Golgi-ER-stress response and self-renewal of cancer stem cells - its molecular mechanism

• Project/Area Number: 24590472
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Akita University
• Principal Investigator: OMORI YASUFUMI 秋田大学, 医学(系)研究科(研究院), 教授 (90323138)
• Co-Investigator(Kenkyū-buntansha): YOSHIOKA Toshiaki 秋田大学, 医学部, 講師 (80302264) ; YAMAMOTO Yohei 秋田大学, 大学院医学系研究科, 助教 (70400512) ; 榎本 克彦 秋田大学, 医学(系)研究科(研究院), 教授 (20151988)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: コネキシン / 癌幹細胞 / 小胞体ストレス / ゴルジ体ストレス / ATF6α / がん進展 / 癌進展 / 転移

Outline of Final Research Achievements

While connexin protein is localized in the plasma membrane in normal cells, it often translocates into and excessively accumulates in Golgi apparatuses in cancer cells. A large amount of connexin protein in Golgi apparatuses enhances activation of ATF6α protein, followed by translocation of the active ATF6α into the nucleus. Eventually, the active ATF6α functions as a transcription factor for the mRNA of GRP78 protein, which helps cancer stem cells to overcome pro-apoptotic endoplasmic reticulum stress. These sequential molecular events contribute to cancer progression and may thus become a new target for cancer control.

Research Products

• [Journal Article] 舌癌細胞の悪性度を規定するConnexin26の細胞内局在 (2015)
  • Author(s): 飯川延子，大森泰文，本田耕平，榎本克彦，石川和夫
  • Journal Title: 耳鼻咽喉科ニューロサイエンス Volume: 29
  • Open Access
• [Journal Article] Dysfunction in gap junction intercellular communication induces aberrant behavior of the inner cell mass and frequent collapses of expanded blastocysts in mouse embyos. (2015)
  • Author(s): Togashi K, Kumagai J, Sato E, Shirasawa H, Shimoda Y, Makino K, Sato W, Kumazawa Y, Omori Y, Terada, Y.
  • Journal Title: J. Assist. Reprod. Genet. Volume: 32 Issue: 6 Pages: 969-976
  • DOI: 10.1007/s10815-015-0479-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic angiomyolipoma: differential diagnosis from other liver tumors in a special reference to vascular imaging - importance of early drainage vein. (2015)
  • Author(s): Yoshioka M, Watanabe G, Uchinami H, Kudoh K, Hiroshima Y, Yoshioka T, Nanjo H, Funaoka M, Yamamoto Y.
  • Journal Title: Surg. Case Rep. Volume: 1 Issue: 1 Pages: 11-11
  • DOI: 10.1186/s40792-014-0008-y
  • Peer Reviewed / Open Access
• [Journal Article] The Transformation of a Nonfunctioning Islet Cell Tumor of the Pancreas into a Proinsulinoma under Conditions of Lung Metastasis (2015)
  • Author(s): Yoshioka M, Shibata S, Uchinami H, Watanabe G, Miyazawa H, Iida M, Yoshida M, Yoshioka T, Nanjo H, Yamamoto Y.
  • Journal Title: Internal Medicine Volume: 54 Issue: 7 Pages: 785-790
  • DOI: 10.2169/internalmedicine.54.3772
  • NAID: 130005063214
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Rapid immunohistochemistry based on alternating current electric field for intraoperative diagnosis of brain tumors. (2015)
  • Author(s): Tanino M, Sasajima T, Nanjo H, Akesaka S, Kagaya M, Kimura T, Ishida Y, Oda M, Takahashi M, Sugawara T, Yoshioka T, Nishihara H, Akagami Y, Goto A, Minamiya Y, Tanaka S; R-IHC Study Group.
