41292293, rs34961586 and rs13017697 are associated with the ectopic expression of this gene in human HSCR and contribute to the susceptibility of this disease in population.
- Are ATPase6 polymorphisms associated with osteosarcoma? [LETTER]
- Exp Mol Pathol 2014 Feb 12.