Publications by authors named "Chikako Shibata"

23 Publications

  • Page 1 of 1

Risk factors of poor prognosis and impairment of activities of daily living in patients with hemorrhagic gastroduodenal ulcers.

BMC Gastroenterol 2021 Jan 6;21(1):16. Epub 2021 Jan 6.

Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kanda-Izumi-cho, Chiyoda-ku, Tokyo, 101-8643, Japan.

Background: Impairment of activities of daily living (ADL) due to hemorrhagic gastroduodenal ulcers (HGU) has rarely been evaluated. We analyzed the risk factors of poor prognosis, including mortality and impairment of ADL, in patients with HGU.

Methods: In total, 582 patients diagnosed with HGU were retrospectively analyzed. Admission to a care facility or the need for home adaptations during hospitalization were defined as ADL decline. The clinical factors were evaluated: endoscopic features, need for interventional endoscopic procedures, comorbidities, symptoms, and medications. The risk factors of outcomes were examined with multivariate analysis.

Results: Advanced age (> 75 years) was a significant predictor of poor prognosis, including impairment of ADL. Additional significant risk factors were renal disease (odds ratio [OR] 3.43; 95% confidence interval [CI] 1.44-8.14) for overall mortality, proton pump inhibitor (PPIs) usage prior to hemorrhage (OR 5.80; 95% CI 2.08-16.2), and heart disease (OR 3.05; 95% CI 1.11-8.43) for the impairment of ADL. Analysis of elderly (> 75 years) subjects alone also revealed that use of PPIs prior to hemorrhage was a significant predictor for the impairment of ADL (OR 8.24; 95% CI 2.36-28.7).

Conclusion: In addition to advanced age, the presence of comorbidities was a risk of poor outcomes in patients with HGU. PPI use prior to hemorrhage was a significant risk factor for the impairment of ADL, both in overall HGU patients and in elderly patients alone. These findings suggest that the current strategy for PPI use needs reconsideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12876-020-01580-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789673PMC
January 2021

Emerging Roles of Exosomal Circular RNAs in Cancer.

Front Cell Dev Biol 2020 8;8:568366. Epub 2020 Oct 8.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Circular RNA (circRNA) is a type of non-coding RNA that forms a covalently closed continuous loop. The expression pattern of circRNA varies among cell types and tissues, and many circRNAs are aberrantly expressed in various cancers. Aberrantly expressed circRNAs have been shown to play crucial roles in carcinogenesis, functioning as microRNA sponges or new templates for protein translation. Recent research has shown that circRNAs are enriched in exosomes. Exosomes are secretory vesicles that mediate intercellular communication through the delivery of cargo, including proteins, lipids, DNA, and RNA. Exosome-mediated crosstalk between cancer cells and the tumor microenvironment promotes the epithelial-mesenchymal transition, angiogenesis, and immune escape, and thus may contribute to cancer invasion and metastasis. In this review, we discuss the biological functions of exosomal circRNAs and their significance in cancer progression. Additionally, we discuss the potential clinical applications of exosomal circRNAs as biomarkers and in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.568366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578227PMC
October 2020

Aberrant expression of a novel circular RNA in pancreatic cancer.

J Hum Genet 2021 Feb 3;66(2):181-191. Epub 2020 Sep 3.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules that are produced from pre-mRNAs through a process known as back-splicing. Although circRNAs are expressed under specific conditions, current understanding of their comprehensive expression status is still limited. Here, we performed a large-scale circRNA profiling analysis in human pancreatic ductal adenocarcinoma (PDAC) tissues, using circular RNA-specific RNA sequencing. We identified more than 40,000 previously unknown circRNAs, some of which were upregulated in PDAC tissues, compared with normal pancreatic tissues. We determined the full-length sequence of a circRNA upregulated in PDAC, which was derived from two noncoding RNA loci on chromosome 12. The novel circRNA, named circPDAC RNA, was not expressed in normal human cells, but was expressed in PDAC and other carcinoma cells. While postulated biological functions, such as peptide production from the circPDAC RNA, were not detected, its aberrant expression was confirmed in other PDAC tissues and in serum from a PDAC patient. These results demonstrate that comprehensive studies are necessary to reveal the expression status of circRNAs and that the circPDAC RNA identified here might serve as a novel biomarker for cancers, including PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-00826-5DOI Listing
February 2021

Long-term survival after palliative argon plasma coagulation for intraductal papillary mucinous neoplasm of the bile duct.