  • Journal Title: Brain Tumor Pathol. Volume: 32 Issue: 1 Pages: 12-19
  • DOI: 10.1007/s10014-014-0188-y
  • NAID: 120005682120
  • Peer Reviewed / Open Access
• [Journal Article] ギャップ結合の破綻と癌幹細胞の自己複製亢進―その病理学的意義 (2014)
  • Author(s): 大森泰文
  • Journal Title: 秋田医学 Volume: 41 Pages: 63-69
  • NAID: 110009864433
  • Acknowledgement Compliant
• [Journal Article] IMP3 RNP safe houses prevent miRNA-directed HMGA2 mRNA decay in cancer and development. (2014)
  • Author(s): Jonson L, Christiansen J, Hansen TV, Vikesa J, Yamamoto Y, Nielsen FC.
  • Journal Title: Cell Rep. Volume: 7 Issue: 2 Pages: 539-551
  • DOI: 10.1016/j.celrep.2014.03.015
  • Peer Reviewed / Open Access
• [Journal Article] Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction (2014)
  • Author(s): Chen M, Zhang Y, Yu V C, Chong Y-S , Yoshioka T and Ge R
  • Journal Title: Cell Death Differ. Volume: 21(5) Issue: 5 Pages: 797-810
  • DOI: 10.1038/cdd.2014.3
  • Peer Reviewed
• [Journal Article] β4 Integrin signaling induces expansion of prostate tumor progenitors, "Beyond the Abstract" (2013)
  • Author(s): Yoshioka, T., Otero, J. and Giancotti, FG.
  • Journal Title: Uro Today Volume: -
• [Journal Article] β4 integrin signaling induces expansion of prostate tumor progenitors. (2013)
  • Author(s): Yoshioka, T., Otero, J., Chen, Y., Kim, Y.M., Koutcher, J.A., Satagopan, J., Reuter, V., Carver, B., de Stanchina, E., Enomoto, K., Greenberg, N.M., Scardino, P.T., Scher, H.I. et al.
  • Journal Title: J. Clin. Invest. Volume: 123 Pages: 682-699
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor-α promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro. (2013)
  • Author(s): Nishikawa Y, Sone M, Nagahama Y, Kumagai E, Doi Y, Omori Y, Yoshioka T, Tokairin T, Yoshida M, Yamamoto Y, Ito A, Sugiyama T, Enomoto K.
  • Journal Title: J Cell Biochem Volume: 114 Issue: 4 Pages: 831-843
  • DOI: 10.1002/jcb.24424
  • NAID: 120006522736
  • Peer Reviewed
• [Journal Article] 肝前駆細胞由来胆管上皮と肝外胆管前駆細胞由来胆管上皮の胆道系での接点 (2013)
  • Author(s): 榎本克彦，山本洋平，鈴木麻弥，吉岡年明，大森泰文，曽根正行，西川祐司
  • Journal Title: 肝胆膵 Volume: 66 Pages: 613-621
• [Journal Article] Recovery of mature hepatocytic phenotype following bile ductular transdifferentiation of rat hepatocytes in vitro (2012)
  • Author(s): Sone M, Nishikawa Y, et al.
  • Journal Title: Am J Pathol Volume: 181 Issue: 6 Pages: 2094-2104
  • DOI: 10.1016/j.ajpath.2012.08.034
  • NAID: 120006658774
  • Peer Reviewed
• [Journal Article] MRGD, a MAS-related G-protein Coupled Receptor, Promotes Tumorigenisis and Is Highly Expressed in Lung Cancer (2012)
  • Author(s): S. Nishimura, M. Uno, Y. Kaneta, K. Fukuchi, H. Nishigohri, J. Hasegawa, H. Komori H, S. Takeda, K. Enomoto, F. Nara, T. Agatsuma
  • Journal Title: PLoS One Volume: 7 Issue: 6 Pages: e38618-e38618
  • DOI: 10.1371/journal.pone.0038618
  • Peer Reviewed
• [Journal Article] The gap junction channel protein connexin 43 is covalently modified and regulated by SUMOylation. (2012)
  • Author(s): Kjenseth, A., Fykerud, T.A., Sirnes, S., Bruun, J., Yohannes, Z., Kolberg, M., Omori, Y., Rivedal, E. and Leithe, E.
