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Masashi Fukayama

Publications and source records attributed to Masashi Fukayama.

At least 37 records · Page 2Linked to original sources
PubMed2005

Cancer risk to the gastric corpus in Japanese, its correlation with interleukin-1beta gene polymorphism (+3953*T) and Epstein-Barr virus infection.

Polymorphisms of interleukin-1 (IL-1) genes have been reported to modify the risk of gastric carcinoma (GC) in Caucasians. The significance of IL-1beta gene polymorphisms was evaluated in Japanese GC patients with or without infection of Helicobacter pylori and Epstein Barr virus (EBV) with special reference to the topographic features of GC. IL-1beta gene polymorphisms at positions -511 and +3953 were evaluated by PCR-RFLP and a penta-allelic polymorphism of IL-1RA by PCR in healthy controls (n = 103) and GC (n =140; corpus 95, antrum 45). EBV-infection was determined in the neoplastic tissues by EBER1 in situ hybridization, and H. pylori infection in nonneoplastic gastric mucosa by PCR targeting of the H. pylori urease A gene. GC consisted of EBV-associated (n = 24) and EBV-negative (n = 116) patients, whereas H. pylori infection was positive in 130 cases. Among IL-1beta gene polymorphisms, genotype IL-1beta+3953 C/T was more frequent in the EBV-negative (21%) and corpus GC (23%) patients, compared to the controls (10%), respectively, although there was no genotype IL-1beta+3953 T/T in either group. Thus, the effect of IL-1beta+3953 T was statistically significant in logistic regression models adjusted for age in EBV negativity (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.02-5.05) and in the corpus GC (2.70, 1.19-6.12) with highest OR 3.55 (1.54-8.23) in EBV-negative corpus GC. There was no significant influence of IL-1 gene polymorphism in EBV-associated GC, but it occurred predominantly in the corpus (24/24) compared to EBV-negative GC (71/116) (p = 0.00002). There was no correlation between H. pylori infection and IL-1 gene polymorphism in GC. The cancer risk of the gastric corpus in Japanese is influenced by IL-1beta+3953 polymorphisms. On the other hand, the risk of EBV-associated GC, which occurs predominantly in the corpus, is not influenced by this pro-inflammatory polymorphism.

Aged↗
PubMed2005

Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers' non-small cell lung carcinomas.

PURPOSE: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC. EXPERIMENTAL DESIGN: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis. RESULTS: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCC-specific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non-small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P < 0.01) and adenocarcinomas (P < 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC. CONCLUSION: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.

Aldehyde Reductase↗
PubMed2005

Epstein-Barr virus (EBV)-encoded BARF1 gene is expressed in nasopharyngeal carcinoma and EBV-associated gastric carcinoma tissues in the absence of lytic gene expression.

The BARF1 gene is located in the BamHI-A fragment of the Epstein-Barr virus (EBV) genome, encodes 221 amino acids, and has activity as an oncogene. Several reports have demonstrated that BARF1 is expressed in the tissues of various EBV-associated epithelioid malignancies. However,BARF1 is thought to be a lytic gene, since its expression is induced upon induction of the lytic cycle in Burkitt's lymphoma cell lines. Therefore, the possibility cannot be excluded that BARF1 expression in EBV-associated epithelioid malignancies reflects spontaneous induction of the lytic cycle in carcinoma cells. The present study aimed to clarify whether BARF1 was expressed as a latent gene or a lytic gene in epithelioid malignancies. Quantitative real-time RT-PCR assay revealed that BARF1 was highly expressed in nasopharyngeal carcinoma (NPC) and EBV-positive gastric carcinoma tissues in the absence of expression of lytic genes. On the other hand, BARF1 protein was detectable only in two of seven NPC tissue samples by immunoblot analysis. Analysis of BARF1-transfected CNE1 cells revealed that BARF1 was quickly secreted into culture medium and was hardly detectable in the cell lysate, which would account for why some NPC tissues were negative for BARF1 protein expression even though they were strongly positive forBARF1 expression at the transcriptional level. The present findings indicate that BARF1 is expressed in NPC and EBV-positive gastric carcinoma tissues as a latent gene and suggest that BARF1 plays a role in the pathogenesis of these malignancies.