Clin J Gastroenterol 2021 Feb 10;14(1):314-318. Epub 2020 Aug 10.

Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kanda-Izumi-cho, Chiyoda-ku, Tokyo, 101-8643, Japan.

Intraductal papillary mucinous neoplasm of the bile duct (IPNB) is an epithelial tumor that can cause obstructive jaundice and cholangitis due to mucin production. Although the effectiveness of argon plasma coagulation in IPNB treatment has been demonstrated, the long-term effect of the therapy is largely unknown. Here, we have presented a patient with IPNB who underwent argon plasma coagulation with a follow-up period of more than 2 years. A 74-year-old woman was referred to our department for treatment of obstructive jaundice. Endoscopic retrograde cholangiopancreatography revealed marked dilation of intrahepatic and extrahepatic bile ducts and thick mucin drainage from the ampulla of Vater. IPNB was diagnosed pathologically from biopsy specimens. Surgery was not recommended because of the extensive intrahepatic spread of the lesion. Endoscopic sphincterotomy, endoscopic papillary large balloon dilation, and insertion of a metallic stent could not resolve the obstructive jaundice. Finally, argon plasma coagulation with percutaneous cholangioscopy was performed 3 times over 1 month. After treatment, obstructive jaundice was resolved and the patient's clinical condition has been stable for more than 2 years, except for a single episode of transient cholangitis. In conclusion, argon plasma coagulation may be an alternative to surgery for the palliation of jaundice with IPNB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-020-01199-0DOI Listing
February 2021

Hepatitis C virus relapse after successful treatment with direct-acting antivirals, followed by sarcomatous changes in hepatocellular carcinoma: a case report.

J Med Case Rep 2020 May 27;14(1):62. Epub 2020 May 27.

Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan.

Background: Combination therapy of interferon and ribavirin has traditionally been used to eradicate hepatitis C virus. The sustained virologic response achieved with interferon-related therapy is persistent, and late relapses after achieving sustained virologic response at 24 weeks using this therapy are reportedly rare (< 1%). In 2014, interferon-free therapy with direct-acting antivirals was developed, and the rate of sustained virologic response was improved. However, the persistence thereof remains uncertain, and the appropriate follow-up period for hepatitis C virus-positive patients is under discussion.

Case Presentation: A 74-year-old Japanese man who had hepatitis C virus-related hepatocellular carcinoma and was successfully treated with radiofrequency ablation four times underwent direct-acting antiviral therapy with daclatasvir and asunaprevir; sustained virologic response at 24 weeks was confirmed. However, although he had no high risk factors for reinfection, hepatitis C virus ribonucleic acid was detected again 6 months after achieving sustained virologic response at 24 weeks. Moreover, he developed active hepatitis with an increased viral load. Five months after development of hepatitis, recurrent hepatocellular carcinoma emerged in segment II, where we had performed radiofrequency ablation 17 months previously. The recurrent hepatocellular carcinoma enlarged quite rapidly and induced multiple peritoneal disseminations and lung metastases. He died 3 months after the abrupt recurrence. A sarcomatous change in the hepatocellular carcinoma was identified during the autopsy.

Conclusions: Although sustained virologic response at 24 weeks has generally been regarded to denote complete eradication of hepatitis C virus, we present a patient in whom hepatitis C virus recurred 6 months after achieving sustained virologic response at 24 weeks with direct-acting antiviral therapy. In addition, a sarcomatous change in hepatocellular carcinoma emerged 5 months after active hepatitis developed due to late hepatitis C virus relapse in this case. The sarcomatous change in hepatocellular carcinoma is generally thought to be related to anticancer therapies, such as radiofrequency ablation. However, in this case, late viral relapse and active hepatitis in addition to the previous radiofrequency ablation could have been the trigger. There may be a need for follow-up of hepatitis C virus ribonucleic acid beyond sustained virologic response at 24 weeks with direct-acting antiviral therapy, owing to the possibility of late viral relapse and tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13256-020-02392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251811PMC
May 2020

Impact of the Sensitivity to Empiric Antibiotics on Clinical Outcomes after Biliary Drainage for Acute Cholangitis.