  • Journal Title: J. Biol. Chem. Volume: 287 Issue: 19 Pages: 15851-15861
  • DOI: 10.1074/jbc.m111.281832
  • Peer Reviewed
• [Journal Article] Smad ubiquitination regulatory factor-2 controls gap junction intercellular communication by modulating endocytosis and degradation of connexin43. (2012)
  • Author(s): Fykerud, T.A., Kjenseth, A., Schink, K.O., Sirnes, S., Bruun, J., Omori, Y., Brech, A., Rivedal, E. and Leithe, E.
  • Journal Title: J. Cell Sci. Volume: 125 Pages: 3966-3976
  • DOI: 10.1242/jcs.093500
  • Peer Reviewed
• [Journal Article] Effective use of gemcitabine in the treatment of undifferentiated carcinoma with osteoclast-like giant cells of the pancreas with portal vein tumor thrombus. (2012)
  • Author(s): Yoshioka, M., Uchinami, H., Watanabe, G., Takahashi, T., Nakagawa, Y., Andoh, H., Yoshioka, T., Nanjo, H. and Yamamoto, Y.
  • Journal Title: Intern. Med. Volume: 51 Pages: 2145-2150
  • NAID: 130002062303
  • Peer Reviewed
• [Journal Article] 肝再生と類洞内皮細胞 (2012)
  • Author(s): 榎本克彦，山本洋平，吉岡年明，大森泰文，西川祐司
  • Journal Title: 生化学 Volume: 84 Pages: 642-648
  • NAID: 10031058809
• [Journal Article] 肝細胞と胆管上皮の相互可塑性 (2012)
  • Author(s): 西川祐司，永濱康晴，曽根正行，山本雅大，榎本克彦
  • Journal Title: 生化学 Volume: 84 Pages: 649-657
  • NAID: 10031058883
• [Presentation] Can exosomal miRNAs derived from human gallbladder cancer cells regulate angiogenesis? (2015)
  • Author(s): Yamamoto Y, Nishijima A, Enomoto K, Omori Y.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08 – 2015-10-10
• [Presentation] ゴルジ体に貯留するconnexin26は頭頸部癌細胞の造腫瘍能を亢進する (2015)
  • Author(s): 飯川延子，大森泰文，本田耕平，石川和夫
  • Organizer: 第39回日本頭頸部癌学会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-06-03 – 2015-06-06
• [Presentation] 肥大した成熟脂肪細胞径は肝の脂肪沈着と相関する (2015)
  • Author(s): 西島亜紀，山本美保子，内橋和芳，青木茂久，大森泰文，杉原甫，戸田修二
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] 頭蓋骨の完全欠損を含む多発奇形を伴った羊膜索症候群の一剖検例 (2015)
  • Author(s): 鈴木麻弥，吉岡年明，山本洋平，西島亜紀，佐藤朗，大森泰文
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] ヒト前立腺癌幹細胞におけるインテグリンβ4の役割 (2015)
  • Author(s): 吉岡年明，山本洋平，鈴木麻弥，西島亜紀，南條博，榎本克彦，大森泰文
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] 迅速免疫染色技術 (R-IHC) を用いた術中迅速病理診断―当院における180症例の検討― (2015)
  • Author(s): 南條博，吉岡年明，廣嶋優子，南谷佳弘，笹嶋寿郎，吉田誠，後藤明輝，大森泰文，中村竜太，赤上陽一
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] ヒト胆嚢癌産生exosome中のmiRNAsが血管新生に与える影響の検討 (2015)
  • Author(s): 山本洋平，西島亜紀，吉岡年明，榎本克彦，大森泰文
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] β4integrin promotes tumorigenesis of human prostate cancer by amplifying ErbB2 and c-Met signaling. (2014)
  • Author(s): Yoshioka T, Yamamoto Y, Nanjo H, Omori Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Prognostic role of Reg 1 (2014)
  • Author(s): Aboshanif M, Kawasaki Y, Ishikawa K, Omori Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Anti-tumor effect of novel anti-HER3 rat monoclonal antibodies. (2014)