Carcinoma↗
PubMed2005

Intrapulmonary solitary fibrous tumor in an eight-year-old male.

We describe an 8-year-old male who had an intrapulmonary solitary fibrous tumor (SFT). SFTs of the pleura are now thought to originate from subpleural mesenchymal cells, and a pathological diagnosis is obtained by a specific marker, i.e., CD34 expression on the tumor cells. The SFT reported here is an extremely rare phenotype in two respects: it originated in a child under age 10 years, and it expanded in an intrapulmonary fashion.

Carcinoma↗
PubMed2005

Epstein-Barr virus-associated gastric carcinoma in the remnant stomach: de novo and metachronous gastric remnant carcinoma.

BACKGROUND: The remnant stomach corresponds to the gastric cardia, but is exposed to a completely different environment. The present study was performed to investigate the role of Epstein-Barr virus (EBV) infection in patients with gastric remnant carcinoma (GRC). METHODS: Clinicopathological features, gastritis, and infection by EBV were investigated in patients with two types of GRC: GRC occurring at an interval of 10 years or longer between operations (de novo GRC group) and GRC occurring within 10 years after the initial operation for gastric carcinoma (metachronous GRC group). RESULTS: EBV involvement in the de novo GRC group (23%) was not significantly different from that in the cardia of non-remnant carcinomas (controls; 18%). EBV involvement showed greater correlations in male patients (18/63; 28%), and in those with gastritis cystica polyposa (GCP; 13/41; 31%), and those with an interval of 20 years or longer (15/50; 30%) than with the other parameters. Multivariate analysis showed a significant correlation between GCP and EBV infection. Histologically, hyperplasia or mild atrophy, and mild lymphocytic infiltration were observed in 56% and 67% of non-neoplastic mucosa of EBV-associated GRC, respectively. In the metachronous GRC group, EBV-encoded mRNA in situ hybridization (EBER-ISH) of 27 pairs of primary gastric carcinomas (GCs) and metachronous GRCs indicated that only six EBV (+) metachronous GRCs were derived from EBV (+) GC. CONCLUSIONS: Epstein-Barr virus infection, together with long-standing inflammation, which causes GCP, may facilitate the development of de novo GRC. Close follow-up of patients treated with distal gastrectomy for EBV-associated GC is necessary to detect metachronous GRC.

Aged↗
PubMed2005

Prevalence of ischemic enterocolitis in patients with acute pancreatitis.

BACKGROUND: A considerable number of acute pancreatitis cases have been reported to be complicated by nonocclusive mesenteric ischemia. However, no reports have ever referred to the incidence of ischemic enterocolitis in patients with acute pancreatitis, using a series of autopsy cases. Here, we report our review of autopsy cases of patients with acute pancreatitis to examine the incidence of associated ischemic enterocolitis. METHODS: The intestinal and pancreatic slides of 48 autopsy cases of patients with acute pancreatitis were reviewed and the incidence of ischemic enterocolitis was determined. Clinical case records were also reviewed. RESULTS: Thirteen (27%) of 48 autopsy cases of patients with acute pancreatitis were complicated by ischemic enterocolitis. The frequency of shock was significantly higher in patients with ischemic enterocolitis than in those without ischemic enterocolitis. The intestinal lesion was diffuse in many cases and gangrene was not an unusual finding. CONCLUSIONS: The incidence of ischemic enterocolitis in patients with acute pancreatitis was much higher than that in the previous reports. Clinicians who treat patients with acute pancreatitis should consider ischemic enterocolitis as one of the frequent and severe complications of this condition.

Acute Disease↗
PubMed2005

Pigmented neurofibroma: review of Japanese patients with an analysis of melanogenesis demonstrating coexpression of c-met protooncogene and microphthalmia-associated transcription factor.