Gut Liver 2020 11;14(6):842-849

Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan.

Background/aims: Empiric antibiotics are given in combination with biliary drainage for acute cholangitis but sometimes turn out to be insensitive to microorganisms in blood and bile. Clinical outcomes were compared according to sensitivity to microorganisms detected in blood and bile culture to evaluate the impact of sensitivity to empiric antibiotics in cholangitis.

Methods: Consecutive patients who underwent biliary drainage for acute cholangitis were retrospectively studied. Clinical outcomes such as 30-day mortality, length of hospital stay and high care unit stay, organ dysfunction and duration of fever were compared in three groups: group A (sensitive to both blood and bile culture), group B (sensitive to blood culture alone) and group C (insensitive to both blood and bile culture).

Results: Eighty episodes of cholangitis were classified according to sensitivity results: 42, 32 and six in groups A, B and C. Escherichia coli and Klebsiella were two major pathogens. There were no significant differences in 30-day mortality rate (7%, 0%, and 0%, p=0.244), length of hospital stay (28.5, 21.0, and 20.5 days, p=0.369), organ dysfunction rate (14%, 25%, and 17%, p=0.500), duration of fever (4.3, 3.2, and 3.5 days, p=0.921) and length of high care unit stay (1.4, 1.2, and 1.7 days, p=0.070) in groups A, B and C. Empiric antibiotics were changed in 11 episodes but clinical outcomes appeared to be non-inferior even in 31 episodes of cholangitis who were on inadequate antibiotics throughout the course.

Conclusions: Sensitivity of empiric antibiotics was not associated with clinical outcomes in acute cholangitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5009/gnl19248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667925PMC
November 2020

Paraneoplastic dermatomyositis appearing after nivolumab therapy for gastric cancer: a case report.

J Med Case Rep 2019 Jun 2;13(1):168. Epub 2019 Jun 2.

Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumicho Chiyoda-ku, Tokyo, 101-8643, Japan.

Background: While dermatomyositis is often associated with malignancy, several autoimmune diseases like myositis can be caused by immune checkpoint inhibitors. Differentially diagnosing malignancy-associated dermatomyositis or myositis caused by immune checkpoint inhibitors is sometimes difficult, particularly when a patient with malignancy shows the symptoms of myositis after checkpoint inhibitor administration. We experienced such a case in which we had difficulties in diagnosing paraneoplastic dermatomyositis or drug-associated myositis. In this case, all of our team initially assumed that the diagnosis was myositis caused by immune checkpoint inhibitors. However, it turned out finally that the diagnosis was paraneoplastic dermatomyositis. Because the diagnosis was unexpected, we report here.

Case Presentation: We report the case of a 71-year-old Japanese man who developed clinical symptoms of myositis, such as muscle aches and weakness, after initiation of nivolumab therapy for his gastric cancer. He was initially diagnosed with nivolumab-induced myositis, because the myositis symptoms appeared after nivolumab administration, and nivolumab is known to trigger various drug-associated autoimmune diseases. However, according to his characteristic skin lesions, the type of muscle weakness, his serum marker profiles, electromyography of his deltoid muscle, and magnetic resonance imaging, he was finally diagnosed as having paraneoplastic dermatomyositis. Accordingly, treatment with intravenously administered corticosteroid pulse treatment, immunoglobulin injection, and tacrolimus was applied; his symptoms subsequently improved. However, to our regret, at day 142 after administration, he died due to rapid worsening of his gastric cancer.

