Characterization of the esophageal carcinogenesis-promoting molecular switch existing inside the isoform of RNA-binding protein

• Project/Area Number: 16K15618
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: The University of Tokushima
• Principal Investigator: IMOTO Issei 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (30258610)
• Co-Investigator(Renkei-kenkyūsha): MASUDA Kiyoshi 徳島大学, 大学院医歯薬学研究部, 准教授 (00457318) ; OTSUJI Eigo 京都府立医科大学, 医学(系)研究科, 教授 (20244600) ; TANGOKU Akira 徳島大学, 大学院医歯薬学研究部, 教授 (10197593)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: RNA結合蛋白 / TIA1 / アイソフォーム / 天然変性領域 / 蛋白リン酸化 / 癌促進作用 / 細胞内局在 / 分子スイッチ / RNA結合タンパク / TIA1a / 癌

Outline of Final Research Achievements

TIA1a is the isoform of TIA1, one of the RNA-binding protein (RBP), having a serine/threonine-rich intrinsically disordered region (IDR) and promoting esophageal squamous cell carcinoma (ESCC). Through changing amino acid of candidate phosphorylation sites around the TIA1a specific region within IDR, subcellular localization of TIA1a and cell growth were altered in ESCC cells. Blocking synthetic peptides inhibited TIA1a cytoplasmic localization. CHK1 was identified as candidate kinase contributing to TIA1a cytoplasmic localization. In addition, TIA1a bound 3'UTR of candidate TIA1a-binding mRNAs in the cytoplasm with other RBPs and regulated mRNA/protein levels of those targets jointly or competitively. These results demonstrated that the phosphorylation of specific sites within IDR may work as a molecular switch to promote cytoplasmic localization of TIA1a and accelerate its cancer-promoting function through binding and regulating target molecules in the cytoplasm of ESCC cells.

Research Products

• [Journal Article] A rare male patient with classic Rett syndrome caused by MeCP2_e1 mutation (2018)
  • Author(s): Tokaji Narumi、Ito Hiromichi、Kohmoto Tomohiro、Naruto Takuya、Takahashi Rizu、Goji Aya、Mori Tatsuo、Toda Yoshihiro、Saito Masako、Tange Shoichiro、Masuda Kiyoshi、Kagami Shoji、Imoto Issei
  • Journal Title: American Journal of Medical Genetics Part A Volume: 176 Issue: 3 Pages: 699-702
  • DOI: 10.1002/ajmg.a.38595
  • Peer Reviewed
• [Journal Article] Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer (2017)
  • Author(s): Hirasawa Akira、Imoto Issei、Naruto Takuya、Akahane Tomoko、Yamagami Wataru、Nomura Hiroyuki、Masuda Kiyoshi、Susumu Nobuyuki、Tsuda Hitoshi、Aoki Daisuke
  • Journal Title: Oncotarget Volume: 8 Issue: 68 Pages: 112258-112267
  • DOI: 10.18632/oncotarget.22733
  • Peer Reviewed / Open Access
• [Journal Article] KH-type splicing regulatory protein is involved in esophageal squamous cell carcinoma progression (2017)
  • Author(s): Y. Fujita, K. Masuda, J. Hamada, K. Shoda, T. Naruto, S. Hamada, Y. Miyakami, T. Kohmoto, M. Watanabe, R. Takahashi, S. Tange, M. Saito, Y. Kudo, H. Fujiwara, D. Ichikawa, A. Tangoku, E. Otsuji, I. Imoto,
  • Journal Title: Oncotarget. Volume: 8 Issue: 60 Pages: 101130-101145
  • DOI: 10.18632/oncotarget.20926
  • Peer Reviewed / Open Access
• [Journal Article] Frequent silencing of RASSF1A by DNA methylation in thymic neuroendocrine tumours (2017)
  • Author(s): Kajiura K, Takizawa H, Morimoto Y, Masuda K, Tsuboi M, Kishibuchi R, Wusiman N, Sawada T, Kawakita N, Toba H, Yoshida M, Kawakami Y, Naruto T, Imoto I, Tangoku A, Kondo K
