Faculty Profiles - SUZUKI Hiroshi

Papers - SUZUKI Hiroshi

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Regulation of autophagy by transforming growth factor-beta (TGF beta) signaling Reviewed International journal

Hiroshi I. Suzuki, Kunihiko Kiyono, Kohei Miyazono

Autophagy Vol. 6 ( 5 ) page： 645 - 647 2010.7

Language：English Publishing type：Research paper (scientific journal) Publisher：LANDES BIOSCIENCE

Transforming growth factor-beta (TGF beta) has broad impacts on an array of diverse cellular functions including cell growth, differentiation, adhesion, migration and apoptosis. Perturbations of the TGF beta signaling pathways are involved in progression of various tumors. Autophagy is a pivotal response of normal and cancer cells to environmental stresses and is induced by various stimuli. Otherwise, autophagy has an intrinsic function in tumor suppression. Recently, we demonstrated that TGF beta induces autophagy in hepatocellular carcinoma cells and mammary carcinoma cells. Autophagy activation by TGF beta is mediated through the Smad and JNK pathways. We show that siRNA-mediated knockdown of autophagy genes suppresses the growth inhibitory function of TGF beta and that autophagy activation potentiates TGF beta-mediated induction of proapoptotic genes, Bim and Bmf, in hepatoma cells. In this context, the autophagy pathway might contribute to the growth inhibitory effect of TGF beta, in conjunction with other antiproliferative pathways downstream of TGF beta signaling. The context and manner by which the TGF beta signaling pathway regulates autophagy have implications for a better understanding of pathological and bidirectional roles of TGF beta signaling pathways in tumorigenesis.

DOI： 10.4161/auto.6.5.12046

Web of Science

PubMed

Erdheim-Chester disease: Multisystem involvement and management with interferon-alpha Reviewed International journal

Hiroshi I. Suzuki, Noriko Hosoya, Kiyoshi Miyagawa, Satoshi Ota, Hiroko Nakashima, Noriko Makita, Mineo Kurokawa

Leukemia Research Vol. 34 ( 1 ) page： E21 - E24 2010.1

Autophagy Is Activated by TGF-beta and Potentiates TGF-beta-Mediated Growth Inhibition in Human Hepatocellular Carcinoma Cells Reviewed International journal

Kunihiko Kiyono, Hiroshi I. Suzuki, Hironori Matsuyama, Yasuyuki Morishita, Akiyoshi Komuro, Mitsunobu R. Kano, Koichi Sugimoto, Kohei Miyazono

Cancer Research Vol. 69 ( 23 ) page： 8844 - 8852 2009.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell growth, differentiation, and apoptosis of various types of cells. Autophagy is emerging as a critical response of normal and cancer cells to environmental changes, but the relationship between TGF-beta signaling and autophagy has been poorly understood. Here, we showed that TGF-beta activates autophagy in human hepatocellular carcinoma cell tines. TGF-beta induced accumulation of autophagosomes and conversion of microtubule-associated protein I light chain 3 and enhanced the degradation rate of long-lived proteins. TGF-beta increased the mRNA expression levels of BECLIN1, ATG5, ATG7, and death-associated protein kinase (DAPK). Knockdown of Smad2/3, Smad4, or DAPK, or inhibition of c-Jun NH(2)-terminal kinase, attenuated TGF-beta-induced autophagy, indicating the involvement of both Smad and non-Smad pathway(s). TGF-beta activated autophagy earlier than execution of apoptosis (6-12 versus 48 h), and reduction of autophagy genes by small interfering RNA attenuated TGF-beta-mediated growth inhibition and induction of proapoptotic genes Bim and Bmf, suggesting the contribution of autophagy pathway to the growth-inhibitory effect of TGF-beta. Additionally, TGF-beta also induced autophagy in some mammary carcinoma cells, including MDA-MB-231 cells. These findings show that TGF-beta signaling pathway activates autophagy in certain human cancer cells and that induction of autophagy is a novel aspect of biological functions of TGF-beta. [Cancer Res 2009;69(23):8844-52]

DOI： 10.1158/0008-5472.CAN-08-4401

Web of Science

PubMed

c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma Reviewed International journal

Kunihiko Kiyono, Hiroshi I. Suzuki, Yasuyuki Morishita, Akiyoshi Komuro, Caname Iwata, Masakazu Yashiro, Kosei Hirakawa, Mitsunobu R. Kano, Kohei Miyazono

CANCER SCIENCE Vol. 100 ( 10 ) page： 1809 - 1816 2009.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-beta family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-beta signaling by dominant-negative TGF-beta type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-beta signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-beta type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-beta was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis. (Cancer Sci 2009; 100: 1809-1816).

DOI： 10.1111/j.1349-7006.2009.01248.x

Web of Science

PubMed

Modulation of microRNA processing by p53 Reviewed International journal

Hiroshi I. Suzuki, Kaoru Yamagata, Koichi Sugimoto, Takashi Iwamoto, Shigeaki Kato, Kohei Miyazono

Nature Vol. 460 ( 7254 ) page： 529 - U111 2009.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour suppressors and oncogenes in tumour development(1), a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis(2-4). This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between Drosha complex and p68, leading to attenuation of miRNA processing activity. These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.