Pigmented neurofibroma (PNF) is a rare variant of neurofibroma showing melanin production. To clarify the clinicopathologic features of PNF and to characterize melanogenesis in PNF, 12 cases of PNF were examined in comparison with schwannoma (SCH, n = 16) and neurofibroma (NF, n = 26). The PNF patients were all Japanese including 7 men and 5 women, and patient age ranged from 11 to 71 years (median, 23.5 years). They showed strong a predisposition for neurofibromatosis type 1. Their tumor size was large, and tumors arose from various sites of skin. Histologically, clusters of epithelioid, dendritic, and spindle melanin-producing cells with faint pigmentation had a tendency to locate in deep dermis and subcutis, which seems to be a characteristic pattern of melanogenesis. There was a transition between melanin-producing cells and Schwann cells. Immunohistochemical examination included known melanogenic markers, microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis, and 2 tyrosine kinase receptors, c-Met and c-Kit, which regulate the development of melanocytes. In PNF, melanin-producing cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (+/-), HMB45 (+/-), c-Met (+), and c-Kit (-). Schwann cells were S100 (+), MITF (-), Melan-A (-), tyrosinase (-), HMB45 (-), c-Met (-), and c-Kit (-), and intermediate spindle cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (-), HMB45 (-), c-Met (+), and c-Kit (-). When compared with SCH and NF, MITF was weakly expressed in a part of tumor cells of SCH, whereas no definite staining was found in NF. c-Met expression was very weak in a scattered manner in SCH (10/15 cases) and NF (10/26 cases). These results suggest that PNF is a unique tumor that shows differentiation toward mature melanin production, but ability of melanin synthesis seems to be impaired. There may be a close relationship between up-regulated MITF and c-Met and the peculiar melanogenic nature of PNF, and both of these are useful diagnostic tools for distinguishing PNFs with less melanin production from NFs.

Adolescent↗
PubMed2005

JC virus genotyping using formalin-fixed, paraffin-embedded renal tissues.

Recently genotyping of JC virus (JCV) DNA in renal tissue was reported to be useful to identify the geographic origin of unidentified cadavers. In the above study, autopsied tissue samples without storage or stored in a frozen state were used. This study examined JCV DNA sequence modifications caused by formalin-fixation, in an attempt to elucidate whether formalin-fixed, paraffin-embedded tissue samples can also be used to determine the genotypes of JCV DNA in the kidney. In four cases, a 610 bp typing region of the JCV genome was PCR-amplified from renal tissues stored for 1 year in three different states: frozen at -80 degrees C [Amaker, B.H., Chandler, F.W., Huey, L.O., Colwell, R.M., 1997. Molecular detection of JC virus in embalmed, formalin-fixed, paraffin-embedded brain tissue. J. Forensic Sci., 1157-1159], formalin-fixed, paraffin-embedded [Ault, G.S., Stoner, G.L., 1992. Two major types of JC virus defined in progressive multifocal leukoencephalopathy brain by early and late coding region DNA sequences. J. Gen. Virol. 73, 2669-2678], and soaked in 5% formalin [Baksh, F.K., Finkelstein, S.D., Swalskey, P.A., Stoner, G.L., Ryschkewitsch, C.F., Randhawa, P.R., 2001. Molecular genotyping of BK and JC virus in human polyomavirus-associated interstitial nephritis after renal transplantation. Am. J. Kidney Dis. 38 (2), 354-365]. The amplified fragments were cloned, and the resultant clones were sequenced. In frozen samples, single sequences ('original' sequences) were detected in all cases. In formalin-fixed, paraffin-embedded samples, not only the original sequences but also those with 1-6 base substitutions were detected. From formalin-soaked samples, the original sequences and those with 1-5 and 10-13 substitutions were detected. The genotyping of JCV DNA was not hampered by the presence of 1-6 substitutions, but a shift in JCV genotypes was observed in sequences with 10-13 substitutions. Thus, it was concluded that the genotypes of JCV DNA in the kidney can be determined only with specimens stored in a frozen state or formalin-fixed for a short time.

Adult↗
PubMed2005

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma.

