Up and down with PARs in vivo.
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Blood Platelets↗
Biomedical subjects
Mohammad Ghazizadeh
Publications and source records attributed to Mohammad Ghazizadeh.
Antisense oligodeoxynucleotides against thrombomodulin suppress the cell growth of lung adenocarcinoma cell line A549.
Thrombomodulin (TM), an anticoagulant factor on endothelial cells, is known to be expressed in non-endothelial cells as well. In neoplastic cells of lung adenocarcinomas, TM is expressed but its correlation with growth potential has not been studied. As TM expression has a negative correlation with cell proliferation in lung squamous cell carcinomas, we examined its growth effect on lung adenocarcinoma cells of the A549 cell line by inhibiting TM expression with antisense oligodeoxynucleotides (ODN). In the antisense ODN transfected cells, the expression of TM mRNA was decreased to 49% at 12 h and 47% at 24 h, which was in accordance with TM expression at the protein level. By IdU (5-iodo-2'-deoxyuridine) incorporation assay, the growth of A549 cells was found to have decreased to 36% of the control level at 24 h post-transfection. The suppression of cell growth was maintained in a concentration-dependent manner for 48 h after transfection, when the expression of TM started to rebound. In the transfected cells, the G1 phase cell count was reduced to 60.7%, compared with 68.2% in the control transfectants. These results suggest that TM expression may play a suppressive role in the proliferation activity of A549 lung adenocarcinoma cells.
Adenocarcinoma↗
Expression of MUC1 and MUC2 mucin gene products in human ovarian carcinomas.
BACKGROUND: Aberrations in expression of mucin glycoproteins have been observed during malignant transformation of human ovarian epithelium. To date, several secretory mucin genes designated the MUC gene family have been identified, of which MUC1 encodes a mammary-type and MUC2 an intestinal-type epithelial mucin. However, information on the expression and potential value of MUC1 and MUC2 mucins in ovarian cancer is limited. METHODS: This study investigated immunohistochemical expressions of MUC1 and MUC2 mucins in 23 benign and 45 malignant human ovarian tumors to assess their clinicopathological relevance. RESULTS: All benign serous tumors and also associated normal-appearing epithelia expressed MUC1 mucin on the cell surfaces. Benign mucinous tumors occasionally expressed MUC1 and MUC2 mucins. Most serous carcinomas (19/21; 90%) expressed MUC1 but not MUC2 mucin. Of the 16 mucinous carcinomas, 10 (62%) and five (31%) expressed MUC1 and MUC2 mucins, respectively. Four of the five clear cell and the three endometroid type carcinomas expressed MUC-1 but not MUC-2 mucin. A significant association was found between a high expression of MUC1 and histological grade (P = 0.005) and also disease stage (P = 0.001). CONCLUSION: These results suggest that a high expression of MUC1 may contribute to a poor prognosis in ovarian carcinoma.
Adult↗
Molecular cytogenetic characterization of drug-resistant leukemia cell lines by comparative genomic hybridization and fluorescence in situ hybridization.
Resistance to chemotherapeutic drugs is one of the major difficulties encountered during cancer chemotherapy. To detect genomic aberrations underlying the acquired drug resistance, we examined three cultured human myelomonocytic leukemia cell sublines each resistant to adriamycin (ADR), 1-beta-1-D-arabinofuranosylcytosine (ara-C), or vincristine (VCR), using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), RT-PCR, and western blot techniques. Chromosomes 7, 10 and 16 most conspicuously showed frequent aberrations among the resistant sublines as compared to the parental KY-821 cell line. In ADR-resistant cells, gains at 7q21, 16p12, 16p13.1-13.3, 16q11.1-q12.1, and losses at 7p22-pter, 7q36-qter, 10p12, 10p11.2-pter, 10q21-q25, 10q26-qter were notable. In ara-C-resistant cells, no remarkable gain or loss on chromosome 7, but losses at 10p14-pter, 10q26-qter and 16p11.2-p11.3 were observed. In VCR-resistant cells, gain at 7q21 and losses at 10p11-p13, 10p15 and 16p11.2-p13.3 were found. FISH identified amplified signals for the MDR-1 gene located at 7q21.1 in ADR- and VCR- but not ara-C-resistant cells, and for the MRP-1 gene located at 16p13.1 in ADR-resistant cells. These findings were validated at the mRNA and protein levels. Overlapping of the amplified MRP-1 gene with MDR-1 gene may play a critical part in the acquisition of resistance to ADR. Resistance to ara-C excluded MDR-1 gene involvement and highlighted other key genes such as MXR gene. Several other genes putatively involved in the development of drug resistance might lie in other aberrated chromosomal regions.
Antimetabolites, Antineoplastic↗
Genome-wide screening of laser capture microdissected gastric signet-ring cell carcinomas.