  • Author(s): Okita K, Abe S, Ueda S, Yagi H, Inoue M, Yoshioka T, Omori Y, Ogura D, Niwa S, Masuko T.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Specificity of novel monoclonal antibodies recognizing CD44v8, v9 and v10 of CD44R1 in human epithelial cancers. (2014)
  • Author(s): Ueda S, Tokiwa R, Okazaki S, Okita K, Yagi H, Yoshioka T, Omori Y, Masuko T.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 舌癌細胞の悪性度を規定するConnexin26の細胞内局在 (2014)
  • Author(s): 飯川延子，大森泰文，本田耕平，榎本克彦，石川和夫
  • Organizer: 第32回耳鼻咽喉科ニューロサイエンス研究会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-08-29
• [Presentation] 腹腔内腫瘍の一例 (2014)
  • Author(s): 廣嶋優子，南條博，吉岡年明，大森泰文，後藤明輝，羽渕友則，山本雄造，柴田浩行
  • Organizer: 第79回日本病理学会東北支部学術集会
  • Place of Presentation: 盛岡市
  • Year and Date: 2014-07-19 – 2014-07-20
• [Presentation] 電界非接触撹拌迅速免疫染色技術を用いた術中迅速病理診断 (2014)
  • Author(s): 南條博，吉岡年明，南谷佳弘，笹嶋寿郎，廣嶋優子，吉田誠，後藤明輝，赤上陽一
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 新生児に発症したFetal lung interstitial tumor(FLIT)の一例 (2014)
  • Author(s): 吉岡年明，南條 博，伊藤 智，蛇口 琢，矢野道広，新井浩和，吉野裕顕，後藤明輝，大森泰文
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 右血胸から出血性shockに陥った心臓原発血管肉腫の1剖検例 (2014)
  • Author(s): 山本洋平，吉岡年明，鈴木麻弥，大森泰文
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 下咽頭腺様嚢胞癌の1例 (2014)
  • Author(s): 川嵜洋平, 本田耕平, 鈴木真輔, 大森泰文, 石川和夫
  • Organizer: 第24回日本頭頸部外科学会
  • Place of Presentation: 高松市
• [Presentation] Intra-Golgi Cx32-induced expansion of cancer stem cells - Involvement of the adaptive response pathway to ER stress. (2013)
  • Author(s): Omori, Y., Yoshioka, T., Yamamoto, Y. and Kawasaki, Y.
  • Organizer: International Gap Junction Conference 2013
  • Place of Presentation: Charleston, SC
• [Presentation] ゴルジ体に局在するコネキシン32により活性化する小胞体ストレス防護的応答の癌幹細胞における役割 (2013)
  • Author(s): 大森泰文, 吉岡年明, 山本洋平, 榎本克彦
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
• [Presentation] ｲﾝﾃｸﾞﾘﾝβ4によるErbB2やc-Metシグナリングの増幅は、前立腺癌細胞の腫瘍発生を促進する (2013)
  • Author(s): 吉岡年明, 山本洋平, 大森泰文, 南條博, 後藤明輝, 榎本克彦
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
• [Presentation] ヒト胆嚢癌株化細胞が分泌するexosomeに含まれるmicroRNAの解析 (2013)
  • Author(s): 山本洋平, 榎本克彦, 大森泰文, 吉岡年明
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
• [Presentation] インテグリンβ4シグナリングは前立腺癌幹細胞の拡大を促進する (2013)
  • Author(s): 吉岡年明, 山本洋平, 大森泰文, 榎本克彦
  • Organizer: 第22回日本がん転移学会学術集会・総会
  • Place of Presentation: 松本市
• [Presentation] A role of INtegrin β4 in the prostate cancer progenitors. (2013)
  • Author(s): Yoshioka, T., Yamamoto, Y., Nanjo, H., Goto, A., Enomoto, K. and Omori, Y.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市
• [Presentation] Reactivity with human cancers and anti-tumor effect of novel anti-HER3 rat monoclonal antibodies. (2013)
  • Author(s): Okita, K., Ueda, S., Tokiwa, R., Yagi, H., Inoue, M., Yoshioka, T. and Masuko, T.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市
