Faculty Profiles - SAKAGUCHI Masakiyo

MISC - SAKAGUCHI Masakiyo

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BRPK/PINK1のmTORC2経路活性化を介したがん進展への寄与(BRPK/PINK1 promotes tumor progression through activation of mTORC2 pathway)

村田等, 阪口政清, 金玉, 片岡健, 許南浩

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 83回・33回 4P - 0934 2010.12

Internalization of REIC/Dkk-3 protein by induced pluripotent stem cell-derived embryoid bodies and extra-embryonic tissues

Ken Kataoka, Masakiyo Sakaguchi, Kun Peng Li, Chika Taketa, Ken-Ichi Yamamoto, Gang Du, Hiroaki Funahashi, Hitoshi Murata, Nam-Ho Huh

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 26 ( 6 ) 853 - 859 2010.12

Language：English Publisher：SPANDIDOS PUBL LTD

REIC/Dkk-3 was first identified as a down-regulated gene in a number of human immortalized cells and human tumor-derived cell lines. Overexpression of the REIC/Dkk-3 gene using an adenovirus vector (Ad-REIC) has showed a potent selective therapeutic effect on various human cancers through induction of ER stress. Furthermore, we recently showed that Ad-REIC has an indirect host-mediated anti-tumor activity by induction of IL-7. However, the physiological function of REIC/Dkk-3 is still unclear. As a first step to study the possible receptor(s) for secreted REIC/Dkk-3, we analyzed the internalization of Cy3-labeled recombinant REIC/Dkk-3 protein. Among the cell lines screened, mouse induced pluripotent stem (iPS) cells showed a unique pattern of internalization. The internalization was observed in peripheral cells of spherical colonies formed spontaneously, but not in undifferentiated iPS cells. When we analyzed embryoid bodies (EBs) derived from iPS cells, REIC/Dkk-3 protein was internalized specifically by differentiated cells located at the periphery of EBs. Interestingly, Dkk-1 was internalized by undifferentiated cells at the center of the EBs. When developmental tissue was analyzed, internalization of REIC/Dkk-3 protein was strictly limited to extra-embryonic tissue, such as the trophectoderm layer of 4.5 days post-coitus (dpc) blastocysts and the chorionic membrane at 16.5 dpc. The mechanism of the internalization was confirmed to be endocytosis. These findings will contribute to knowledge on the interaction of REIC/Dkk-3 with a possible receptor(s).

DOI： 10.3892/ijmm_00000534

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Transcriptional regulation of a brown adipocyte-specific gene, UCP1, by KLF11 and KLF15

Ken-ichi Yamamoto, Masakiyo Sakaguchi, Reinhold J. Medina, Aya Niida, Yoshihiko Sakaguchi, Masahiro Miyazaki, Ken Kataoka, Nam-ho Huh

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 400 ( 1 ) 175 - 180 2010.9

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Several growth factors and transcription factors have been reported to play important roles in brown adipocyte differentiation and modulation of thermogenic gene expression, especially the expression of UCP1. In this study, we focused on KLF11 and KLF15, which were expressed highly in brown adipose tissue. Our data demonstrated that KLF11 and KLF15 interacted directly with the UCP1 promoter using GC-box and GT-boxes, respectively. Co-transfection of KLF11 and KLF15 in the mesenchymal stem cell line muBM3.1 during brown adipocyte differentiation enhanced the expression level of UCP1. KLF11, but not KLF15, was essential for UCP1 expression during brown adipocyte differentiation of muBM3.1. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2010.08.039

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アデノウイルス受容体(CAR;CXADR)の固形癌細胞の増殖制御における役割の解析(Biological role of Coxsackievirus and Adenovirus Receptor (CXADR) in cancer cell proliferation)

小屋恵理子, 阪口政清, 松井誠, 冨田勇樹, 許南浩, 近藤英作

日本癌学会総会記事 69回 268 - 268 2010.8

スキルス胃がん腹膜播種へのREIC/Dkk-3遺伝子治療の効果(REIC/Dkk-3 gene therapy suppresses peritoneal dissemination of scirrhous gastric carcinoma)

片岡健, タン・スエスエ, 阪口政清, アバルスァ・フェルナンド, 村田等, 八代正和, 那須保友, 公文裕巳, 許南浩

日本癌学会総会記事 69回 252 - 253 2010.8

新規がん抑制遺伝子REIC/Dkk-3の増殖性皮膚疾患での発現減少(Reduced expression of REIC/Dkk-3, a putative tumor suppressor gene, in hyperproliferative epidermis)

