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Biomedical subjects

Okio Hino

Publications and source records attributed to Okio Hino.

At least 19 recordsLinked to original sources
PubMed2006

Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway.

Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles in insulin signaling. However, little is known about the relationship between TSC2 and FoxO1. Here we identified TSC2 as a FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. Among FoxOs, only FoxO1 can be associated with TSC2. The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. Overexpression of wild type FoxO1 enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. Knockdown of endogenous FOXO1 in human vascular endothelial cells decreased phosphorylation of p70 S6K. Prolonged overexpression of wild type FoxO1 enhanced phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum. These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of TSC2 function.

Animals↗
PubMed2006

A novel tumor marker, Niban, is expressed in subsets of thyroid tumors and Hashimoto's thyroiditis.

Niban is a recently identified molecular marker of renal carcinogenesis in the Tsc2 gene-mutant Eker rat. Niban expression is most dramatically increased in the early stage of renal carcinogenesis and might decline during malignant progression. Niban is also expressed in various histologic types of human renal cell carcinoma. Therefore, Niban might be a good marker for renal carcinogenesis in both animal models and humans. In the present study, we examined Niban expression in various thyroid lesions by immunohistochemical staining using polyclonal rabbit antihuman Niban antibody. Normal thyroid tissue never stained for Niban. Niban was most frequently expressed in tumors with oxyphilic cytoplasm, including oxyphilic variants of papillary carcinoma (4/4 = 100%), oxyphilic variants of follicular adenoma (7/7 = 100%), and oxyphilic variants of follicular carcinoma (5/5 = 100%). Eighty-one percent (44/54) of papillary carcinoma cases, including microcarcinomas, and follicular variants were also positively stained for Niban at variable intensities. Follicular carcinomas were less frequently and less intensely stained. In nonneoplastic lesions, cells were rarely positively stained. In Hashimoto's thyroiditis, scattered cells with oxyphilic cell metaplasia were weakly Niban-positive. Reverse transcriptase-polymerase chain reaction and Western blot analysis of frozen tissue confirmed Niban expression at the molecular level in 4 cases of papillary carcinoma. Taken together, Niban expression is up-regulated in various types of thyroid tumors. We postulate that Niban expression may play an important role in the tumorigenic process of the thyroid in several scenarios. (1) Niban expression may be closely related to the carcinogenic process, especially from the early stage of papillary thyroid carcinoma. (2) Niban may be closely associated with altered mitochondrial functions in preneoplastic and neoplastic processes of the thyroid. (3) Niban may be a molecular marker of the oxyphilic phenotype under various conditions. Further functional studies of Niban will clarify the role of Niban in various thyroid lesions.

Biomarkers, Tumor↗
PubMed2006

Birt-Hogg-Dubé (BHD) gene mutations in human gastric cancer with high frequency microsatellite instability.

Birt-Hogg-Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by benign hamartomatous skin lesions and an increased risk of pneumothorax and renal tumors. Many of the patients harbor insertion/deletion mutations in the hypermutable poly(C)(8) tract in exon 11 of the BHD gene. This mutational hot spot is also reported to be a target of mutation in microsatellite instability (MSI) sporadic colorectal tumors. To test if the BHD gene is a potential mutational target in gastric cancer, we screened for mutations in all of the coding exons of the BHD gene in 30 cases of MSI gastric cancer as well as 50 cases of microsatellite stable (MSS) gastric cancer. Mutations in the poly(C)(8) tract of BHD were detected in 3 of 19 MSI-high cases (15.8%), and none of 11 MSI-low cases. All BHD mutated cases also showed mutations of both BAX and TGFbetaRII. No mutations were detected in the other exons of the BHD gene. No BHD mutations were found in MSS gastric cancer cases. Taken together, these findings show that the BHD gene is a rare target in MSI-high gastric cancer, and BHD mutation tends to occur downstream in the mutational events of other major MSI-high target genes.

Adult↗
PubMed2006

Novel ELISA system for detection of N-ERC/mesothelin in the sera of mesothelioma patients.