Conclusion: Differentially diagnosing paraneoplastic dermatomyositis or drug-associated myositis caused by immune checkpoint inhibitors is difficult in some cases. The differential diagnosis is crucial because it influences the decision regarding the appropriateness of the use of immunosuppressive treatment against the autoimmune diseases as well as the decision regarding the appropriateness of the continuous use of immune checkpoint inhibitors against the primary cancers. Because subclinical autoimmune disease may become overt after administering immune checkpoint inhibitors, non-apparent autoimmune diseases, which have already existed, should also be considered to avoid the delay of appropriate treatment, when symptoms of autoimmune diseases are recognized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13256-019-2105-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545224PMC
June 2019

MicroRNAs and liver disease.

J Hum Genet 2017 Jan 26;62(1):75-80. Epub 2016 May 26.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The biological roles of microRNAs (miRNAs) have been extensively studied. miRNA122 represents more than half of the miRNAs expressed in the liver and has various physiological and pathological functions, which include enhancing hepatitis virus replication, regulating lipid metabolism and suppressing hepatocellular carcinoma. miRNAs, whether globally or individually, have been linked with hepatocarcinogenesis. Furthermore, some miRNAs have been shown to be involved in the pathogenesis of nonalcoholic steatohepatitis. Using nucleotide-based strategies, these miRNAs may be developed as potential therapeutic targets. Because changes in miRNA expression can be measured in sera, they may be used as non-invasive biomarkers if they correctly reflect the pathological state of the liver. In this review, we show the biological roles of representative miRNAs in liver disease and discuss the current issues that remain to be clarified for future clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jhg.2016.53DOI Listing
January 2017

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression.

Nucleic Acids Res 2015 Sep 17;43(15):7577-89. Epub 2015 Jul 17.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

The reduced expression levels and functional impairment of global miRNAs are related to various human diseases, including cancers. However, relatively little is known about how global miRNA function may be upregulated. Here, we report that global miRNA function can be enhanced by Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors. The regulation of miRNA function by ROCK inhibitors is mediated, at least in part, by poly(A)-binding protein-interacting protein 2 (PAIP2), which enhances poly(A)-shortening of miRNA-targeted mRNAs and leads to global upregulation of miRNA function. In the presence of a ROCK inhibitor, PAIP2 expression is enhanced by the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) through increased ROCK1 nuclear localization and enhanced ROCK1 association with HNF4A. Our data reveal an unexpected role of ROCK1 as a cofactor of HNF4A in enhancing PAIP2 transcription. ROCK inhibitors may be useful for the various pathologies associated with the impairment of global miRNA function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkv728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551943PMC
September 2015

Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine.

Oncotarget 2015 Apr;6(10):8339-52

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Reduced expression of microRNA122 (miR122), a liver-specific microRNA, is frequent in hepatocellular carcinoma (HCC). However, its biological significances remain poorly understood. Because deregulated amino acid levels in cancers can affect their biological behavior, we determined the amino acid levels in miR122-silenced mouse liver tissues, in which intracellular arginine levels were significantly increased. The increased intracellular arginine levels were through upregulation of the solute carrier family 7 (SLC7A1), a transporter of arginine and a direct target of miR122. Arginine is the substrate for nitric oxide (NO) synthetase, and intracellular NO levels were increased in miR122-silenced HCC cells, with increased resistance to sorafenib, a multikinase inhibitor. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib. Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib. These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480756PMC
http://dx.doi.org/10.18632/oncotarget.3234DOI Listing
April 2015

Diagnostic and therapeutic application of noncoding RNAs for hepatocellular carcinoma.

World J Hepatol 2015 Jan;7(1):1-6

Chikako Shibata, Motoyuki Otsuka, Takahiro Kishikawa, Motoko Ohno, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike, Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression posttranscriptionally, targeting thousands of messenger RNAs. Long noncoding RNAs (lncRNAs), another class of noncoding RNAs, have been determined to be also involved in transcription regulation and translation of target genes. Since deregulated expression levels or functions of miRNAs and lncRNAs in hepatocellular carcinoma (HCC) are frequently observed, clinical use of noncoding RNAs for novel diagnostic and therapeutic applications in the management of HCCs is highly and emergently expected. Here, we summarize recent findings regarding deregulated miRNAs and lncRNAs for their potential clinical use as diagnostic and prognostic biomarkers of HCC. Specifically, we emphasize the deregulated expression levels of such noncoding RNAs in patients' sera as noninvasive biomarkers, a field that requires urgent improvement in the clinical surveillance of HCC. Since nucleotide-based strategies are being applied to clinical therapeutics, we further summarize clinical and preclinical trials using oligonucleotides involving the use of miRNAs and small interfering RNAs against HCC as novel therapeutics. Finally, we discuss current open questions, which must be clarified in the near future for realistic clinical applications of these new strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4254/wjh.v7.i1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295186PMC
January 2015

The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels.