杜剛, 片岡健, 阪口政清, 牧野輝彦, 清水忠道, 許南浩

日本癌学会総会記事 69回 316 - 316 2010.8

マウス骨髄間葉系幹細胞の褐色脂肪分化をKLF11およびKLF15は促進する

片岡健, 山本健一, 阪口政清, HUH Nam‐ho

硬組織再生生物学会学術大会・総会プログラム・抄録集 19th 40 2010.7

Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3

Ryuta Tanimoto, Masakiyo Sakaguchi, Fernando Abarzua, Ken Kataoka, Kaoru Kurose, Hitoshi Murata, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

INTERNATIONAL JOURNAL OF CANCER 126 ( 7 ) 1562 - 1569 2010.4

Language：English Publisher：JOHN WILEY & SONS INC

We have recently shown that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) exhibits a potent tumor-specific cell-killing function for various human cancers. It has also become evident that some human cancers are resistant to Ad-REIC-induced apoptosis. The aim of the present study was to determine the molecular mechanisms of resistance to Ad-REIC. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. Infection efficiency of the adenovirus vector and expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By screening for alteration in levels and functional status of proteins involved in Ad-REIC-induced apoptosis, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. Expression levels of BiP and rates of apoptosis induced by Ad-REIC were inversely correlated. Down-regulation of BiP with siRNA sensitized the resistant cells to Ad-REIC in vivo as well as in culture. These results indicate that BiP is a major determinant of resistance to Ad-REIC-induced apoptosis. Thus BiP is useful for diagnosis of inherent and acquired resistance of cancers and also as a target molecule to overcome resistance to the gene therapeutic Ad-REIC.

DOI： 10.1002/ijc.24764

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分化誘導したマウスES細胞及びiPS細胞におけるCy3標識REIC/Dkk‐3タンパク質のエンドサートーシスによる取り込み

片岡健, 阪口政清, LI Kun Peng, DU Gang, 武田千佳, 舟橋弘晃, 村田等, HUH Nam‐Ho

組織培養研究 29 ( 1 ) 74 - 74 2010.3

褐色脂肪細胞分化におけるKLF11とKLF15の役割

山本健一, 阪口政清, MEDINA Reinhold, 新居田彩, 宮崎正博, 片岡健, HUH Nam‐Ho

組織培養研究 29 ( 1 ) 82 2010.3

関節症性乾癬におけるバイオマーカーとしての血清S100A8/A9蛋白

青地聖子, 辻和英, 阪口政清, 許南浩, 津田達也, 山西清文, 小宮根真弓, 岩月啓氏

日本皮膚科学会雑誌 120 ( 3 ) 691 2010.3

S100A11, a dual growth regulator of epidermal keratinocytes.

Sakaguchi M, Huh NH

Amino Acids 1111 - 1111 2010

BRPK/PINK1のmTORC2経路活性化を介したがん浸潤への寄与(BRPK/PINK1 enhances invasiveness of cancer cells trough activation of mTORC2 pathway)

村田等, 阪口政清, 片岡健, 許南浩

日本癌学会総会記事 68回 205 - 205 2009.8

Overexpression of REIC/Dkk-3 in Normal Fibroblasts Suppresses Tumor Growth via Induction of Interleukin-7

Masakiyo Sakaguchi, Ken Kataoka, Fernando Abarzua, Ryuta Tanimoto, Masami Watanabe, Hitoshi Murata, Swe Swe Than, Kaoru Kurose, Yuji Kashiwakura, Kazuhiko Ochiai, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh

JOURNAL OF BIOLOGICAL CHEMISTRY 284 ( 21 ) 14236 - 14244 2009.5

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through a mechanism triggered by endoplasmic reticulum stress. Adenovirus vectors show no target cell specificity and thus may elicit unfavorable side effects through infection of normal cells even upon intra-tumoral injection. In this study, we examined possible effects of Ad-REIC on normal cells. We found that infection of normal human fibroblasts (NHF) did not cause apoptosis but induced production of interleukin (IL)-7. The induction was triggered by endoplasmic reticulum stress and mediated through IRE1 alpha, ASK1, p38, and IRF-1. When Ad-REIC-infected NHF were transplanted in a mixture with untreated human prostate cancer cells, the growth of the cancer cells was significantly suppressed. Injection of an IL-7 antibody partially abrogated the suppressive effect of Ad-REIC-infected NHF. These results indicate that Ad-REIC has another arm against human cancer, an indirect host-mediated effect because of overproduction of IL-7 by mis-targeted NHF, in addition to its direct effect on cancer cells.