Gastric signet-ring cell carcinoma comprises a distinct category of gastric cancers and has been reported to have poor prognosis. In an attempt to define genetic changes involved in the pathogenesis of this lesion in an in vivo state, we isolated signet-ring cell carcinoma cells from freshly fixed smears of tumor tissues of 7 primary gastric signet-ring cell carcinomas by laser capture microdissection and applied comparative genomic hybridization (CGH) to screen for DNA sequence copy number changes. Frequent chromosomal gains were detected on 2q, 5p, 7q, 14q and 20q, each in 6/7 cases, on 9q, 12q, 17q, and 19q, each in 5/7 cases, and on 18p in 4/7 cases. Frequent losses were observed on 6p and 17p, each in 5/7 cases, on 6q, and 21p, each in 4/7 cases, and on 3p, 8p and 8q, each in 3/7 cases. Losses on 6p have rarely been observed in conventional types of gastric carcinomas reported in the literature. These data provide the first evidence for the occurrence of specific genomic aberrations in gastric signet-ring cell carcinomas. Our observation of frequent losses on 6p chromosomal arm may provide novel abnormalities of potential significance in gastric signet-ring cell carcinomas, suggesting the involvement of genes residing in this region in the genesis of the disease.
Adenocarcinoma↗
Supplementation of heterologous complement induces anti-Thy-1.1 nephritis in the Mongolian gerbil (Meriones unguiculatus).
Anti-Thy-1.1 nephritis in the rat is a popular experimental model for mesangial proliferative glomerulonephritis (GN). This model is characterized by direct binding of anti-Thy-1.1 antibody with Thy-1.1 antigen expressed on mesangial cells (MCs) of glomeruli in the rat. A single injection of anti-rat thymocyte serum (ARTS) results in GN with proteinuria and extensive mesangiolysis. Development of mesangiolysis and proteinuria are complement-dependent. We previously demonstrated Thy-1.1 antigen, similar to the rat, in thymocytes, brain cells and MCs of the kidney in the Mongolian gerbil (MG). In this study, we attempted to develop a MG nephritis model, but an injection of ARTS did not induce GN. An additional injection of guinea pig serum as a complement after ARTS injection resulted in anti-Thy-1.1 nephritis in MG. Degeneration of MCs and neutrophil infiltration were observed 1 hr after GP serum injection. Mesangiolysis and fibrin exudation occurred 12 hr after the injection and MC proliferation was apparent 7 days after the injection. In the complement-dependent hemolytic test, MG serum could not hemolyze sheep erythrocytes. These results suggested low activity, or depletion of some factors, in complements of MG serum.
Animals↗
Comparative genomic hybridization study of genetic changes associated with vindesine resistance in esophageal carcinoma.
The acquisition of drug-resistance is a major problem for cancer patients undergoing chemotherapy. To clarify genetic alterations in cancer cells that develop drug-resistance, comparative genomic hybridization (CGH) was applied to esophageal squamous cell carcinoma cell lines (SH-1V1, SH-1V2, SH-1V4 and SH-1V8) and chemoresistance-related genes in altered chromosomal regions were evaluated. These cell lines were derived from the parental SH-1 cell line, after multiple steps of selection by an increasing exposure to vindesine. SH-1V8 cells were strongly resistant to vindesine. DNA copy number at 16p which includes the MRP (multidrug resistance related protein) gene was markedly increased in all cell lines examined. Increased DNA copy numbers were found at the regions of 5q31-32, 10q11.1-23, and 14q32-qter in SH-1V8 cells that acquired resistance to other drugs as well. Both SH-1V4 and SH-1V8 showed increased DNA copy numbers at 7q11.1-22, 16q12.1-qter, 19p13.2-13.3, 19q11-13.2 and 20q13.1-qter. The chromosomal region of 7q11.1-22 including MDR-1 (multidrug resistance-1) gene was highly amplified in SH-1V4 and SH-1V8. Amplification of the MRP region suggests the prerequisite of developing resistance to vindesine, and further amplification of MDR-1 may play a critical role in acquiring drug-resistance. Several unknown genes related to the induction of chemoresistance might be concealed in other altered chromosomal regions.
Chromosome Aberrations↗
Role of cdk4, p16INK4, and Rb expression in the prognosis of bronchioloalveolar carcinomas.
BACKGROUND: The p16(INK4) protein has been identified as a potent inhibitor of cyclin-dependent kinase (cdk)4 by blocking cdk4-mediated phosphorylation of the tumor suppressor retinoblastoma (Rb) protein, thus allowing Rb-mediated growth suppression. OBJECTIVES: Loss of p16(INK4) has been associated with a poor cancer prognosis, but its potential significance in bronchioloalveolar carcinomas (BACs) has not been explored. METHODS: We examined immunohistochemical expression of p16(INK4), cdk4, and Rb proteins in 38 BACs and correlated their expression levels with known clinicopathological features of the disease. RESULTS: All BACs expressed cdk4, while 89 and 82% expressed p16(INK4) and Rb proteins, respectively. None of the clinicopathological factors correlated with p16(INK4), cdk4, or Rb expression separately. A low p16(INK4)/cdk4 ratio was significantly associated with a high disease stage (p = 0.04), and the ratio tended to be lower in mucinous than nonmucinous tumors. BACs with a low p16(INK4)/cdk4 ratio showed significantly higher Rb expression levels (p = 0.02). Univariable survival analyses showed a significantly lower 5-year survival probability in patients with a high stage (p = 0.002) or low p16(INK4)/cdk4 ratio (p = 0.01). CONCLUSIONS: The results suggest a role of the cdk4/p16(INK4) pathway in the prognosis of BACs. Further studies are warranted to clarify whether a low p16(INK4)/cdk4 ratio may identify tumors that are destined to behave unfavorably.
Adenocarcinoma, Bronchiolo-Alveolar↗