Virology 2014 Aug 14;462-463:42-8. Epub 2014 Jun 14.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 5-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Despite recent progress in the development of direct-acting antivirals against hepatitis C virus (HCV), chronic HCV infection remains an important health burden worldwide. MicroRNA122 (miR122), a liver-specific microRNA (miRNA), positively regulates HCV replication, and systemic application of antisense oligonucleotides against miR122 led to the long-lasting suppression of HCV viremia in human clinical trials. Here, we report that apigenin, a flavonoid and an inhibitor of maturation of a subset of miRNAs, inhibits HCV replication in vitro. Apigenin decreased the expression levels of mature miR122 without significantly affecting cell growth. Because supplementation of synthesized miR122 oligonucleotides or overexpression of constitutively active TRBP blocked these effects, the inhibitory effects of apigenin on HCV replication seemed to be dependent on the reduction of mature miR122 expression levels through inhibition of TRBP phosphorylation. Thus, apigenin intake, either through regular diet or supplements, may decrease HCV replication in chronically infected patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2014.05.024DOI Listing
August 2014

Specific delivery of microRNA93 into HBV-replicating hepatocytes downregulates protein expression of liver cancer susceptible gene MICA.

Oncotarget 2014 Jul;5(14):5581-90

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). To date, the lack of efficient in vitro systems supporting HBV infection and replication has been a major limitation of HBV research. Although primary human hepatocytes support the complete HBV life cycle, their limited availability and difficulties with gene transduction remain problematic. Here, we used human primary hepatocytes isolated from humanized chimeric uPA/SCID mice as efficient sources. These hepatocytes supported HBV replication in vitro. Based on analyses of mRNA and microRNA (miRNA) expression levels in HBV-infected hepatocytes, miRNA93 was significantly downregulated during HBV infection. MiRNA93 is critical for regulating the expression levels of MICA protein, which is a determinant for HBV-induced HCC susceptibility. Exogenous addition of miRNA93 in HBV-infected hepatocytes using bionanocapsules consisted of HBV envelope L proteins restored MICA protein expression levels in the supernatant. These results suggest that the rescued suppression of soluble MICA protein levels by miRNA93 targeted to HBV-infected hepatocytes using bionanocapsules may be useful for the prevention of HBV-induced HCC by altering deregulated miRNA93 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170619PMC
http://dx.doi.org/10.18632/oncotarget.2143DOI Listing
July 2014

First detection of Echinococcus multilocularis infection in two species of nonhuman primates raised in a zoo: a fatal case in Cercopithecus diana and a strongly suspected case of spontaneous recovery in Macaca nigra.

Parasitol Int 2014 Aug 26;63(4):621-6. Epub 2014 Apr 26.

Department of Infectious Diseases, Hokkaido Institute of Public Health, North 19, West 12, Kitaku, Sapporo 060-0819, Hokkaido, Japan.

The causative parasite of alveolar echinococcosis, Echinococcus multilocularis, maintains its life cycle between red foxes (Vulpes vulples, the definitive hosts) and voles (the intermediate hosts) in Hokkaido, Japan. Primates, including humans, and some other mammal species can be infected by the accidental ingestion of eggs in the feces of red foxes. In August 2011, a 6-year-old zoo-raised female Diana monkey (Cercopithecus diana) died from alveolar echinococcosis. E. multilocularis infection was confirmed by histopathological examination and detection of the E. multilocularis DNA by polymerase chain reaction (PCR). A field survey in the zoo showed that fox intrusion was common, and serodiagnosis of various nonhuman primates using western blotting detected a case of a 14-year-old female Celebes crested macaque (Macaca nigra) that was weakly positive for E. multilocularis. Computed tomography revealed only one small calcified lesion (approximately 8mm) in the macaque's liver, and both western blotting and enzyme-linked immunosorbent assay (ELISA) showed a gradual decline of antibody titer. These findings strongly suggest that the animal had recovered spontaneously. Until this study, spontaneous recovery from E. multilocularis infection in a nonhuman primate had never been reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parint.2014.04.006DOI Listing
August 2014

