Investigation of potential therapeutic targets for esophageal squamous cell carcinoma focused on the functional modification of cancer stimulating RNA binding protein.

• Project/Area Number: 15K08949
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokushima
• Principal Investigator: MASUDA Kiyoshi 徳島大学, 大学院医歯薬学研究部(医学系), 准教授 (00457318)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: RNA結合蛋白質 / 転写後調節機構 / 食道がん / 食道癌

Outline of Final Research Achievements

We found two RBPs, TIA1 and KHSRP, could have tumor-promoting functions in esophagus cancer.
Among two major isoforms of human TIA1, TIA1a and TIA1b, TIA1a was expressed in both the nucleus and cytoplasm. We revealed that only TIA1a promoted anchorage-dependent and anchorage-independent cell proliferation via induction of cell cycle promoters, such as CCNA2 and SKP2. Then, we found that phosphorylation of the specific amino acid residue within TIA1a could regulate molecular function of TIA1a and introduced synthetic peptide could efficiently translocate cytoplasmic TIA1a into nuclear.
We also found that KHSRP silencing inhibited cell growth, and migration/invasion in ESCC cells. miRNA microarray analysis identified a set of KHSRP-regulating miRNAs, including miR-150b, miR-21, and miR-301a. Silencing of KHSRP reduced expressions of these miRNAs and suppressed migration/invasion of ESCC cells with higher levels of their target mRNAs and proteins, including BMP6, TIMP3 and PDCD4.