  • Journal Title: Lung Cancer Volume: 111 Pages: 116-123
  • DOI: 10.1016/j.lungcan.2017.05.019
  • NAID: 120006539750
  • Peer Reviewed
• [Journal Article] Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis (2017)
  • Author(s): N. Okamoto, T. Kohmoto, T. Naruto, K. Masuda, T. Komori, I. Imoto
  • Journal Title: Hum Genome Var Volume: 4 Issue: 1 Pages: 1-4
  • DOI: 10.1038/hgv.2017.36
  • Peer Reviewed / Open Access
• [Journal Article] The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection (2017)
  • Author(s): Okada A, Kohmoto T, Naruto T, Yokota I, Kotani Y, Shimada A, Miyamoto Y, Takahashi R, Goji A, Masuda K, Kagami S, Imoto I
  • Journal Title: Hum Genome Var Volume: 4 Issue: 1 Pages: 17031-17031
  • DOI: 10.1038/hgv.2017.31
  • NAID: 120006955877
  • Peer Reviewed / Open Access
• [Journal Article] Construction of a combinatorial pipeline using two somatic variant calling methods for whole exome sequence data of gastric cancer (2017)
  • Author(s): Kohmoto T, Masuda K, Naruto T, Tange S, Shoda K, Hamada J, Saito M, Ichikawa D, Tajima A, Otsuji E, Imoto I.
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 3.4 Pages: 233-240
  • DOI: 10.2152/jmi.64.233
  • NAID: 130006105184
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements (2017)
  • Author(s): Kohmoto T, Okamoto N, Naruto T, Murata C, Ouchi Y, Fujita N, Inagaki H, Satomura S, Okamoto N, Saito M, Masuda K, Kurahashi H, Imoto I
  • Journal Title: Mol Cytogenet Volume: 10 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s13039-017-0316-6
  • NAID: 120006937633
  • Peer Reviewed / Open Access
• [Journal Article] Clinical utility of circulating cell-free Epstein-Barr virus DNA in patients with gastric cancer. (2017)
  • Author(s): Shoda K, Ichikawa D, Fujita Y, Masuda K, Hiramoto H, Hamada J, Arita T, Konishi H, Kosuga T, Komatsu S, Shiozaki A, Okamoto K, Imoto I, Otsuji E.
  • Journal Title: Oncotarget Volume: 17 Issue: 17 Pages: 28796-28804
  • DOI: 10.18632/oncotarget.15675
  • NAID: 120006306639
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma (2017)
  • Author(s): K.Kajiura, K.Masuda, T.Naruto, T.Kohmoto, M.Watanabe, M.Tsuboi, H.Takizawa, K.Kondo, A.Tangoku, I.Imoto
  • Journal Title: Oncotarget Volume: 8 Issue: 2 Pages: 2890-2905
  • DOI: 10.18632/oncotarget.13761
  • Peer Reviewed / Open Access
• [Journal Article] Genome-first approach diagnosed Cabezas syndrome via novel CUL4B mutation detection. (2017)
  • Author(s): Okamoto N, Watanabe M, Naruto T, Matsuda K, Kohmoto T, Saito M, Masuda K, Imoto I.
  • Journal Title: Hum Genome Var Volume: 4 Issue: 1 Pages: 16045-16045
  • DOI: 10.1038/hgv.2016.45
  • NAID: 120006955876
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A 590 kb deletion caused by non-allelic homologous recombination between two LINE-1 elements in a patient with mesomelia-synostosis syndrome. (2017)
  • Author(s): Kohmoto T, Naruto T, Watanabe M, Fujita Y, Ujiro S, Okamoto N, Horikawa H, Masuda K, Imoto I.
  • Journal Title: Am J Med Genet A Volume: 173 Issue: 4 Pages: 1082-1086
  • DOI: 10.1002/ajmg.a.38122
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Detection of 1p36 deletion by clinical exome-first diagnostic approach. (2016)
  • Author(s): Watanabe M, Horikawa H, et al.