• [Presentation] 乾酪壊死を伴ったWarthin腫瘍 (2013)
  • Author(s): 川嵜洋平, 近江永豪, 大森泰文, 石川和夫
  • Organizer: 第58回日本唾液腺学会
  • Place of Presentation: 東京都
• [Presentation] 新生児に発生した肺腫瘤の一例 (2013)
  • Author(s): 吉岡年明, 矢野道広, 蛇口琢, 吉野裕顕, 南條博, 後藤明輝
  • Organizer: 第77回日本病理学会東北支部学術集会
  • Place of Presentation: 新潟市
• [Presentation] ストレス応答がもたらす癌幹細胞の自己複製亢進 (2013)
  • Author(s): 大森泰文
  • Organizer: 秋田県泌尿器科集談会
  • Place of Presentation: 秋田市
  • Invited
• [Presentation] 頭頸部癌細胞におけるconnexin26の局在の変化の影響 (2013)
  • Author(s): 飯川延子，大森泰文，本田耕平，榎本克彦，石川和夫
  • Organizer: 第114回日本耳鼻咽喉科学会総会・学術講演会
  • Place of Presentation: 札幌市
• [Presentation] コネキシン32のゴルジ体内貯留による癌幹細胞自己複製亢進はゴルジ－小胞体ストレス応答経路を介する (2012)
  • Author(s): 大森泰文，吉岡年明，山本洋平，榎本克彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京都
• [Presentation] ラット傷害肝および部分肝切除における肝細胞でのheregulin発現の検討 (2012)
  • Author(s): 吉岡年明，西川祐司，山本洋平，大森泰文，南條 博，榎本克彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京都
• [Presentation] マウス成熟肝細胞はin vitroおよびin vivoにおいて細胆管上皮へと分化転換しうる (2012)
  • Author(s): 永濱康晴，曽根正行，陳錫，岡田陽子，辛氷，山本雅大，榎本克彦，西川祐司
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京都
• [Presentation] [Morning Lectures] Liver cancer stem cell and stress response. (2012)
  • Author(s): Enomoto, K.
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌市
• [Presentation] [Symposium] Recto-verso of connexin in cancer development and progression. (2012)
  • Author(s): Omori, Y.
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌市
• [Presentation] Study of expression of heregulin in the human liver metastasis. (2012)
  • Author(s): Yoshioka, T., Nishikawa, Y., Yamamoto, Y., Omori, Y., Nanjo, H. and Enomoto, K.
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌市
• [Presentation] Characterization of microRNAs in exosomes derived from human gallbladder carcinoma cell lines. (2012)
  • Author(s): Yamamoto, Y., Omori, Y., Yoshioka, T. and Enomoto, K.
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌市
• [Presentation] Mature mouse hepatocytes can transdifferentiate into bile ductular cells in vivo. (2012)
  • Author(s): Nishikawa, Y., Nagahama, Y., Chen, X., Yamamoto, M. and Enomoto, K.
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌市
• [Presentation] 肝癌幹細胞とゴルジ・ERストレス応答 (2012)
  • Author(s): 榎本克彦
  • Organizer: 第17回日本肝臓医生物学研究会
  • Place of Presentation: 旭川市
• [Book] 図説 分子病態学 改訂第5版 (2014)
  • Author(s): 榎本克彦, 山本洋平
  • Total Pages: 408
  • Publisher: 中外医学社
• [Book] Hepatocellular Carcinoma - Basic Research (2012)
  • Author(s): Omori, Y., Kawasaki, Y., Li, Q., Yoshioka, T., Yamamoto, Y. and Enomoto, K.
  • Total Pages: 402
  • Publisher: InTech
• [Remarks] 秋田大学大学院医学系研究科 分子病態学・腫瘍病態学講座
  • URL: http://www.med.akita-u.ac.jp/~byouri1/
• [Remarks] 秋田大学大学院医学系研究科 分子病態学・腫瘍病態学講座
  • URL: http://www.med.akita-u.ac.jp/~byouri1/