Research Products

• [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] 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] 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] 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] RNA Binding Proteins and Genome Integrity (2017)
  • Author(s): Nishida K, Kuwano Y, Nishikawa T, Masuda K, Rokutan K
  • Journal Title: Int J Mol Sci Volume: 18 Issue: 7 Pages: 1341-1341
  • DOI: 10.3390/ijms18071341
  • NAID: 120006535039
  • 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] 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] 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, Shinozaki A, Okamoto K, Imoto I, Otsuji E.
  • Journal Title: Oncotarget Volume: 印刷中
  • NAID: 120006306639
  • 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] Adverse parenting is associated with blunted salivary cortisol awakening response and altered expression of glucocorticoid receptor β and β2-adrenergic receptor mRNAs in leukocytes in Japanese medical students (2017)
  • Author(s): Kawai T, Kuwano Y, Masuda K, Fujita K, Tanaka H, Nishikawa T, Rokutan K, Nishida K
  • Journal Title: Stress Volume: 20 Issue: 2 Pages: 159-166
  • DOI: 10.1080/10253890.2017.1297415
  • Peer Reviewed / 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] 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] Exome-first approach identified a novel gloss deletion associated with Lowe syndrome. (2016)
  • Author(s): Watanabe M, Nakagawa R, Kohmoto T, Naruto T, Suga K, Goji A, Horikawa H, Masuda K, Kagami S, Imoto I.
  • Journal Title: Hum Genome Var Volume: 3 Issue: 1 Pages: 16037-16037
  • DOI: 10.1038/hgv.2016.37
  • NAID: 120006955875
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Serine/arginine-rich splicing factor 7 regulates p21-dependent growth arrest in colon cancer cells (2016)
  • Author(s): Saijo S, Kuwano Y, Masuda K, Nishikawa T, Rokutan K, Nishida K
  • Journal Title: J Med Invest Volume: 63 Issue: 3.4 Pages: 219-226
  • DOI: 10.2152/jmi.63.219
  • NAID: 130005245836
  • 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
• [Journal Article] Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome (2016)
  • Author(s): Kuwano Y, Nishida K, Akaike Y, Kurokawa K, Nishikawa T, Masuda K, Rokutan K
  • Journal Title: Int J Mol Sci Volume: 17 Issue: 10 Pages: 10-10
  • DOI: 10.3390/ijms17101638
  • NAID: 120006535037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma (2015)
  • Author(s): Hamada J, Shoda K, Masuda K, Fujita Y, Naruto T, Kohmoto T, Miyakami Y, Watanabe M, Kudo Y, Fujiwara H, Ichikawa D, Otsuji E, Imoto I
  • Journal Title: Oncotarget Volume: - Issue: 13 Pages: 17111-17128
  • DOI: 10.18632/oncotarget.7937
  • NAID: 120006240043
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells (2015)
  • Author(s): Kajita K, Kuwano Y, Satake Y, Kano S, Kurokawa K, Akaike Y, Masuda K, Nishida K, Rokutan K
  • Journal Title: Oncogenesis Volume: - Issue: 4 Pages: e213-e213
  • DOI: 10.1038/oncsis.2016.18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monitoring the HER2 copy number status in circulating tumor DNA by droplet digital PCR in patients with gastric cancer (2015)
  • Author(s): Shoda K, Ichikawa D, Fujita Y, Masuda K, Hiramoto H, Hamada J, Arita T, Konishi H, Komatsu S, Shiozaki A, Kakihara N, Okamoto K, Taniguchi H, Imoto I, Otsuji E.
  • Journal Title: Gastric Cancer Volume: -
  • NAID: 40021062596
  • Peer Reviewed
• [Journal Article] Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3’UTR of BCL2 mRNA. (2015)
  • Author(s): Kuwano Y, Nishida K, Kajita K, Satake Y, Akaike Y, Fujita K, Kano S, Masuda K, Rokutan K.
  • Journal Title: Cell Death Differ. Volume: 22 (5) Issue: 5 Pages: 815-825
  • DOI: 10.1038/cdd.2014.176
  • Peer Reviewed / Open Access
• [Journal Article] A novel frameshift mutation of CHD7 in a Japanese patient with CHARGE syndrome (2015)
  • Author(s): Kohmoto T, Naruto T, Watanabe M, Masuda K, Suga K, Shono M, Nakagawa R, Kagami S, Imoto I.
  • Journal Title: Hum Genome Variation Volume: -
  • NAID: 120006955871
  • Peer Reviewed / Open Access
• [Journal Article] A novel COL11A1 mutation affecting splicing in a patient with Stickler syndrome (2015)
  • Author(s): Kohmoto T, Naruto T, Masuda K, Morita K, Harada H, Tsuji A, Kashimada K, Enomoto K, Morio T, Imoto I.
  • Journal Title: Hum Genome Variation Volume: 2 Pages: 15043-15043
  • Peer Reviewed / Open Access
• [Journal Article] Simultaneous detection of both single nucleotide variations and copy number alterations by next-generation sequencing in Gorlin syndrome (2015)