We have developed a novel enzyme-linked immunosorbent assay (ELISA) system for the detection of N-ERC/mesothelin in the serum of mesothelioma patients and have begun to examine its clinical usefulness. N-ERC/mesothelin is a 31-kDa protein that forms the N-terminal fragment of the full-length 71-kDa ERC/mesothelin protein, and is physiologically secreted into the blood of mesothelioma patients where it can be detected using our sandwich ELISA containing two antibodies (rabbit polyclonal anti-ERC/mesothelin antibody-282 and mouse monoclonal antibody 7E7). Our ELISA system has thus far detected much higher serum levels of N-ERC/mesothelin in mesothelioma patients than in healthy controls or patients with other lung or pleural diseases. In conclusion, N-ERC/mesothelin is a promising candidate tumor marker for mesothelioma.

Animals↗
PubMed2006

Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt-Hogg-Dubé syndrome.

In the Nihon rat, an established model of hereditary renal cell carcinoma (RCC), the propensity for tumor development, is inherited as an autosomal dominant trait due to a single germline nucleotide insertion mutation in the rat Bhd ortholog. The Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disease characterized by fibrofolliculoma, pulmonary cysts, spontaneous pneumothorax, and renal neoplasm. The renal lesions of the Nihon rat are characterized, and extrarenal lesions are also described in this work. The earliest lesion of the RCC was identified as an altered tubule at as early as 3 weeks of age and rapidly progressed through adenoma to carcinoma with the primary cell type being clear/acidophilic where some similarities were evident to RCCs in BHD syndrome. The Nihon rats demonstrate a heterotopic ossification within RCCs and three extrarenal lesions, clear cell hyperplasia/adenoma of the endometrium, clear cell change of the epithelium of striated portions of salivary glands, and cardiac rhabdomyomatosis. This rat model of hereditary RCC provides a useful tool for analyzing the series of events leading to renal tumorigenesis and for studying BHD gene functions.

Adenoma↗
PubMed2006

Genetic and environmental factors in hereditary predisposition to tumors: a conceptual overview.

Cancer is a heritable disorder of somatic cells. Carcinogenesis at the cellular level is like an opened Japanese fan, because initiated cells grow in several directions and tumors suggest the edge of the fan by having many gene abnormalities. We discuss here the primal force and gene networks (federal headship) in renal carcinogenesis. The Eker (Tsc2 mutant) rat model of hereditary renal carcinoma (RC) is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Recently, we discovered a new hereditary renal carcinoma in the rat in Japan, and the rat was named the "Nihon" rat. We suggest that its predisposing (Bhd) gene is a novel renal tumor suppressor gene. We present these unique models as part of the study of problems in carcinogenesis; e.g., multistep carcinogenesis, cancer prevention and the development of the therapeutic treatments that can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s).

Animals↗
PubMed2006

Malignant perivascular epithelioid cell tumor of the colon: report of a case with molecular analysis.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm, and malignant cases are extremely rare. A case of malignant PEComa arising in the colon is described herein. The patient was a 43-year-old Japanese woman without a history of tuberous sclerosis complex. The tumor occurred in the abdominal cavity attached to the serosal side of the descending colon. Histologically, the tumor consisted of sheets or closely packed nests of epithelioid cells with clear or eosinophilic cytoplasms. The tumor cells were positive for HMB-45 but negative for S-100 protein and cytokeratins by immunohistochemical staining. Ki-67 labeling index was 2.9%. Peritoneal dissemination of tumor occurred at 20 months and the patient died of tumor at 38 months after the initial operation. This was considered to be a case of malignant PEComa, based on the histological and clinical features. Tumor cells showed overexpression of cyclin D1 but lacked the loss of heterozygosity of the TSC1 and TSC2 genes. The result suggests that the overexpression of cyclin D1 may play an important role in the tumorigenesis of PEComa. Because PEComas can behave in an aggressive manner, careful follow up is warranted.

Adult↗
PubMed2006

Molecular tumor markers for asbestos-related mesothelioma: serum diagnostic markers.