  • Journal Title: Hum Genome Var Volume: 3 Issue: 1
  • DOI: 10.1038/hgv.2016.6
  • Description: in press
  • Peer Reviewed / Open Access
• [Journal Article] A novel missense mutation of COL5A2 in a patient with Ehlers-Danlos syndrome. (2016)
  • Author(s): Watanabe M, Nakagawa R, Naruto T, Kohmoto T, Suga K, Goji A, Kagami S, Masuda K, Imoto I.
  • Journal Title: Hum Genome Var Volume: 3 Issue: 1 Pages: 16030-16030
  • DOI: 10.1038/hgv.2016.30
  • NAID: 120006955874
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel frameshift mutation of CHD7 in a Japanese patient with CHARGE syndrome. (2016)
  • Author(s): Kohmoto T, Shono M, Naruto T, Watanabe M, Suga K, Nakagawa R, Kagami S, Masuda K, Imoto I.
  • Journal Title: Hum Genome Var Volume: 3 Issue: 1
  • DOI: 10.1038/hgv.2016.4
  • NAID: 120006955871
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome (2016)
  • Author(s): Kohmoto T, Tsuji A, Morita K, Naruto T, Masuda K, Kashimada K, Enomoto K, Morio T, Harada H, Imoto I
  • Journal Title: Hum Genome Var Volume: 3 Issue: 1 Pages: 16003-16003
  • DOI: 10.1038/hgv.2016.3
  • Peer Reviewed / Open Access
• [Journal Article] Novel human mutation and CRISPR/Cas genome-edited mice reveal importance of C-terminal domain of MSX1 in tooth and palate development (2016)
  • Author(s): S.N.Mitsui, A.Yasue, K.Masuda, T.Naruto, Y.Minegishi, S.Oyadomari, S.Noji, I.Imoto, E.Tanaka
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 38398-38398
  • DOI: 10.1038/srep38398
  • Peer Reviewed / Open Access
• [Presentation] 成人領域のゲノム医療の社会実装が小児遺伝に与える影響と課題ーがんゲノム医療を中心にー (2018)
  • Author(s): 井本逸勢
  • Organizer: 第40回日本小児遺伝学会学術集会
  • Invited
• [Presentation] Functional modification of TIA1 could be a potential therapeutic target for esophageal squamous cell carcinoma (2017)
  • Author(s): Masuda K, Hamada J, Fujita Y, Shoda K, Kohmoto T, Tange S, Imoto I
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Identification of CPIG7.2 as a candidate for triple-negative breast cancer -associated gene through pan-cancer analysis (2017)
  • Author(s): Tange S, Masuda K, Kohmoto T, Tajima A, Imoto I
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Identification of novel tumor-promoting gene, OEGC1, as a putative prognosticator for gastric cancer (2017)
  • Author(s): Kohmoto T, Masuda K, Shoda K, Tange S, Imoto I
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] RNA結合蛋白質MRF1による癌関連miRNA発現異常を介した癌促進機構 (2017)
  • Author(s): 井本逸勢、藤田悠司、河本知大、丹下正一朗、増田清士
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 脂肪委縮症を伴う希少疾患の遺伝カウンセリングと診療科間連携に関する考察 (2017)
  • Author(s): 井本逸勢，宮本容子，吉田友紀子, 桑内敬子, 郷司彩, 島田亜紀, 小谷裕美子, 横田一郎
  • Organizer: 第41回日本遺伝カウンセリング学会学術集会
• [Presentation] The first Japanese patient of Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) diagnosed via POLD1 mutation detection (2017)
  • Author(s): Imoto I, Kohmoto T, Naruto T, Goji A, Okada A, Yokota I, Kotani M, Shimada A, Miyamoto Y, Masuda K, Kagami S