Expression profiling of hepatocellular carcinoma has demonstrated that glypican 3 (GPC3), a heparan sulfate proteoglycan anchored to the membrane, is expressed at a markedly elevated level in hepatocellular carcinoma. In this paper, two monoclonal antibodies against GPC3, GPC3-C02 and A1836A, were confirmed to specifically recognize GPC3 molecule in cells from hepatocellular carcinoma and hepatoblastoma cell lines by immunoblotting, and both were confirmed to recognize different epitopes of the GPC3 molecule by epitope mapping. Then, we evaluated the feasibility of GPC3-immunohistochemistry in the pathological diagnosis of benign and malignant hepatocellular lesions by applying these monoclonal antibodies to formalin-fixed and paraffin-embedded specimens. The immunoreactivity turned out to be identical in the two monoclonal antibodies and was thus confirmed to represent the actual expression of the GPC3 molecule. The expression was observed in the fetal liver, but not in normal adult liver, liver cirrhosis or hepatitis except for a tiny focus of a regenerative nodule of fulminant hepatitis. Diffusely positive staining of GPC3 was observed in malignant hepatocytes in hepatoblastomas and in hepatocellular carcinomas (47/56, 84%). GPC3 expression was independent of the differentiation and size of the hepatocellular carcinoma. On the other hand, there was only weak and focal staining in low-grade (2/8) and high-grade dysplastic nodules (6/8). GPC3 immunoreactivity was detected in only one of 23 metastatic lesions of colorectal carcinoma, and its expression was entirely absent in the liver cell adenoma (0/7), carcinoid tumor (0/1), and cholangiocellular carcinoma (0/16). When compared with immunohistochemistry of hepatocyte antigen and alpha-fetoprotein, GPC3-immunohistochemistry was significantly much more specific and sensitive for hepatocellular carcinomas. Thus, GPC3 was confirmed to be one of the oncofetal proteins now attracting attention for their promise both as markers of hepatocellular carcinoma in routine histological examination and as targets in monoclonal antibody-based hepatocellular carcinoma therapy.

Antibodies, Monoclonal↗
PubMed2005

Pulmonary adenocarcinomas with enteric differentiation: histologic and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas.

Primary pulmonary adenocarcinomas with enteric differentiation (PAED) are mainly composed of tall-columnar cells that show similarity to intestinal epithelia and colorectal carcinomas. In this study, we analyzed the immunostaining profiles of 7 PAEDs in comparison with 14 metastatic colorectal carcinomas (MCRs) and 30 usual pulmonary adenocarcinomas (PACs), using antibodies against CDX-2, cytokeratin 7 (CK7), cytokeratin 20 (CK20), TTF-1, surfactant apoprotein-A (SP-A), Napsin A, and MUC2. The positive rates for CDX-2, CK7, CK20, TTF-1, SP-A, Napsin A, and MUC2 were 71%, 100%, 43%, 43%, 14%, 0%, and 43%, respectively, in the PAEDs; 100%, 0%, 86%, 0%, 0%, 0%, and 57% in the MCRs; 3%, 100%, 0%, 93%, 73%, 90%, and 0% in PACs. As expected, immunoreactivity of CDX-2, CK20, and MUC2 was detected in PAEDs. The observed decrease or loss of immunoreactivity for TTF-1, SP-A, and Napsin A indicates that these lesions demonstrate a shift away from their pulmonary phenotype, although CK7 expression was retained. The results indicate that CK7 and CK20 may be useful markers for distinction of PAEDs from MCRs.

Adenocarcinoma↗
PubMed2005

Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease).

Gastrointestinal stromal tumor (GIST), as well as the hyperplastic lesions of intestinal neural tissue and its supporting structures, is a gastrointestinal complication of type 1 neurofibromatosis (NF1) (von Recklinghausen's disease). In the present study, we analyzed the histologic and immunohistochemical features, and the c-kit and PDGFRA gene mutations of 36 GISTs derived from 9 NF1 patients. Distinctively, multiple GISTs arose preferentially in the small intestine. The histologic features of NF1-associated GISTs are almost similar to those of non-NF1 GISTs, but characteristically most of the NF1-associated GISTs contained skeinoid fibers. Thirty-three GISTs (92%) showed immunoreactivity for KIT, and 23 tumors (64%) showed diffuse or mosaic-like immunoreactivity for S-100 protein. Hyperplasic lesions, which may be the hyperplasia of interstitial cells of Cajal, were observed around some GISTs. Exons 9, 11, 13, and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene were amplified and directly sequenced. Point mutations of c-kit gene or PDGFRA gene were identified only in three (8%) and two (6%) tumors, respectively. NF1-associated GISTs, showing the dual differentiation of interstitial cells of Cajal and Schwann cells, develop in close association with the myenteric nerve structure of gastrointestinal tract of NF1 patients. The point mutations of c-kit and PDGFRA gene may play a limited role in the tumorigenesis of NF1-associated GISTs.

