Up and down with PARs in vivo.
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Blood Platelets↗
Biomedical subjects
Oichi Kawanami
Publications and source records attributed to Oichi Kawanami.
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↗
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↗
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↗
Histological study of papillary thyroid carcinoma treated with percutaneous ethanol injection therapy.
An 86-year-old male patient was treated by percutaneous ethanol injection therapy (PEIT), following tumorectomy of a papillary thyroid carcinoma and a modified radical neck dissection for its metastasis. After seven treatments with PEIT, the patient was admitted to hospital for a tracheotomy to treat progressive severe dyspnea. Seven days later the patient died from acute renal failure caused by diabetic ketoacidosis. At autopsy, tumor masses were found to comprise mostly scar tissue, and the remaining neoplastic cells often showed anaplastic changes. Fresh coagulation necrosis and hemorrhages were scattered throughout the tumor lesions and their microvessels were occasionally occluded by thrombus. These changes were seen prominently, especially at the central areas of PEIT treatment. Given these findings, we believe that PEIT may be useful in providing local control for the progression of thyroid cancer, especially in cases of unresectable malignant thyroid tumors.
Administration, Cutaneous↗
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↗
Up-regulation and overproduction of DVL-1, the human counterpart of the Drosophila dishevelled gene, in cervical squamous cell carcinoma.
The Dvl-1 gene on chromosome 1p36 belongs to a family of highly conserved secreted proteins which regulates embryonic induction, generation of cell polarity and specification of cell fate through activation of Wnt signaling pathways. Wnt signaling activates the gene encoding DVL-1; the latter suppresses beta-catenin by promoting its degradation through enhanced inactivation of glycogen-synthase-kinase 3 (GSK3). Here we demonstrate increased expression of DVL-1 mRNA in over two thirds of primary cervical squamous cell cancers (11 of 15 cases) when compared to corresponding non-cancerous uterine squamous cell tissues. In addition, we noted up-regulation of cyclin D1, a downstream effector of Wnt signal pathway in cervical cancer. Immunohistochemical staining demonstrated that DVL-1 protein was prominent in the cytoplasm of cancer cells whereas it was unreactive in the surrounding normal cervical squamous cells. These data indicate that amplification and increased expression of the DVL-1 gene may play some role in the development of a portion of human cervical squamous cell cancer through derangement of the Wnt signaling pathway.
Adult↗
Growth-suppressive function of phosphatidylethanolamine-binding protein in anaplastic thyroid cancer.
BACKGROUND: A cDNA microarray analysis of anaplastic thyroid cancer cell lines (ACL) was recently performed and the down-regulation of phosphatidylethanolamine-binding protein (PBP) [RAF kinase inhibitor protein (RKIP)] in ACL compared to normal thyroid tissues was identified. MATERIALS AND METHODS: The expression levels of PBP in primary anaplastic and papillary thyroid cancer, thyroid cancer cell lines (anaplastic, papillary and follicular) and several normal human organs were examined. To examine the function of PBP, cell-growth assays were performed. RESULTS: PBP expression was reduced in anaplastic thyroid cancers, compared to either normal thyroid tissues or differentiated thyroid cancers. PBP was expressed ubiquitously in normal human tissues. Exogenous PBP expression suppressed ACL growth, and suggested a tumor suppressive function of PBP in ACL. CONCLUSION: This is the first report demonstrating that PBP may be a tumor suppressor whose loss is associated with development of anaplastic thyroid cancer from differentiated thyroid cancer.
Cell Line, Tumor↗