Education 【 display / non-display 】

Education 【 display / non-display 】

• 1983

  -

  1985

  Gifu University   農学研究科獣医学専攻  

  　View Summary

  修士

• 1979

  -

  1983

  Gifu University   農学部   獣医学科  

Degree 【 display / non-display 】

Degree 【 display / non-display 】

• Doctor of Medical Science

Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

• 2009.04

  -

  Now

  日本分子生物学会

• 2004.04

  -

  Now

  日本臨床分子形態学会

• 1998.04

  -

  Now

  米国細胞生物学会

• 1995.04

  -

  Now

  日本細胞生物学会

• 1993.04

  　

  　

  日本癌学会

Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Cell biology  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   School of Medicine, Department of Cell Science, Institute of Cancer Research   Professor  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• 細胞生物学

• 実験病理学

• Cell Science

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• The roles of tight junction protein cingulin in human endometrioid endometrial cancer.

  Arisa Kura, Kimihito Saito, Takumi Konno, Takayuki Kohno, Hiroshi Shimada, Tadahi Okada, Soshi Nishida, Daichi Ishii, Motoki Matsuura, Tsuyoshi Saito, Takashi Kojima

  Tissue barriers     2361976 - 2361976  2024.06  [International journal]

  　View Summary

  The bicellular tight junction molecule cingulin (CGN) binds to microtubules in centrosomes. Furthermore, CGN contributes to the tricellular tight junction (tTJ) proteins lipolysis-stimulated lipoprotein receptor (LSR) and tricellulin (TRIC). CGN as well as LSR decreased during the malignancy of endometrioid endometrial cancer (EEC). Although tTJ protein LSR is involved in the malignancy of some cancers, including EEC, the role of CGN is unknown. In this study, we investigated the roles of CGN with tTJ proteins in human EEC cells by using the CGN-overexpressing EEC cell line Sawano. In 2D cultures, CGN was colocalized with LSR and TRIC at tTJ or at γ-tubulin-positive centrosomes. In immunoprecipitation with CGN antibodies, CGN directly bound to LSR, TRIC, and β-tubulin. Knockdown of CGN by the siRNA decreased the epithelial barrier and enhanced cell proliferation, migration and invasion, as well as knockdown of LSR. In the Sawano cells cocultured with normal human endometrial stromal cells, knockdown of CGN decreased expression of LSR and TRIC via MAPK and AMPK pathways. In 2.5D cultures, knockdown of CGN induced the formation of abnormal cysts and increased the permeability of FD-4 to the lumen. In 2D and 2.5D cultures, treatment with β-estradiol with or without EGF or TGF-β decreased CGN expression and the epithelial permeability barrier and enhanced cell migration, and pretreatment with EW7197+AG1478, U0126 or an anti-IL-6 antibody prevented this. In conclusion, CGN, with tTJ proteins might suppress the malignancy of human EEC and its complex proteins are sensitive to estrogen and growth factors derived from stromal cells.

  DOI PubMed

• The Roles and Regulatory Mechanisms of Tight Junction Protein Cingulin and Transcription Factor Forkhead Box Protein O1 in Human Lung Adenocarcinoma A549 Cells and Normal Lung Epithelial Cells.

  Daichi Ishii, Yuma Shindo, Wataru Arai, Takumi Konno, Takayuki Kohno, Kazuya Honda, Masahiro Miyajima, Atsushi Watanabe, Takashi Kojima

  International journal of molecular sciences   25 ( 3 )  2024.01  [International journal]

  　View Summary

  Tight junction (TJ) protein cingulin (CGN) and transcription factor forkhead box protein O1 (FOXO1) contribute to the development of various cancers. Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for some cancers. HDAC inhibitors affect the expression of both CGN and FOXO1. However, the roles and regulatory mechanisms of CGN and FOXO1 are unknown in non-small cell lung cancer (NSCLC) and normal human lung epithelial (HLE) cells. In the present study, to investigate the effects of CGN and FOXO1 on the malignancy of NSCLC, we used A549 cells as human lung adenocarcinoma and primary human lung epithelial (HLE) cells as normal lung tissues and performed the knockdown of CGN and FOXO1 by siRNAs. Furthermore, to investigate the detailed mechanisms in the antitumor effects of HDAC inhibitors for NSCLC via CGN and FOXO1, A549 cells and HLE cells were treated with the HDAC inhibitors trichostatin A (TSA) and Quisinostat (JNJ-2648158). In A549 cells, the knockdown of CGN increased bicellular TJ protein claudin-2 (CLDN-2) via mitogen-activated protein kinase/adenosine monophosphate-activated protein kinase (MAPK/AMPK) pathways and induced cell migration, while the knockdown of FOXO1 increased claudin-4 (CLDN-4), decreased CGN, and induced cell proliferation. The knockdown of CGN and FOXO1 induced cell metabolism in A549 cells. TSA and Quisinostat increased CGN and tricellular TJ protein angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) in A549. In normal HLE cells, the knockdown of CGN and FOXO1 increased CLDN-4, while HDAC inhibitors increased CGN and CLDN-4. In conclusion, the knockdown of CGN via FOXO1 contributes to the malignancy of NSCLC. Both HDAC inhibitors, TSA and Quisinostat, may have potential for use in therapy for lung adenocarcinoma via changes in the expression of CGN and FOXO1.