DOI： 10.1038/nature08199

Web of Science

PubMed

Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor beta Signaling Reviewed International journal

Akiyoshi Komuro, Masakazu Yashiro, Caname Iwata, Yasuyuki Morishita, Erik Johansson, Yoshiko Matsumoto, Akira Watanabe, Hiroyuki Aburatani, Hiroyuki Miyoshi, Kunihiko Kiyono, Yo-taro Shirai, Hiroshi I. Suzuki, Kosei Hirakawa, Mitsunobu R. Kano, Kohei Miyazono

JOURNAL OF THE NATIONAL CANCER INSTITUTE Vol. 101 ( 8 ) page： 592 - 604 2009.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor beta (TGF-beta) expression and thick stromal fibrosis. However, the association of TGF-beta signaling with diffuse-type gastric carcinoma has not been investigated in detail.
We used a lentiviral infection system to express a dominant-negative TGF-beta type II receptor (dnT beta RII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided.
Expression of dnT beta RII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnT beta RII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnT beta RII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnT beta RII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues.
Disruption of TGF-beta signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.

DOI： 10.1093/jnci/djp058

Web of Science

PubMed

Resovist-enhanced MRI for preoperative assessment of colorectal hepatic metastases: a case of multiple bile duct hamartomas associated with colon cancer Reviewed

Hiroshi Suzuki, Giichiro Tsurita, Soichiro Ishihara, Masaaki Akahane, Joji Kitayama, Hirokazu Nagawa

Case Rep Gastroenterol Vol. 2 ( 3 ) page： 509 - 516 2008.9

Late-onset pneumatosis cystoides intestinalis associated with non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation. Reviewed

Hiroshi I Suzuki, Koji Izutsu, Takuro Watanabe, Kumi Oshima , Yoshinobu Kanda, Toru Motokura, Shigeru Chiba, Mineo Kurokawa

International Journal of Hematology Vol. 88 ( 1 ) page： 116 - 118 2008.7

Herpes simplex encephalitis and subsequent cytomegalovirus encephalitis after chemoradiotherapy for central nervous system lymphoma: a case report and literature review. Reviewed

Hiroshi I Suzuk, Akira Hangaishi, Noriko Hosoya, Takuro Watanabe , Yoshinobu Kanda, Toru Motokura, Shigeru Chiba, Mineo Kurokawa

International Journal of Hematology Vol. 87 ( 5 ) page： 538 - 541 2008.6

Antileukemic immunity associated with antineutrophil antibody production after allogeneic hematopoietic SCT for myeloid/NK-cell precursor acute leukemia. Reviewed

Hi Suzuki, T Suzuki, A Kamijo, S Oota, H Sato, A Hangaishi, T Takahashi, Y Kanda, T Motokura, S Chiba, M Kurokawa

Bone Marrow Transplantation Vol. 42 ( 4 ) page： 285 - 287 2008.5

Disseminated adenovirus disease by multiple adenovirus serotypes following allogeneic hematopoietic stem cell transplantation. Reviewed

Hiroshi I Suzuki, Takashi Asai, Kiyomi Okada, Yukumasa Kazuyama, Tsuyoshi Takahashi, Yoshinobu Kanda, Shigeru Chiba, Mineo Kurokawa

Biology of Blood and Marrow Transplantation Vol. 14 ( 3 ) page： 353 - 355 2008.5

Drug-induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia. Reviewed

Hiroshi I Suzuki, Takashi Asai, Zenshiro Tamaki, Akira Hangaishi, Shigeru Chiba, Mineo Kurokawa

Haematologica Vol. 93 ( 3 ) page： 469 - 470 2008.3

Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Reviewed

Masako Oka, Caname Iwata, Hiroshi I Suzuki, Kunihiko Kiyono, Yasuyuki Morishita, Tetsuro Watabe, Akiyoshi Komuro, Mitsunobu R Kano, Kohei Miyazono

Blood Vol. 111 ( 9 ) page： 4571 - 4579 2008.2

Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells. Reviewed

Kazuya Ogawa, Akira Saito, Hisanori Matsui, Hiroshi Suzuki, Satoshi Ohtsuka, Daisuke Shimosato, Yasuyuki Morishita, Tetsuro Watabe, Hitoshi Niwa, Kohei Miyazono

Journal of Cell Science Vol. 120 page： 55 - 65 2007.1

RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Reviewed

Hiroshi Takayanagi, Sunhwa Kim, Koichi Matsuo, Hiroshi Suzuki, Tomohiko Suzuki, Kojiro Sato, Taeko Yokochi, Hiromi Oda, Kozo Nakamura, Nobutaka Ida, Erwin F Wagner, Tadatsugu Taniguchi

Nature Vol. 416 ( 6882 ) page： 744 - 749 2002.4

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Papers - SUZUKI Hiroshi