  • Organizer: American Society of Human Genetics 2017
  • Int'l Joint Research
• [Presentation] RNA結合蛋白質TIA1の機能調節に着目した新規食道癌治療法の開発 (2017)
  • Author(s): Masuda K, Kohmoto T, Hamada J, Shoda K, Fujita Y, Tange S, Saito M, Imoto I
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] MeCP2-e1 遺伝子変異が検出された典型的Rett症候群の男児例 (2017)
  • Author(s): 郷司彩，伊藤弘道，戸梶成美，河本知大，成戸卓也，森達夫，東田好広，増田清士，香美祥二，井本逸勢
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] The contribution of deleterious germ-line mutations of susceptibility (2017)
  • Author(s): Hirasawa A, Imoto I, Naruto T, Akahane T, Yamagami T, Susumu N, Tsuda H, Aoki D
  • Organizer: American Association for Cancer Research Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] がんのPrecision Medicineとがんゲノム医療 (2017)
  • Author(s): 井本逸勢
  • Organizer: 第15回日本乳癌学会近畿地方会
  • Invited
• [Presentation] がん・遺伝疾患の臨床ゲノム解析の現場 (2017)
  • Author(s): 井本逸勢
  • Organizer: NGS現場の会第五回研究会
  • Invited
• [Presentation] Frequent silencing of the candidate tumor suppressor TSLAC1 by promoter methylation in early stage lung adenocarcinoma. (2016)
  • Author(s): Kohmoto T, Kajiura K, Naruto T,Masuda K、Kondo K, Tangoku A, Imoto I.
  • Organizer: The 66th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: Vancouver （Canada）
  • Year and Date: 2016-10-21
  • Int'l Joint Research
• [Presentation] Long interspersed nuclear element-1 (LINE1)-mediated 8q13 microdeletion detected in a Japanese case with mesomelia-synostoses syndrome. (2016)
  • Author(s): Imoto I, Naruto T, Kohmoto T, Watanabe M, Ujiro S, Masuda K.
  • Organizer: The 66th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: Vancouver （Canada）
  • Year and Date: 2016-10-20
  • Int'l Joint Research
• [Presentation] がん体細胞変異検出の特性からみた検査の考え方 (2016)
  • Author(s): 井本逸勢
  • Organizer: 第23回日本遺伝子診療学会大会
  • Place of Presentation: イイノホール＆カンファレンスセンター（東京都・千代田区）
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] 肺腺癌の早期からDNAメチル化により高頻度に発現抑制を受ける新規癌抑制遺伝子候補TSLAC1の同定 (2016)
  • Author(s): 成戸卓也、梶浦耕一郎、増田清士、近藤和也、丹黒章、井本逸勢
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-08
• [Presentation] RNA結合蛋白質TIA1による食道癌進展機構の解明 (2016)
  • Author(s): 増田清士、濵田隼一、庄田勝俊、藤田悠司、井本逸勢
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-07
• [Presentation] 新規RNA結合蛋白質MRF1は癌関連microRNA発現以上を誘導し食道癌の進展を促進する (2016)
  • Author(s): 藤田悠司、増田清士、井本逸勢
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-07
• [Presentation] EBV関連胃癌患者における遊離DNAの有用性の検討 (2016)
  • Author(s): 庄田勝俊、市川大輔、藤田悠司、増田清士、濵田隼一、有田智洋、小西博貴、小松周平、塩崎敦、岡本和真、井本逸勢、大辻英吾
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-07
• [Book] 婦人科腫瘍遺伝カウンセリングマニュアル (2018)
  • Author(s): 関沢 明彦、佐村 修、四元淳子
  • Total Pages: 130
  • Publisher: 中外医学社
  • ISBN: 9784498060869
• [Book] 遺伝/ゲノム看護 (2018)
  • Author(s): 井ノ上逸朗、有森 直子、溝口満子
  • Total Pages: 260
  • Publisher: 医歯薬出版
  • ISBN: 9784263236994
• [Remarks] 徳島大学医学部人類遺伝学分野
  • URL: http://jiniden.ait231.tokushima-u.ac.jp/web/
• [Remarks] 徳島大学医学部人類遺伝学分野
  • URL: http://www.tokushima-u.ac.jp/med/culture/jinruiiden/