  DOI PubMed

• The interplay between the epithelial permeability barrier, cell migration and mitochondrial metabolism of growth factors and their inhibitors in a human endometrial carcinoma cell line.

  Takumi Konno, Takayuki Kohno, Shin Kikuchi, Arisa Kura, Kimihito Saito, Tadahi Okada, Hiroshi Shimada, Yuya Yamazaki, Tomoki Sugiyama, Motoki Matsuura, Yuki Ohsaki, Tsuyoshi Saito, Takashi Kojima

  Tissue barriers     2304443 - 2304443  2024.01  [International journal]

  　View Summary

  It is known that there are abnormalities of tight junction functions, cell migration and mitochondrial metabolism in human endometriosis and endometrial carcinoma. In this study, we investigated the effects of growth factors and their inhibitors on the epithelial permeability barrier, cell migration and mitochondrial metabolism in 2D and 2.5D cultures of human endometrioid endometrial carcinoma Sawano cells. We also investigated the changes of bicellular and tricellular tight junction molecules and ciliogenesis induced by these inhibitors. The growth factors TGF-β and EGF affected the epithelial permeability barrier, cell migration and expression of bicellular and tricellular tight junction molecules in 2D and 2.5D cultures of Sawano cells. EW-7197 (a TGF-β receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-β and EGF in 2D and 2.5D cultures. EW-7197 and AG1478 induced ciliogenesis in 2.5D cultures. In conclusion, TGF-β and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer.

  DOI PubMed

• Downregulation of angulin-1/LSR induces malignancy via upregulation of EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma A549 cells.

  Wataru Arai, Takumi Konno, Takayuki Kohno, Yuki Kodera, Mitsuhiro Tsujiwaki, Yuma Shindo, Hirofumi Chiba, Masahiro Miyajima, Yuji Sakuma, Atsushi Watanabe, Takashi Kojima

  Oncotarget   14   261 - 275  2023.03  [International journal]

  　View Summary

  Abnormal expression of bicellular tight junction claudins, including claudin-2 are observed during carcinogenesis in human lung adenocarcinoma. However, little is known about the role of tricellular tight junction molecule angulin-1/lipolysis-stimulated lipoprotein receptor (LSR). In the lung adenocarcinoma tissues examined in the present study, expression of claudin-2 was higher than in normal lung tissues, while angulin-1/LSR was poorly or faintly expressed. We investigated how loss of angulin-1/LSR affects the malignancy of lung adenocarcinoma cell line A549 and normal human lung epithelial (HLE) cells. The EGF receptor tyrosine kinase inhibitor AG1478 prevented the increase of claudin-2 expression induced by EGF in A549 cells. Knockdown of LSR induced expression of claudin-2 at the protein and mRNA levels and AG1478 prevented the upregulation of claudin-2 in A549 cells. Knockdown of LSR induced cell proliferation, cell migration and cell metabolism in A549 cells. Knockdown of claudin-2 inhibited the cell proliferation but did not affect the cell migration or cell metabolism of A549 cells. The TGF-β type I receptor inhibitor EW-7197 prevented the decrease of LSR and claudin-2 induced by TGF-β1 in A549 cells and 2D culture of normal HLE cells. EW-7197 prevented the increase of cell migration and cell metabolism induced by TGF-β1 in A549 cells. EW-7197 prevented the increase of epithelial permeability of FITC-4kD dextran induced by TGF-β1 in 2.5D culture of normal HLE cells. In conclusion, downregulation of angulin-1/LSR induces malignancy via EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma.

  DOI PubMed

• Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells.