Adult↗
PubMed2005

Overexpression of MUC13 is associated with intestinal-type gastric cancer.

Mucins are secreted or transmembrane glycoproteins that are expressed mainly in the digestive tract. This family of proteins has been the focus of much gastric cancer research as some transmembrane mucins are implicated in tumorigenesis and make attractive targets for cancer diagnosis and therapeutics. Mucins have also been utilized to classify gastric cancer by differentiating between gastric and intestinal phenotypes. Here we show that transmembrane mucin MUC13 is upregulated in gastric cancer. By quantitative real-time reverse transcription-polymerase chain reaction and immunoblot analysis, overexpression of MUC13 was verified in more than half of the samples examined. In immunohistochemical analysis, MUC13 staining was observed in 74 of 114 cases of gastric cancer (64.9%), predominantly in intestinal type (P < 0.001), and in 9 of 10 cases of intestinal metaplasia, precancerous lesions of intestinal-type gastric cancer, but not observed in normal gastric mucosa. Moreover, MUC13 staining patterns characteristic of histological type were identified: staining was on the apical side of tubular glands in intestinal type and on the cytoplasm in diffuse type. These results suggest that MUC13 is a good differentiation marker for gastrointestinal mucosa and that it may have a causal role that correlates with two distinct gastric tumorigenesis pathways.

Biomarkers, Tumor↗
PubMed2005

Loss of TSLC1 expression in lung adenocarcinoma: relationships with histological subtypes, sex and prognostic significance.

The TSLC1 (tumor suppressor in lung cancer 1) gene is a tumor suppressor recently identified through functional complementation in a lung adenocarcinoma cell line A549. In this study we immunohistochemically examined the loss of TSLC1 expression in 93 cases of surgically resected lung adenocarcinoma, and investigated its correlation with clinicopathological parameters, including histological subtypes of tumors. The prognostic significance of loss of TSLC1 expression was analyzed by univariate and multivariate analyses, in parallel with other prognostic markers such as p53, p27, and Ki-67. In non-cancerous lung tissue, TSLC1 was weakly positive in bronchial and bronchiolar epithelial cells, type II pneumocytes and bronchial glands. Overall, TSLC1 was negative in 60 of 93 lung adenocarcinomas. TSLC1 was mainly localized in the cytoplasm of the cells, but cell membrane staining was also observed, especially at sites of cell-cell adhesion. TSLC1-negative tumors were more frequently observed in male cases (41/54 cases, 70.0%) than in female cases (19/39 cases, 48.7%) (P < 0.01). Notably, TSLC1 expression was preserved in a non-invasive, bronchiolo-alveolar histological pattern of tumor cells (P < 0.0001). Survival analyses showed that loss of TSLC1 expression was associated with lower patient survival in univariate and multivariate analyses (P < 0.05 and P = 0.059, respectively). Subset analyses further showed that the prognostic impact of loss of TSLC1 was significant for male patients (P = 0.0089), but not for female patients. We conclude that TSLC1 is expressed in a subset of lung adenocarcinomas, especially in those with bronchiolo-alveolar spread pattern. Loss of TSLC1 is associated with lower patient survival, supporting its role as a tumor suppressor.

Adenocarcinoma↗
PubMed2005

Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes.

Previous studies suggest that some S100 proteins are involved in the progression of certain types of cancer. However, no comprehensive data is currently available on the expression of S100 family genes in lung adenocarcinomas. Oligonucleotide array, quantitative reverse transcription-polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively. Immunohistochemical analyses of 94 primary lung adenocarcinomas showed that positive S100A2 expression (33/94, 35.1%) was significantly associated with lymphatic invasion (P=0.0233) and positive S100A4 expression (19/94, 20.2%) with vascular invasion (P=0.0454). Interestingly, a strong inverse relationship was found between S100A4 and p53 expression (P=0.0008). Survival analyses showed that S100A4 positivity was associated with poor patient prognosis (P=0.042). S100A2 positivity was not associated with patient survival when the whole patient group was analyzed; however, S100A2 positivity was a favorable prognostic indicator in patients with p53-negative tumors (P=0.0448). Finally, we used oligonucleotide array analyses and identified potential S100A2 and S100A4 target genes involved in cancer progression: S100A2 induced RUNX3 and REPRIMO; S100A4 induced EZRIN, RUNX1 and WISP1; S100A2 repressed EGFR, NFKB2 and RELA2; and S100A4 repressed ANXA10 and IL1RN. Thus, the present study demonstrates involvement of S100A2 and S100A4 in the progression of lung adenocarcinomas and an inverse association between S100A4 and p53 expression, and provides a list of targets regulated by S100A2 and S100A4.