Mesothelioma is an aggressive tumor arising from the mesothelium, and is usually associated with previous exposure to asbestos. The incubation period of the tumor may be described as 30-40 years, and the prognosis is dismal. In addition to immunohistochemical markers, recently, serum markers for the diagnosis of mesothelioma have been reported as candidates. In contrast, the expression in renal carcinoma (ERC) gene has been discovered in the Eker rat model (Tsc2 gene mutant), which is a homolog of the human mesothelin/megakaryocyte potentiating factor gene, and a novel ELISA system (N-ERC/mesothelin) has been developed. It has also been found that N-ERC/mesothelin is very stable and plentiful in the blood. In the present paper the potential utility of molecular diagnostic markers is reviewed, including ELISA systems for asbestos-related mesothelioma.

Animals↗
PubMed2006

[An 80-year-old woman with progressive stroke, who had rheumatoid arthritis and antiphospholipid syndrome].

We report an 80-year-old woman who had rheumatoid arthritis and antiphospholipid syndrome. She was treated for rheumatoid arthritis since her thirties. At 76 years of age, she was diagnosed antiphospholipid syndrome serologically. She felt It. limb weakness and dysarthria and was admitted to the hospital on July 18, 2003. The brain MRI showed T2 hyperintensity signal on the rt. pre-central lobe. She was treated by the argatroban, edaravone, glycerol, and aspirin. However, she became bedridden and fed by NG-tube because her symptoms progressed in spite of the therapy. Progression of stroke stopped by adding heparin at last. After that, she repeated pneumonia. She was found dead on the bed August 2, 2003. The patient was discussed in a CPC. The chief discussant arrived at a conclusion that the cause of infarction was angitis due to rheumatoid arthritis. Other possibilities were multiple thrombus due to antiphospholipid syndrome, amyloid angiopathy, and atherosclerotic infarction. Post-mortem study revealed sputum obstruction in her bronchus, string deposition in her organs. The brain showed infarction on the rt. pre-central lobe. There were multiple thrombus in the leptomeningeal artery, but few atherosclerotic changes of the small arteries. Amyloid didn't deposit in the brain artery and the parenchyma. Pathologist concluded that her infarction was induced with multiple thrombus due to antiphospholipid syndrome.

Aged, 80 and over↗
PubMed2006

Neuromuscular abundance of RB1CC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation.

RB1-inducible coiled-coil 1 (RB1CC1) is a novel tumor suppressor implicated in the regulation of RB1 expression. It is abundant in post-mitotic neuromuscular cells, which are matured and enlarged, but scarce in smaller leukocytes, indicating an association between RB1CC1 status and cell size. To clarify whether RB1CC1 is involved in cell size control, we investigated the contribution of RB1CC1 to the TSC-mTOR pathway, which plays an important role in the control through translational regulation. RNAi-mediated knockdown of RB1CC1 reduced the activation of mTOR and S6K as well as the size of HEK293 and C2C12 cells. Such knockdown also suppressed RB1 expression and the population of G1-phase cells. Exogenous expression of RB1CC1 maintained S6K activity and cell size, and decreased TSC1/hamartin contents under nutritionally starved conditions, which usually inhibit the mTOR-S6K pathway. Furthermore, RB1CC1 interfered with and degraded TSC1 through the ubiquitin-proteasomal pathway. A lentiviral RNAi for RB1CC1 reduced the size of mouse leg muscles. These findings suggest that RB1CC1 is required to maintain both RB1 expression and mTOR activity. The activity of mTOR was supported by RB1CC1 through TSC1 degradation. RB1CC1 preserved cell size without cell cycle progression especially in neuromuscular tissues, and the abundance contributed to the non-proliferating enlarged cell phenotype.

Animals↗
PubMed2006

Gene expression profile of DNA binding protein A transgenic mice.

We recently reported that the expression of dbpA (DNA binding protein A) is associated with advanced stages of human hepatocellular carcinoma (HCC) and that its transcription is positively regulated by E2F1, which is also implicated in hepatocarcinogenesis. To study the in vivo effect of dbpA on hepatocarcinogenesis, we generated the dbpA-transgenic mouse that specifically expressed a transgene in hepatocytes. Here, we studied the effect of dbpA on the expression of other cellular genes by using microarray analyses. The expression profiles from livers of 31- and 32-week-old male transgenic mice [Tg(+)] that did not show any morphological changes and from livers of their male wild-type littermates [Tg(-)] were compared. Expression differences detected by microarray analyses were validated by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA samples from livers of 3 pairs of Tg(+) and (-) mice. The 11 up-regulated genes included 7 carcinogenesis-related genes (Igfbp1, Tff3, Hpx, Orm2, Ctsl, Plg, Jdp1), and the 9 down-regulated genes included Car3 that is associated with the protection of cells from attack by oxygen radicals. We confirmed that the expression of Igfbp1 (insulin like growth factor binding protein 1) was reduced by siRNA targeting dbpA in the human HCC cell line. In conclusion, our present data suggested that dbpA could be positively involved in carcinogenesis by changing the expression profiles of cellular genes.