  Takayuki Kohno, Takashi Kojima

  Cancers   14 ( 20 )  2022.10  [International journal]

  　View Summary

  Macropinocytosis is an essential mechanism for the non-specific uptake of extracellular fluids and solutes. In recent years, additional functions have been identified in macropinocytosis, such as the intracellular introduction pathway of drugs, bacterial and viral infection pathways, and nutritional supplement pathway of cancer cells. However, little is known about the changes in cell function after macropinocytosis. Recently, it has been reported that macropinocytosis is essential for endometrial cancer cells to initiate malignant progression in a dormant state. Macropinocytosis is formed by a temporary split of adjacent bicellular junctions of epithelial sheets, rather than from the apical surface or basal membrane, as a result of the transient reduction of tight junction homeostasis. This novel type of macropinocytosis has been suggested to be associated with the malignant pathology of endometriosis and endometrioid endometrial carcinoma. This review outlines the induction of malignant progression of endometrial cancer cells by macropinocytosis based on a new mechanism and the potential preventive mechanism of its malignant progression.

  DOI PubMed

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• 肺腺癌におけるタイト結合分子cingulinおよび転写因子FOXO1の役割

  石井 大智, 進藤 悠真, 新井 航, 金野 匠, 幸野 貴之, 宮島 正博, 小島 隆, 渡辺 敦

  肺癌 ( (NPO)日本肺癌学会 )  62 ( 6 ) 635 - 635  2022.11

• 正常ヒト肺上皮細胞におけるTGF-βとHDAC阻害剤のタイト結合分子および上皮バリアへの影響

  進藤 悠真, 新井 航, 金野 匠, 幸野 貴之, 宮島 正博, 小島 隆, 渡辺 敦

  日本呼吸器外科学会雑誌 ( (一社)日本呼吸器外科学会 )  35 ( 3 ) RO18 - 3  2021.05

• タイト結合分子Cluadin-2をターゲットにした子宮内膜癌治療のin vitroにおける検討

  嶋田 浩志, 岡田 匡氷, 金野 匠, 幸野 貴之, 松浦 基樹, 郷久 晴朗, 岩崎 雅宏, 小島 隆, 齋藤 豪

  日本婦人科腫瘍学会雑誌 ( (公社)日本婦人科腫瘍学会 )  39 ( 1 ) 285 - 285  2021.01

• タイト結合による子宮内膜の悪性化制御機序

  郷久 晴朗, 嶋田 浩志, 岩崎 雅宏, 染谷 真行, 金野 匠, 菊池 真, 幸野 貴之, 玉手 雅人, 松浦 基樹, 小島 隆, 齋藤 豪

  北日本産科婦人科学会総会・学術講演会プログラム・抄録集 ( 東北連合産科婦人科学会・北日本産科婦人科学会 )  67回   36 - 36  2019.09

• 子宮内膜悪性化におけるタイト結合分子claudin-2の関与

  郷久 晴朗, 嶋田 浩志, 岩崎 雅宏, 秋元 太志, 西村 庸子, 玉手 雅人, 寺田 倫子, 松浦 基樹, 金野 匠, 幸野 貴之, 小島 隆, 齋藤 豪

  日本婦人科腫瘍学会雑誌 ( (公社)日本婦人科腫瘍学会 )  37 ( 3 ) 497 - 497  2019.06

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Awards 【 display / non-display 】

Awards 【 display / non-display 】

• 秋山財団 一般助成

  2005  

• 日本臨床分子形態学会論文賞

  2005  

• 日本臨床電子顕微鏡学会奨励賞

  2004  

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• 唾液腺免疫性疾患における腺機能障害に対する基礎的研究

  基盤研究(C)

  Project Year :

  2021.04

  -

  2024.03

   

  高野 賢一, 小島 隆, 一宮 慎吾, 亀倉 隆太

  　View Summary

  すでに確立しているヒト唾液腺腺管上皮細胞の培養系を用いて、タイト結合分子の中でも特にcutokinesisにおけるlipolysis-stimulated lipoprotein receptor (LSR)およびtricellulinに着目した。現在のところ、 2細胞間タイト結合分子であるoccludin, claudin-7, zonula occludens-1 cingulinや極性に関与するPAR3が、cytokinesisにおいて発現増強し、上皮バリア機能も保たれ、LSRやtricellulin がアセチル化チューブリン陽性中央体やガンマチューブリン陽性中心体にHook2とともに認められた。Hook2をノックダウンすると上皮バリア機能低下や関連分子の発現が中心体から消失した。LSRの多様な機能が示唆されている。

• Analyses of malignant mechanisms via abnormality of novel multifunctional tricellular junction molecules in cancer cells

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2019.04

  -

  2022.03

   

  Kojima Takashi

  　View Summary

  Multifunctional tricellular junction molecule angulin-1/LSR maintains the epithelial barrier and induces stability of the collecting cells. Its expression contributes to the malignancy of cancer cells via the binding effects with various functional molecules at tricellular contacts. We performed a multilateral analysis for the regulatory mechanisms and the roles LSR/ASPP2/PAR3/YAP complex proteins in normal human cells and cancer. As result, in various cancer cells, angulin-1/LSR is regulated via multiple intercellular signaling and prevents the malignancy.