Adenocarcinoma↗
PubMed2004

Lung adenocarcinoma associated with familial adenomatous polyposis. Clear cell carcinoma with beta-catenin accumulation accompanied by atypical adenomatous hyperplasia.

A 46-year-old man presented with a lung tumor 17 years after a subtotal colectomy and 13 years after a partial duodenectomy for familial adenomatous polyposis (FAP). There had been no malignant transformation in the specimens from his colectomy and duodenectomy, and a current gastrointestinal investigation revealed no evidence of malignancy. Pathological analysis of the lung tumor demonstrated adenocarcinoma with clear cells and a papillary structure, accompanied by tiny tumorous nodules in the background lung parenchyma. Many of the nodules were multifocal adenocarcinoma; however, some of the nodules demonstrated atypical adenomatous hyperplasia (AAH). This is the first case report of a lung adenocarcinoma accompanied by AAH in a FAP patient. Immunohistochemical and loss of heterozygosity studies revealed unique features of the lesions reflecting a disruption of the adenomatous poliposis coli-beta-catenin pathway.

Adenocarcinoma↗
PubMed2004

High-density methylation of p14ARF and p16INK4A in Epstein-Barr virus-associated gastric carcinoma.

Promoter hypermethylation of various tumor-related genes is extremely frequent in gastric carcinoma (GC) associated with Epstein-Barr virus (EBV). To investigate the significance of the promoter methylation in this type of GC, we examined the methylation densities of the promoter regions of p14ARF and p16INK4A in EBV-associated (n=7) and EBV-negative (n=14) GC. Bisulfite sequencing demonstrated a high frequency of concurrent methylation of p14ARF and p16INK4A promoter regions in EBVaGC. Methylation was observed in all 29 CpG sites of p14ARF and all 16 sites of p16INK4A with equally high densities. In EBV-negative GC, the methylation profiles differed between the 2 genes. Promoter methylation was sporadic and variable in p14ARF, and only the last position of CpG in p14ARF was methylated at high frequency. High-density methylation in p16INK4A was observed in a subset of GC, but the first position of CpG was never methylated in EBV-negative GC. These findings suggest the presence of mechanisms of de novo and maintenance methylation specific to EBVaGC that might be associated with EBV infection.

Adult↗
PubMed2004

Overexpression of cdk4/cyclin D1, a possible mediator of apoptosis and an indicator of prognosis in human primary lung carcinoma.

The relation between expression of cell cycle-regulator molecules and apoptosis was examined in surgical specimens and cultured human lung carcinoma cell lines. Immunohistochemical analysis for 133 cases revealed 2 types of staining pattern. The first group consisted of 95 cases (71.4%) characterized by apoptotic cells showing intensely positive staining for cdk4 and cyclin D1 but negative for other proteins (type A). In the second group (type B), comprising 38 cases (28.6%), apoptotic cells exhibited intense positive staining for any cyclins and cdks. Most of the latter cases had lost expression of Rb protein. When tumor cells retrieved from paraffin-embedded tissue were examined by flow cytometry, higher proportions of cells expressing only cdk4 or cyclin D1 in type A cases and of cells expressing any cyclin or cdk in type B cases showed a subdiploid DNA content. In survival analysis using the LI of apoptotic cells and cyclin/cdk-positive cells, the high-apoptosis/high-cyclin D1 group showed the poorest prognosis. Furthermore, forced overexpression of only cdk4 or cyclin D1 induced apoptosis in cultured cells with normal Rb protein, whereas overexpression of any cyclin or cdk induced apoptosis in cells defective for Rb protein. In conclusion, upregulation of cdk4/cyclin D1 may be a primary and critical factor in induction of apoptosis in human lung carcinomas in vivo. Moreover, inactivation of Rb protein renders cells more prone to apoptosis by abnormal expression of any cell-cycle protein.

Apoptosis↗