Animals↗
PubMed2005

The up-regulation of Y-box binding proteins (DNA binding protein A and Y-box binding protein-1) as prognostic markers of hepatocellular carcinoma.

PURPOSE: The development of hepatocellular carcinoma is associated with the chronic inflammation of the liver caused by various factors such as hepatitis B or C virus infection. Previously, we reported DNA binding protein A (dbpA) as a candidate molecule that can accelerate inflammation-induced hepatocarcinogenesis. DbpA belongs to the Y-box binding protein family, and Y-box binding protein-1 (YB-1), the prototype member of this family, is reported to be a prognostic marker of malignant diseases other than hepatocellular carcinoma. The purpose of this study is to examine the significance of the expression of dbpA or of the T-to-G transversion in the dbpA promoter region, which enhances the promoter activity in vitro, for the progression of hepatocellular carcinoma. EXPERIMENTAL DESIGN: We studied the expression of dbpA (as well as of YB-1) in 82 formalin-fixed hepatocellular carcinoma tissues by immunohistochemistry and determined the sequence of the dbpA promoter region in 42 frozen hepatocellular carcinoma tissues. We examined the relationship between these findings and the clinicopathologic factors of hepatocellular carcinoma patients. RESULTS: DbpA expression was associated with the advanced stages of hepatocellular carcinoma, and the cases with the nuclear dbpA expression had a poor prognosis. DbpA contributed more significantly to this association than YB-1. Furthermore, the T-to-G transversion in the dbpA promoter region was related to the nuclear localization of dbpA. CONCLUSION: DbpA was a more significant prognostic marker of hepatocellular carcinoma than YB-1. The T-to-G transversion in the dbpA promoter region was suggested to be a predisposing factor for the progression of hepatocellular carcinoma.

Antibodies, Monoclonal↗
PubMed2005

Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression.

The role of tumor suppressor haploinsufficiency in oncogenesis is still poorly understood. The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner. In contrast, we found that while Tsc2 heterozygosity unmasks Pten haploinsufficiency in growth and tumor suppression, tumorigenesis in Tsc2+/- mutants is surprisingly not accelerated by Pten heterozygosity, even though mTOR activation is cooperatively enhanced by compound Pten/Tsc2 heterozygosity. We show that the wild-type alleles of both Pten and Tsc2 are retained in prostate tumors from both Pten+/- and Pten+/-Tsc2+/- mice, whereas TSC-related tumor lesions are invariably associated with Tsc2 loss of heterozygosity (LOH) in both Tsc2+/- and Pten+/-Tsc2+/- mice. These findings demonstrate that inactivation of TSC2 is epistatic to PTEN in the control of tumor initiation and progression and, importantly, that both Pten and Tsc2 are haploinsufficient for suppression of tumorigenesis initiated by Pten heterozygosity, while neither Pten nor Tsc2 is haploinsufficient for repression of carcinogenesis arising from Tsc2 heterozygosity, providing a rationale for the differential cancer susceptibility of the two human conditions associated with PTEN or TSC2 heterozygous mutations.

Animals↗
PubMed2005

A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis.