DOI： 10.1074/jbc.M808002200

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BRPK/PINK1のmTORC2活性化を介したがん進展への寄与

村田等, 阪口政清, 片岡健, 許南浩

組織培養研究 28 ( 1 ) 66 - 66 2009.3

Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression

Masami Watanabe, Yuji Kashiwakura, Peng Huang, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Munenori Takaoka, Yasutomo Nasu, Masakiyo Sakaguchi, Nam-Ho Huh, Hiromi Kumon

INTERNATIONAL JOURNAL OF ONCOLOGY 34 ( 3 ) 657 - 663 2009.3

Language：English Publisher：SPANDIDOS PUBL LTD

The REIC/Dkk-3 gene has been reported to be a tumor suppressor and the expression is significantly down-regulated in a broad range of cancer cell types. The protein is secretory, but the physiological function remains unclear. This study demonstrated that recombinant REIC/Dkk-3 protein induced the differentiation of human CD14(+) monocytes into a novel cell type ((REIC/Dkx-3)Mo). (REIC/Dkk-3)Mo resembles immature dendritic cells generated with IL-4 and GM-CSF. Both these cell populations exhibit similar proportions of CD11c(+), CD40(+), CD86(+) and HLA-DR(+) cells and endocytic capacity, but (REIC/Dkk-3)Mo is negative for CD1a antigen. An analysis of the signal transducers and activators of transcription (STAT) pathways revealed that REIC/Dkk-3 induces phosphorylation of STAT 1 and STAT 3. Furthermore, intratumoral administration of REIC/Dkk-3 protein significantly suppressed tumor growth with CD11c(+) and CD8(+) (dendritic and killer T cell marker, respectively) cell accumulation and enhanced anticancer cytolytic activity of splenocytes. These data indicated a cytokine-like role of REIC/Dkk-3 protein in monocyte differentiation that might be exploited therapeutically.

DOI： 10.3892/ijo_00000191

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分化したマウスES細胞およびiPS細胞のCy3標識REIC/Dkk‐3タンパク質の取り込み

片岡健, 阪口政清, 李坤鵬, 武田千佳, 山本健一, 許南浩

再生医療 8 223 2009.2

REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

K. Kawasaki, M. Watanabe, M. Sakaguchi, Y. Ogasawara, K. Ochiai, Y. Nasu, H. Doihara, Y. Kashiwakura, N-h Huh, H. Kumon, H. Date

CANCER GENE THERAPY 16 ( 1 ) 65 - 72 2009.1

Language：English Publisher：NATURE PUBLISHING GROUP

The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH(2)-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.

DOI： 10.1038/cgt.2008.58

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Suppression of Carbon Tetrachloride-Induced Liver Fibrosis by Transplantation of a Clonal Mesenchymal Stem Cell Line Derived From Rat Bone Marrow

Marhaen Hardjo, Masahiro Miyazaki, Masakiyo Sakaguchi, Takuro Masaka, Sukaeni Ibrahim, Ken Kataoka, Narn-ho Huh

CELL TRANSPLANTATION 18 ( 1 ) 89 - 99 2009

Language：English Publisher：COGNIZANT COMMUNICATION CORP

Transplantation of hepatocytes or bone marrow-derived cells has been shown to ameliorate liver fibrosis in animal models, but no direct comparison of relative efficiency has been made. The aim of this study was to compare the efficiency of a bone marrow-derived clonal mesenchymal stem cell line established by LIS (rBM25/S3) with that of its adipogenic or hepatogenic differentiation derivative for Suppression of rat liver fibrosis. After induction of differentiation of rBM25/S3 cells into adipogenic or hepatogenic cells in Culture, we intrasplenically transplanted the three types of cells into rats (3 x 10(7) cells/rat) before and 4 weeks after initiation of carbon tetrachloride treatment (1 ml/kg body weight twice a week for 8 weeks) to induce liver fibrosis. Undifferentiated rBM25/S3 cells were the most effective for suppression of liver fibrosis, followed by the adipogenic cells and hepatogenic cells. Expression levels of MMP-2 and MMP-9 were also highest in undifferentiated rBM25/S3 cells. These results indicate that bone marrow-derived clonal mesenchymal stem cell lines are useful for further mechanistic studies on cell-mediated suppression of liver fibrosis and that such cell lines will provide information on an appropriate cell source for transplantation therapy for cirrhosis.

DOI： 10.3727/096368909788237140

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REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of interleukin-7.

Chen J, Watanabe M, Huang P, Sakaguchi M, Ochiai K, Nasu Y, Ouchida M, Huh NH, Shimizu K, Kashiwakura Y, Kaku H, Kumon H

Int J Mol Med 24 ( 6 ) 789 - 794 2009

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MISC - SAKAGUCHI Masakiyo