The role of microRNAs in hepatocarcinogenesis: current knowledge and future prospects.

J Gastroenterol 2014 Feb 21;49(2):173-84. Epub 2013 Nov 21.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 5-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan,

MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression post-transcriptionally through complementary base pairing with thousands of messenger RNAs. Although the precise biological functions of individual miRNAs are still unknown, miRNAs are speculated to play important roles in diverse biological processes through fine regulation of their target gene expression. A growing body of data indicates the deregulation of miRNAs during hepatocarcinogenesis. In this review, we summarize recent findings regarding deregulated miRNA expression and their possible target genes in hepatocarcinogenesis, with emphasis on inflammation-related hepatocarcinogenesis. Because miRNA-based strategies are being applied to clinical therapeutics, precise knowledge of miRNA functions is crucial both scientifically and clinically. We discuss the current open questions from these points of view, which must be clarified in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00535-013-0909-8DOI Listing
February 2014

Regulation of the expression of the liver cancer susceptibility gene MICA by microRNAs.

Sci Rep 2013 ;3:2739

1] Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan [2].

Hepatocellular carcinoma (HCC) is a threat to public health worldwide. We previously identified the association of a single nucleotide polymorphism (SNP) at the promoter region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of hepatitis-virus-related HCC. Because this SNP affects MICA expression levels, regulating MICA expression levels may be important in the prevention of HCC. We herein show that the microRNA (miR) 25-93-106b cluster can modulate MICA levels in HCC cells. Overexpression of the miR 25-93-106b cluster significantly suppressed MICA expression. Conversely, silencing of this miR cluster enhanced MICA expression in cells that express substantial amounts of MICA. The changes in MICA expression levels by the miR25-93-106b cluster were biologically significant in an NKG2D-binding assay and an in vivo cell-killing model. These data suggest that the modulation of MICA expression levels by miRNAs may be a useful method to regulate HCCs during hepatitis viral infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep02739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781398PMC
July 2014

Unique haploinsufficient role of the microRNA-processing molecule Dicer1 in a murine colitis-associated tumorigenesis model.

PLoS One 2013 2;8(9):e71969. Epub 2013 Sep 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

A widespread downregulated expression of microRNAs (miRNAs) is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and -suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071969PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759383PMC
April 2014

The flavonoid apigenin improves glucose tolerance through inhibition of microRNA maturation in miRNA103 transgenic mice.

Sci Rep 2013 ;3:2553

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Polyphenols are representative bioactive substances with diverse biological effects. Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function. The effects were mediated by impaired maturation of a subset of miRNAs, probably through inhibition of the phosphorylation of TRBP, a component of miRNA-generating complexes via impaired mitogen-activated protein kinase (MAPK) Erk activation. While glucose intolerance was observed in miRNA103 (miR103)-overexpressing transgenic mice, administration of apigenin improved this pathogenic status likely through suppression of matured miR103 expression levels. These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep02553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757358PMC
February 2014

Inhibition of microRNA122 decreases SREBP1 expression by modulating suppressor of cytokine signaling 3 expression.

