Publications by authors named "Takuma Iwata"

5 Publications

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Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells.

Cancer Gene Ther 2021 Apr 8. Epub 2021 Apr 8.

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

Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.
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http://dx.doi.org/10.1038/s41417-021-00326-4DOI Listing
April 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.
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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.
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http://dx.doi.org/10.1038/s10038-020-00826-5DOI Listing
February 2021

Expression of circular RNA CDR1‑AS in colon cancer cells increases cell surface PD‑L1 protein levels.

Oncol Rep 2019 Oct 19;42(4):1459-1466. Epub 2019 Jul 19.

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

The expression of CDR1‑AS, a representative circular RNA, is closely linked with poor prognosis in gastrointestinal cancers, such as colon, liver, and pancreatic cancers. Although it is well known that CDR1‑AS antagonizes microRNA‑7 function through its sequence similarities in the brain, its biological function and link with the malignant potential of cancer cells remain unclear, partly due to the difficulties of ectopic expression of circular RNAs. In the present study, SW620, a colon cancer cell line that stably expresses CDR1‑AS RNA circularized, was established using the laccase 2 gene cassette, and its biological function associated with malignant behavior was determined. In contrast to previous studies, cell growth or invasion ability was not altered by CDR1‑AS expression. However, the expression levels of CMTM4 and CMTM6, which were recently recognized as critical regulators of PD‑L1 protein expression at the cell surface, were significantly increased. Accordingly, the cell surface PD‑L1 protein levels were increased in CDR1‑AS‑expressing cells. Notably, the effects were not canceled out by overexpressing microRNA‑7, indicating that the increase in cell surface PD‑L1 in CDR1‑AS‑expressing cells was not dependent on microRNA‑7 function. These results indicated that expression of this circular RNA in cancer cells may lead to poor prognosis by increasing cell surface PD‑L1 levels through microRNA‑7‑independent mechanisms.
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http://dx.doi.org/10.3892/or.2019.7244DOI Listing
October 2019

Inflammation and de-differentiation in pancreatic carcinogenesis.

World J Clin Cases 2018 Dec;6(15):882-891

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

Pancreatic cancer is a malignancy with an extremely poor prognosis. Chronic pancreatitis is a well-known risk factor for pancreatic cancer. Inflammation is thought to influence carcinogenesis through DNA damage and activation of intracellular signaling pathways. Many transcription factors and signaling pathways co-operate to determine and maintain cell identity at each phase of pancreatic organogenesis and cell differentiation. Recent studies have shown that carcinogenesis is promoted through the suppression of transcription factors related to differentiation. Pancreatitis also demonstrates transcriptional changes, suggesting that multifactorial epigenetic changes lead to impaired differentiation. Taken together, these factors may constitute an important framework for pancreatic carcinogenesis. In this review, we discuss the role of inflammation and de-differentiation in the development of pancreatic cancer, as well as the future of novel therapeutic applications.
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http://dx.doi.org/10.12998/wjcc.v6.i15.882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288496PMC
December 2018
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