Miyano K.,National Cancer Center Research Institute
Anesthesia and Analgesia | Year: 2015
BACKGROUND:: The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to μ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively.METHODS:: We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording.RESULTS:: Tramadol and M1 (0.01–10 μM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1–10 μM) and M1 (1–10 μM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 μM) decreased the inward currents induced by AITC.CONCLUSIONS:: These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds. © 2015 International Anesthesia Research Society
Kanai Y.,National Cancer Center Research Institute
Cancer Science | Year: 2010
Alterations of DNA methylation, which result in chromosomal instability and silencing of tumor-related genes, are among the most consistent epigenetic changes observed in human cancers. Analysis of tissue specimens has revealed that DNA methylation alterations participate in multistage carcinogenesis, even from the early and precancerous stages, especially in association with chronic inflammation and/or persistent viral infection, such as chronic hepatitis or liver cirrhosis resulting from infection with hepatitis B or C virus. DNA methylation alterations can account for the histological heterogeneity and clinicopathological diversity of human cancers. Overexpression of DNA methyltransferase 1 is not a secondary result of increased cell proliferative activity, but is significantly correlated with accumulation of DNA hypermethylation in CpG islands of tumor-related genes. Alteration of DNA methyltransferase 3b splicing may result in chromosomal instability through DNA hypomethylation in pericentromeric satellite regions. Genome-wide analysis of DNA methylation status has revealed that the DNA methylation profile at the precancerous stage is basically inherited by the corresponding cancers developing in individual patients. DNA methylation status is not simply altered at the precancerous stage; rather, DNA methylation alterations at the precancerous stage may confer vulnerability to further genetic and epigenetic alterations, generate more malignant cancers, and thus determine patient outcome. Therefore, genome-wide DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication, and thus provide an avenue for cancer prevention and therapy on an individual basis. © 2009 Japanese Cancer Association.
Kondo T.,National Cancer Center Research Institute
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2014
A biomarker is a crucial tool for measuring the progress of disease and the effects of treatment for better clinical outcomes in cancer patients. Diagnostic, predictive, and prognostic biomarkers are required in various clinical settings. The proteome, a functional translation of the genome, is considered a rich source of biomarkers; therefore, sizable time and funding have been spent in proteomics to develop biomarkers. Although significant progress has been made in technologies toward comprehensive protein expression profiling, and many biomarker candidates published, none of the reported biomarkers have proven to be beneficial for cancer patients. The present deceleration in biomarker research can be attributed to technical limitations. Additional efforts are required to further technical progress; however, there are many examples demonstrating that problems in biomarker research are not so much with the technology but in the study design. In the study of biomarkers for early diagnosis, candidates are screened and validated by comparing cases and controls of similar sample size, and the low prevalence of disease is often ignored. Although it is reasonable to take advantage of multiple rather than single biomarkers when studying diverse disease mechanisms, the annotation of individual components of reported multiple biomarkers does not often explain the variety of molecular events underlying the clinical observations. In tissue biomarker studies, the heterogeneity of disease tissues and pathological observations are often not considered, and tissues are homogenized as a whole for protein extraction. In addition to the challenge of technical limitations, the fundamental aspects of biomarker development in a disease study need to be addressed. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. © 2013 Elsevier B.V. All rights reserved.
Chiba T.,Kyoto University |
Marusawa H.,Kyoto University |
Ushijima T.,National Cancer Center Research Institute
Gastroenterology | Year: 2012
Chronic inflammation, regardless of infectious agents, plays important roles in the development of various cancers, particularly in digestive organs, including Helicobacter pyloriassociated gastric cancer, hepatitis C viruspositive hepatocellular carcinoma, and colitis-associated colon cancers. Cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations of various proto-oncogenes and tumor-suppressor genes. During chronic inflammation, infectious agents such as H pylori and hepatitis C virus as well as intrinsic mediators of inflammatory responses, including proinflammatory cytokines and reactive oxygen and nitrogen species, can induce genetic and epigenetic changes, including point mutations, deletions, duplications, recombinations, and methylation of various tumor-related genes through various mechanisms. Furthermore, inflammation also modulates the expressions of microRNAs that influence the production of several tumor-related messenger RNAs or proteins. These molecular events induced by chronic inflammation work in concert to alter important pathways involved in normal cellular function, and hence accelerate inflammation-associated cancer development. Among these, recent studies highlighted an important role of activation-induced cytidine deaminase, a nucleotide-editing enzyme essential for somatic hypermutation and class-switch recombination of the immunoglobulin gene, as a genomic modulator in inflammation-associated cancer development. © 2012 AGA Institute.
Ichimura K.,National Cancer Center Research Institute
Brain Tumor Pathology | Year: 2012
The isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are mutated in 50-80% of astrocytomas, oligodendrogliomas or oligoastrocytomas of grades II and III, and secondary glioblastomas; they are, however, seldom mutated in primary glioblastomas and never in other types of glioma. Gliomas with IDH1/2 mutations always harbor either TP53 mutations or total 1p/19q loss. This suggests these two types of tumor may arise from common progenitor cells that have IDH1/2 mutations, subsequently evolving into each tumor type with the acquisition of TP53 mutations or total 1p/19q loss. Survival is significantly longer for patients with IDH-mutated gliomas than for those with IDH-wild type tumors. This observation indicates that IDH status defines biologically different subgroups among gliomas. The molecular pathogenesis of IDH1/2 mutations in the development of gliomas is unclear. The mutated IDH1/2 enzyme generates D-2- hydroxyglutarate. Several theories have been proposed, including: Increased angiogenesis because of accumulation of HIF-1α; a glioma CpG island methylator phenotype (G-CIMP) induced by inhibition of TET2; and increased vulnerability to oxidative stress because of depletion of antioxidants. Elucidating the pathogenesis of IDH mutations will aid better understanding of the molecular mechanisms of gliomagenesis and may lead to the development of novel molecular classification and therapy. © The Japan Society of Brain Tumor Pathology 2012.