Biochem Biophys Res Commun 2013 Aug 24;438(1):230-5. Epub 2013 Jul 24.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

While inhibition of microRNA122 (miR122) function in vivo results in reduced serum cholesterol and fatty acid levels, the molecular mechanisms underlying the link between miR122 function and lipid metabolism remains unclear. Because the expression of SREBP1, a central transcription factor involved in lipid metabolism, is known to be increased by suppressor of cytokine signaling 3 (SOCS3) expression, and because we previously found that SOCS3 expression is regulated by miR122, in this study, we examined the correlation between miR122 status and the expression levels of SOCS3 and SREBP1. SREBP1 expression decreased when SOCS3 expression was reduced by miR122 silencing in vitro. Conversely, SREBP1 expression in miR122-silenced cells was restored by enforced expression of SOCS3. Such correlations were observed in human liver tissues with different miR122 expression levels. These signaling links may explain one of the molecular mechanisms linking inhibition of miR122 function or decreased expression of miR122 to decreased fatty acid and cholesterol levels, in the inhibition of miR122 function, or in pathological status in chronic liver diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2013.07.064DOI Listing
August 2013

Current status of miRNA-targeting therapeutics and preclinical studies against gastroenterological carcinoma.

Mol Cell Ther 2013 13;1. Epub 2013 Dec 13.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655 Japan.

Expanding knowledge about the crucial roles of microRNAs (miRNAs) in human diseases has led to the idea that miRNAs may be novel, promising therapeutic targets against various pathological conditions. The recent success of a human clinical trial using anti-miR-122 oligonucleotides against chronic hepatitis C virus has paved the way for this approach. In this review, we summarize briefly the current status of clinical trials of miRNA-targeting therapy and several representative preclinical trials against hepato-gastrointestinal carcinoma. In addition, we describe the currently available technologies for modification and delivery of oligonucleotides, which are essential in providing efficient, specific and safe approaches to targeting miRNAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/2052-8426-1-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448951PMC
June 2015

Receptor for activated protein kinase C: requirement for efficient microRNA function and reduced expression in hepatocellular carcinoma.

PLoS One 2011 15;6(9):e24359. Epub 2011 Sep 15.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

MicroRNAs (miRNAs) are important regulators of gene expression that control physiological and pathological processes. A global reduction in miRNA abundance and function is a general trait of human cancers, playing a causal role in the transformed phenotype. Here, we sought to newly identify genes involved in the regulation of miRNA function by performing a genetic screen using reporter constructs that measure miRNA function and retrovirus-based random gene disruption. Of the six genes identified, RACK1, which encodes "receptor for activated protein kinase C" (RACK1), was confirmed to be necessary for full miRNA function. RACK1 binds to KH-type splicing regulatory protein (KSRP), a member of the Dicer complex, and is required for the recruitment of mature miRNAs to the RNA-induced silencing complex (RISC). In addition, RACK1 expression was frequently found to be reduced in hepatocellular carcinoma. These findings suggest the involvement of RACK1 in miRNA function and indicate that reduced miRNA function, due to decreased expression of RACK1, may have pathologically relevant roles in liver cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174171PMC
February 2012

Fluid-fluid level in a giant epidermal cyst of the buttock.

J Dermatol 2007 Mar;34(3):193-7

Division of Dermatology, Higashi-Ohmi Keiai Hospital, Yokaichi, Higashi-Ohmi, Japan.

We describe a case of a giant epidermal cyst of the buttock that demonstrated a fluid-fluid level on imaging. There have been no previously reported cases of epidermal cysts containing a fluid-fluid level, so our case was considered to be very exceptional. A 39-year-old man had had a slowly enlarging giant subcutaneous mass in the left buttock for more than 10 years. It was elastic-soft, well-circumscribed and smooth-surfaced. Ultrasonography showed a well-circumscribed hypoechoic mass with a fluid-fluid level in the subcutis of the left buttock. Magnetic resonance imaging (MRI) showed a well-circumscribed cystic mass measuring 8 cm x 5.5 cm x 5.5 cm in the same place that the ultrasonography indicated. It was hypointense on the T1-weighted image, hyperintense on the T2-weighted image, and contained a fluid-fluid level on both the T1- and T2-weighted images. It bordered on the anus, but neither adhered nor formed a fistula with it. A surgical excision was performed. The mass was diagnosed histopathologically as an epidermal cyst. The occurrence of fluid-fluid levels in epidermal cysts should be kept in mind in the differential diagnosis of subcutaneous soft tissue tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1346-8138.2007.00248.xDOI Listing
March 2007
-->