Intracellular oxidative stress from mitochondria is thought to be important in carcinogenesis and tumorigenesis, but direct experimental proof is limited. In this study, a transgenic mouse cell line (SDHC E69) with a mutated SDHC gene (a subunit of complex II in the electron transport chain) was constructed to test this question. The SDHC E69 cells overproduced superoxide anion (O(2)(-)) from mitochondria, had elevated cytoplasmic carbonyl proteins and 8-OH-deoxyguanine in their DNA as well as significantly higher mutation frequencies than wild type. There were many apoptotic cells in this cell line, as predicted by the observed increase in caspase 3 activity, decrease in mitochondrial membrane potential, and structural changes in their mitochondria. In addition, some cells that escaped from apoptosis underwent transformation, as evidenced by the fact that SDHC E69 cells caused benign tumors when injected under the epithelium of nude mice. These results underscore the notion that mitochondrially generated oxidative stress can contribute to nuclear DNA damage, mutagenesis, and ultimately, tumorigenesis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Frequent down-regulation of HIVEP2 in human breast cancer.

The HIVEP2 gene, located on 6q23-q24, belongs to a family of genes that encodes large zinc fingers containing transcription factor proteins. Although this gene has been implicated in the regulation of immune responses and cellular proliferation, its functions are largely unknown. In the present study, we investigated HIVEP2 gene abnormalities in microdissected breast cancer tissue. For real-time quantitational RT-PCR analysis of paired normal and tumor tissues, mRNA levels were down-regulated to a maximum of 96%. The overall median expression level in breast cancer (33 cases) was significantly lower than that in normal breast tissue (normalized median value of 4.49 versus 17.68; p < 0.0001). Through full-length 5'-RACE (rapid amplification of cDNA ends) analysis, we identified multiple exons in the 5'-untranslated regions with multiple transcriptional start sites, four of which were located in a large CpG island. No tissue- or cancer-specific usage patterns for the transcription start sites were identified by multiplex RT-PCR analysis. Only faint methylation was detected in the 5' region of the island in normal cells and breast cancer tissue, indicating physiological, aging and no tumor-specific methylation. Mutation screening showed only germline polymorphisms. Thus, down-regulation of the HIVEP2 genes frequently occurs and may be one of the genetic events responsible for breast cancer, and their transcription may be regulated by complex mechanisms involving interactions with other factors and/or by other genetic/epigenetic mechanisms.

5' Untranslated Regions↗
PubMed2005

Intentional delay of human hepatocarcinogenesis due to suppression of chronic hepatitis.

Human hepatocellular carcinomas (HCCs) are preceded by chronic hepatitis and cirrhosis. Despite a clear viral etiology [hepatitis B virus (HBV) and hepatitis C virus (HCV)] of human hepatocarcinogenesis, the mechanism is complex and the distinct molecular pathway or molecules to explain this phenomenon are not yet known. Hepatitis viral, 'inflammation-mediated' hepatocarcinogenesis greatly influences the incidence of somatic genetic events in hepatocytes by increasing the number of target cells, or the proliferation of once-hit hepatocytes, eventually leading to HCCs. These conditions may be designated as the 'hypercarcinogenic state'. Our goal is to lead the 'hypercarcinogenic state' to the 'normo- or hypocarcinogenic' state and to prevent HCC development (intentional delay of HCC).

CCAAT-Enhancer-Binding Proteins↗
PubMed2004

Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors.

Flat colorectal tumors, characterized by high-grade dysplasia from early small flat mucosal lesions, exhibit a relatively aggressive clinical behavior and are known for their infrequent K-ras mutations. In this study, we investigated the methylation status of the RASSF1A promoter in association with 3p LOH and K-ras mutations in 48 flat colorectal tumors (39 early carcinomas and nine intramucosal high-grade dysplasias). RASSF1A hypermethylation was detected in 39 of 48 (81.3%) tumors and RASSF1A methylation was also detected in 19 of 39 (49%) normal colonic mucosal tissues. 3p21.3 LOH was detected in 20 of 42 (47.6%) cases, but RASSF1 methylation was detected in cases with LOH (14 cases) and retention of 3p21.3 (20 cases). K-ras mutations were detected in seven of 48 (14.6%) tumors and the concordant occurrence of K-ras mutation and RASSF1A methylation was detected in three of 48 cases (6.3%). Overall, there was a statistically significant mutually exclusive relationship between K-ras mutations and RASSF1A methylation. In conclusion, promoter hypermethylation of RASSF1A is a frequent event and may start early in the background normal mucosa in this tumor type. An alternative cascade of abnormalities in RAS transduction pathways may be responsible for the flat morphology and aggressive nature of flat colorectal neoplasms.

Adult↗