  • Author(s): Morita K, Naruto T, Tanimoto K, Yasukawa C, Oikawa Y, Masuda K, Imoto I, Inazawa J, Omura K, Harada H.
  • Journal Title: PLoS One Volume: 10 Issue: 11 Pages: e0140480-e0140480
  • DOI: 10.1371/journal.pone.0140480
  • NAID: 120006871193
  • Peer Reviewed / Open Access
• [Journal Article] Ectopic Aire expression in 1 the thymic cortex reveals inherent properties of Aire as a tolerogenic factor within the medulla (2015)
  • Author(s): Nishijima H, Kitano S, Miyachi H, Morimoto J, Kawano H, Hirota F, Morita R, Mouri Y, Masuda K, Imoto I, Ikuta K, Matsumoto M.
  • Journal Title: J Immunol Volume: 195 Issue: 10 Pages: 4641-4649
  • DOI: 10.4049/jimmunol.1501026
  • Peer Reviewed / Open Access
• [Journal Article] A unique TBX5 microdeletion with microinsertion detected in patient with Holt-Oram syndrome. (2015)
  • Author(s): Morine M, et al.
  • Journal Title: Am J Med Genet A Volume: 167 Issue: 12 Pages: 3192-3196
  • DOI: 10.1002/ajmg.a.37359
  • Peer Reviewed
• [Journal Article] Deep intronic GPR143 mutation in a Japanese family with ocular albinism. (2015)
  • Author(s): Naruto T, Okamoto N, Masuda K, Endo T, Hatsukawa Y, Kohmoto T, Imoto I.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 11334-11334
  • DOI: 10.1038/srep11334
  • NAID: 120006875681
  • Peer Reviewed / Open Access
• [Presentation] Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma (2017)
  • Author(s): 増田清士、濱田隼一、庄田勝俊、藤田悠司、井本逸勢
  • Organizer: Keystone symposia Protein-RNA Interactions: Scale, Mechanisms, Structure and Function of Coding and Noncoding RNPs
  • Place of Presentation: バンフ（カナダ）
  • Year and Date: 2017-02-05
• [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] 食道扁平上皮癌におけるRNA結合蛋白質TIA1を介した新規癌進展機構の解明 (2016)
  • Author(s): 増田清士、濱田隼一、庄田勝俊、藤田悠司、成戸卓也、井本逸勢
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-11-30
• [Presentation] RNA結合蛋白質MRF1は癌関連miRNA発現異常を誘導し食道癌の進展を促進する (2016)
  • Author(s): 増田清士、井本逸勢
  • Organizer: 第24回日本消化器関連学会週間
  • Place of Presentation: 神戸コンベンションセンター（兵庫県、神戸市）
  • Year and Date: 2016-11-03
• [Presentation] Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma (2016)
  • Author(s): 増田清士、濱田隼一、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: 2016-10-06
• [Presentation] RNA binding protein, SSP, induces cell viability of squamous cell carcinoma by posttranscriptional regulation (2015)
  • Author(s): 増田清士、濱田隼一、庄田勝俊、井本逸勢
  • Organizer: 第３８回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県、神戸市）
  • Year and Date: 2015-12-01
• [Presentation] A novel RNA binding protein, MRF1, induces cell growth in squamous cell carcinoma modulating microRNA expression (2015)
  • Author(s): 増田清士、宮上侑子、濱田哲司、藤田悠司、濱田隼一、庄田勝俊、井本逸勢
  • Organizer: Cell Symposia Human Genomics
  • Place of Presentation: A Star Genome Institute of Singapore （シンガポール）
  • Year and Date: 2015-11-08
• [Presentation] RNA binding protein, SSP, has the isoform-specific function and induces cell viability of squamous cell carcinoma (2015)
  • Author(s): 藤田悠司、増田清士、河本知大、渡邊美季、濱田隼一、庄田勝俊、成戸卓也、井本逸勢
  • Organizer: Cell Symposia Human Genomics
  • Place of Presentation: A Star Genome Institute of Singapore （シンガポール）
  • Year and Date: 2015-11-08
• [Presentation] A novel RNA binding protein, MRF1, induces cell growth in squamous cell carcinoma modulating cancer-associated microRNA expression (2015)
  • Author(s): 増田清士、藤田悠司、濱田隼一、庄田勝俊、井本逸勢
  • Organizer: 第７４回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Identification of a RNA binding protein, SSP, inducing cell viability of squamous cell carcinoma by posttranscriptional regulation (2015)
  • Author(s): 濱田隼一、庄田勝俊、増田清士、井本逸勢
  • Organizer: 第７４回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2015-10-08
• [Remarks] 食道がんの進行に関わるマイクロRNAを制御する新しいがん促進分子KHSRPの同定とその分子機構の解明
  • URL: http://www.tokushima-u.ac.jp/docs/2017092100035/
• [Remarks] EBウイルス関連胃がん患者では、循環血漿中DNAを用いることで低侵襲に診断や経過観察が可能
  • URL: http://www.tokushima-u.ac.jp/docs/2017032100057/
• [Remarks] MSX1遺伝子C末端領域における新規変異検出と疾患責任性のゲノム編集技術を用いた検証
  • URL: http://www.tokushima-u.ac.jp/docs/2017011100047/
• [Remarks] 肺腺がんの早期から不活性化される新規がん抑制遺伝子の発見
  • URL: http://www.tokushima-u.ac.jp/docs/2016120600059/
• [Remarks] 食道がんの診断・治療の標的になりうる重要なタンパク質異常の発見
  • URL: http://www.tokushima-u.ac.jp/docs/2016031400069/
• [Remarks] 食道がんの進行を制御する新しい分子（TIA1）の発見とその分子メカニズムの解明
  • URL: http://www.tokushima-u.ac.jp/docs/2016031400076/
• [Remarks] 胃がん患者における循環血中腫瘍 DNA 中の HER2 コピー数のモニタリング
  • URL: http://www.tokushima-u.ac.jp/docs/2016022600102/
• [Remarks] 胃がん治療の重要な標的分子の遺伝子異常を血液で検出
  • URL: http://www.tokushima-u.ac.jp/docs/2016022900011/