• Mitochondrial pyruvate carrier modulates the epithelial–mesenchymal transition in cholangiocarcinoma (Oncology Reports, in press)

    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Ohashi et al. demonstrated the mitochondrial pyruvate carrier (MPC) plays a role in the intrahepatic cholangiocarcinoma (ICC). ICC has a poor prognosis even after complete tumor resection. MPC is located in the mitochondrial inner membrane and is involved in the oxidative phosphorylation. The present study indicates that MPC is important in the control of epithelial–mesenchymal transition (EMT), which characterizes metastasis of tumor cells, and could be a novel therapeutic target in some cancers.

  • Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer (Oncotarget, in press)

    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Nishizawa et al. demonstrated that epitranscriptome N6-methyladenosine (m6A) reader, YT521-B homology YTH domain family YTHDF1,  plays a role in the malignant behavior of colorectal cancer cells in an oncogene transcription factor c-Myc  dependent manner. Given that the m6A was first reported in RNA modification and is most common in the epitranscriptome issues of various RNAs, the present study indicated that YTHDF1 may be involved in the translation of numerous tumor related proteins. We are exploring further the transcription and ribosomal translation mechanism of epitranscriptome dependent pathway in the tumor microenvironment such as hypoxia.

  • Hypoxia stimulates the cytoplasmic localization of oncogenic long noncoding RNA LINC00152 in colorectal cancer (Int J Oncol, in press)

    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Nishizawa et al. demonstrated a long noncoding RNA, LINC00152, plays a pivotal role in cellular processes of colorectal cancer cells via the cytoplasmic localization under hypoxic tumor microenvironment. The present study indicated that lncRNA networks could provide diagnostic tools and novel therapeutic targets.

  • Epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells (Int J Oncol, in press)

    In the collaboration with the Department of Radiation Oncology, Osaka University, Taketo, et al. investigated a Epitranscriptome N6-methyladenosine (m6A) writer, methyltransferase-like 3 (METTL3), and showed the significance in chemo- and radioresistance in pancreatic cancer cells. Given that m6A is the most abundant epitranscriptome modification in mammalian mRNA and recent years have seen major progress in m6A epitranscriptomics, the present study indicates as tumor biology its crucial roles in initiation and progression of cancer through the regulation and mechanism of RNA stabilities, mRNA splicing, microRNA processing, and mRNA translation. We are now studying which factors control m6A dynamically, what occurs as the resultant of written/erased/read process by RNA modification, and how significant m6A marking is for each of the numerous genes, in order to discover draggable targets against intractable pancreatic cancer.

  • MicroRNA profiles involved in trifluridine resistance (Oncotarget, 2017)

    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Tsunekuni et al. demonstrated the microRNA profiles involved in trifluridine (FTD) resistance.  FTD is a key component of the novel oral antitumor drug trifluridine/tipiracil, which was approved for the treatment of patients with metastatic colorectal cancer refractory to standard chemotherapies. A comprehensive analysis of microRNA profiles was performed in colorectal cell lines resistant to FTD, in order to explore the underlying mechanisms of resistance to the drug. The data indicate the significance of microRNA network and the candidacy of microRNAs as a potential predictive clinical marker of FTD treatment.

  • Micro-RNA-130a-3p regulates gemcitabine-resistance via PPARG in cholangiocarcinoma (Annal. Surg. Oncol., 2017)

    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Asukai et al. demonstrated that miR-130a-3p was upregulated in gemcitabine-resistant cholangiocancinoma (CCA) cell lines, and its expression levels were closely related to prognosis of CCA patients. The data support that CCA patients with PPARγ positive were more effective for gemcitabine than those with negative.

  • MicroRNA miR-374, a potential radio sensitizer for carbon ion beam radiotherapy (Oncology reports, 2016)
    In the collaboration with the Department of Radiation Oncology, Osaka University (Prof. Ogawa, K.), Baek et al.
    studied microRNA (miRNA) profiles of a control and X-ray- and carbon ion beam-resistant cells to identify miRNAs that can be used as radio sensitizers and biomarkers. Expression of miRNAs shown to be upregulated or downregulated in the microarray analysis was studied. miRNA miR-374 has the potential to be a new radio sensitizer for carbon ion beam radiotherapy and a new biomarker to determine the optimal treatment for cancer.

  • Metabolic adaptation to nutritional stress in human colorectal cancer ( Scientific Reports, 2016 )
    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Miyo and Konno et al.
    demonstrated that colorectal cancer cells survived under the condition of glucose depletion, and their resistance to such conditions depended on genomic alterations rather than on KRAS mutation alone. Metabolomic analysis demonstrated that those cells maintained tricarboxylic acid cycle activity and ATP production under such conditions. The study showed that pivotal roles of GLUD1 and SLC25A13 in nutritional stress. Thus GLUD1 and SLC25A13 may serve as new targets in treating refractory colorectal cancer which survive in malnutritional microenvironments.

  • The one-carbon metabolism pathway highlights therapeutic targets for gastrointestinal cancer (Int J Oncol, 2017)
    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Konno et al.
    demonstrated the importance of one-carbon metabolism pathway in drug discovery. In this review, they focused on the understanding of the one-carbon metabolism pathway to unravel the link between the causes and effects of cancer phenotypes. The characterization of one-carbon metabolism is indispensable to the development of precision medicine in the context of cancer diagnostics and therapeutics. They review the historical issues associated with one-carbon metabolism and highlight the recent advances in cancer research.

  • Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer (Scientific Reports, 2016)

    In collaboration with the Department of Surgery, Osaka University (Profs. Masaki Mori and Yuichiro Doki), Colvin et al. demonstrate that in colorectal cancer cells that even in the absence of isocitrate dehydrogenase (IDH) mutation, the levels of the oncometabolite D-2 hydroxyglutarate (D-2HG) and its enantiomer L-2HG were elevated through glutamine anaplerosis. D-2HG, but not L-2HG, increased the trimethylation of histone H3 lysine 4 of the promoter region of ZEB1 , the master regulator of epithelial-mesenchymal transition (EMT), also increased the expression of the ZEB1 gene to directly induce EMT in colorectal cancer cells. Furthermore, they demonstrated that D-2HG levels to be elevated in colorectal cancer specimens, particularly in those associated with distant metastasis, supporting the observations in vitro and implicating the contribution of D-2HG in metastasis, the major cause of death in this disease.