• 膵管内乳頭粘液性腫瘍の新規マウスモデルで発見された病態分子の臨床応用的機能解明

  基盤研究(C)

  Project Year :

  2018.04

  -

  2022.03

   

  山口 洋志, 小島 隆, 竹政 伊知朗, 木村 康利, 今村 将史, 永山 稔, 及能 大輔

  　View Summary

  膵管内乳頭粘液性腫瘍（Intraductal papillary mucinous neoplasm: IPMN）は膵腫瘍性嚢胞の最多を占める疾患であり、経時的に腺腫から非浸潤癌、浸潤癌と進行し、浸潤癌まで進行すると予後不良となる。しかし、その正確な悪性度や進行度の評価は困難であり、現状では画像所見や臨床徴候から予測しているが、治療方針を決定する上で大きな問題となる場合がある。そのため、IPMNの病態を反映する新規診断・治療標的分子の同定が急務であると考えられる。 本研究は、IPMNの発生に密接に関与する変異GNAS遺伝子を、任意のタイミングで膵臓特異的に発現させることができ、IPMNが発生する新規遺伝子改変マウスから得られた知見を基盤としている。この変異GNAS遺伝子によって発現誘導される病態関連分子に関して、ヒトIPMNにおける機能を明らかにし、新規診断・治療標的分子となり得るのか、その臨床応用的意義を明らかにすることを最終目的としている。これまでの研究活動スタート支援(16H07095)の成果から、主にIL(インターロイキン)-1ファミリーとSOX転写因子等に注目した解析を行っている。 当科におけるIPMN切除例のデータベースを作成し、臨床・病理学的特徴や手術成績、長期予後を明らかにした。さらに、術後死亡、疾患特異的死亡と関連する因子を同定し解析を進めている。腺腫病変と浸潤癌病変では切除後の予後が有意に異なることから、腺腫病変と浸潤癌病変を選んで、上記病態関連分子を中心に免疫染色を進め、病態分子発現状態の違いを解明している。In vitro解析として、IL-1ファミリーとSOX転写因子の発現調節機構に関して、GNAS遺伝子下流のシグナル伝達経路に注目し、薬理学的刺激や阻害による病態分子の変化をリアルタイムPCRや蛍光免疫染色で解析している。

• The mechanisms of salivary gland fibrosis in IgG4-related disease

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2018.04

  -

  2021.03

   

  Takano Kenichi

  　View Summary

  The aim of this study was to investigate the mechanisms driving fibrosis in the submandibular glands (SMG) of patients with IgG4-related disease (IgG4-RD). Our results suggest fibrosis in the SMG of affected patients is closely linked to the proliferation of fibroblasts following induction of IL-6 and WISP1 by inflammatory cytokines. The Th2 cytokines TSLP and IL-33 are also upregulated in affected SMG, and thus may cause chronic inflammation and IgG4 accumulation.

• Characterization of distal airway stem-like cells expressing N-terminally truncated p63 and thyroid transcription factor-1 in the human lung

  Grant-in-Aid for Young Scientists (B)

  Project Year :

  2017.04

  -

  2019.03

   

  Tanaka Yusuke, HIRAI sachie, YAMAGUCHI miki, SUMI toshiyuki, TADA makoto, SAITO atsushi, CHIBA hirofumi, KOJIMA takashi, WATANABE atsushi, TAKAHASHI hiroki, SAKUMA yuji

  　View Summary

  We found that human lung epithelial (HuL) cells, derived from normal, peripheral lung tissue, in monolayer, mostly express both the N-terminally truncated isoform of p63 (delta Np63), a marker for airway basal cells, and thyroid transcription factor-1 (TTF-1), a marker for alveolar epithelial cells, even though these two molecules are usually expressed in a mutually ex- clusive way. Three-dimensionally cultured HuL cells differentiated to form bronchiole-like and alveolus-like organoids. We also uncovered a few bronchiolar epithelial cells expressing both delta Np63 and TTF-1 in the human lung, suggesting that these cells are the cells of origin for HuL cells. Taken together, delta Np63+ TTF-1+ peripheral airway epithelial cells are possibly the human counterpart of mouse DASCs and may offer potential for future regenerative medicine.

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