Development of a biomarker in gynecologic cancer to predict outcome with abnormal expression of cell polarity molecules.

• Project/Area Number: 24592506
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: NAGASAKA KAZUNORI 東京大学, 医学部附属病院, 助教 (30624233)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); 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: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 細胞極性制御機構 / バイオマーカー / 網羅的解析 / 転写産物 / 脱リン酸化酵素 / 細胞極性決定因子 / リン酸化機構 / 網羅的転写産物解析 / 子宮頸癌 / ヒトパピローマウイルス / 発癌メカニズム / 転写物 / ノンコーディングRNA / 国際情報交換

Outline of Final Research Achievements

We performed CAGE (Cap Analysis Gene Expression) analysis to investigated transcriptome start sites (TSSs) from the perspective of both the HPV and human genomes. The result showed that the cell polarity and adhesion pathway is dramatically downregulated, and we found a novel antisense viral transcript only seen in CIN cervical cells. Using the molecular and biochemical analyses, we found that cell polarity protein hScrib regulates Ras-ERK pathway, and the activity is mediated in part through recruitment of protein phosphatase 1γ (PP1γ). Furthermore, we have explored the potential role of PP1γ in HPV-induced cervical malignancy. Then, we have found a striking concordance with cellular redistribution in pattern of expression, and this loss of PP1γ expression and redistribution in pattern of expression occurs progressively as the lesions develop. Taken together, we have concluded that PP1γ would be a novel biomarker to predict disease progression for HPV induced malignancy.

Research Products

• [Journal Article] Characterization of novel transcripts of human papillomavirus type 16 using CAGE technology (2015)
  • Author(s): Taguchi A, Nagasaka K, Kawana K, Hashimoto K, Kusumoto-Matsuo R, Plessy C, Miranda T, Nakamura H, Bonetti A, Oda K, Kukimoto I, Carninci P, Banks L, Osuga Y, Fujii T,
  • Journal Title: J Virol Volume: 89 Issue: 4 Pages: 2448-2452
  • DOI: 10.1128/jvi.03433-14
  • Peer Reviewed / Open Access
• [Journal Article] HPV-16 impairs the subcellular distribution and levels of expression of protein phosphatase 1γ in cervical malignancy. (2015)
  • Author(s): Seiki T, Nagasaka K, Kranjec C, Kawana K, Maeda D, Nakamura H, Taguchi A, Matsumoto Y, Arimoto T, Wada-Hiraike O, Oda K, Nakagawa S, Yano T, Fukayama M, Banks L, Osuga Y, Fujii T.
  • Journal Title: BMC Cancer Volume: 7 Issue: 1 Pages: 230-230
  • DOI: 10.1186/s12885-015-1141-0
  • NAID: 120007089068
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High-risk HPV correlates with recurrence after laser ablation for treatment of patients with CIN3: a long-term follow-up retrospective study, (2014)
  • Author(s): Inaba K, Nagasaka K, Kawana K, Arimoto T, Matsumoto Y, Tsuruga T, Mori-Uchino M, Miura S, Sone K, Oda K, Nakagawa S, Yano T, Kozuma S, Fujii T
  • Journal Title: J Obstet Gynaecol Res Volume: 40 Issue: 2 Pages: 554-60
  • DOI: 10.1111/jog.12196
  • Peer Reviewed
• [Journal Article] Positive peritoneal cytology at interval debulking surgery is independent poor prognostic factor in patients with stage T3c advanced ovarian carcinoma (2014)
  • Author(s): Nagasaka K, Kawana K, Tomio K, Eguchi S, Miura S, Tsuruga T, Mori-Uchino M, Tanikawa M, Tsukazaki T, Sone K, Adachi K, Matsumoto Y, Arimoto T, Oda K, Osuga Y, Fujii T
  • Journal Title: J Obstet Gynecol Res Volume: Nov. 25 Issue: 5 Pages: 554-560
  • DOI: 10.1111/jog.12616
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyusaturated fatty acids in vitro and in vivo. (2014)
  • Author(s): Taguchi A, Kawana K, Tomio K, Yamashita A, Isobe Y, Nagasaka K, Koga K, Inoue T, Nishida H, kojima S, Adachi K, Matsumoto Y, Arimoto T, Wada-Hiraike O, Oda K, kang JX, Arai H, Arita M, Osuga Y, Fujii T.
  • Journal Title: PLoS One Volume: 27 Issue: 2 Pages: e89605-e89605
  • DOI: 10.1371/journal.pone.0089605
  • Peer Reviewed
• [Journal Article] Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells. (2014)
  • Author(s): A. Miyasaka, K. Oda, Y. Ikeda, O. Wada-Hiraike, T. Kashiyama, A. Enomoto, N. Hosoya, T. Koso, T. Fukuda, K. Inaaba, K. Sone, Y. Uehara, R. Kurikawa, K. Nagasaka, Y.Matsumoto, T. Arimoto, S. Nakagawa, H. Kuramoto, K. Miyagawa, T. Yano, K. Kawana, Y. Osuga, T. Fujii.
  • Journal Title: BMC Cancer Volume: - Issue: 1 Pages: 179-179
  • DOI: 10.1186/1471-2407-14-179
  • Peer Reviewed
• [Journal Article] Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer. (2013)
  • Author(s): Ikeda Y, Oda K, Hiraike-Wada O, Koso T, Miyasaka A, Kashiyama T, Tanikawa M, Sone K, Nagasaka K, Maeda D, Kawana K, Nakagawa S, Fukayama M, Tetsu O, Fujii T, Yano T, Kozuma S
  • Journal Title: Oncol Rep Volume: 30 Issue: 2 Pages: 584-588
  • DOI: 10.3892/or.2013.2515
  • NAID: 120007089077
  • Peer Reviewed
• [Journal Article] PDZ domains and viral infection: versatile potentials of HPV-PDZ interactions in relation to malignancy. (2013)
  • Author(s): Nagasaka K, Kawana K, Osuga Y, Fujii T.
  • Journal Title: BioMed research international Volume: 2013 Pages: 369712-369712
  • DOI: 10.1155/2013/369712
  • Peer Reviewed
• [Journal Article] Increased tissue level of omega-3 polyunsaturated fatty acids prevents pathological preterm birth. (2013)
  • Author(s): Yamashita A, Kawana K, Tomio K, Taguchi A, Isobe Y, Iwamoto R, Masuda K, Furuya H, Nagamatsu T, Nagasaka K, Oda K, Wada-Hiraike O, Yamashita T, Taketani Y, Kang JX, Arai H, Arita M, Kozuma S, Fujii T.
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 3113-3113
  • DOI: 10.1038/srep03113
  • Peer Reviewed
• [Journal Article] A novel interaction between hScrib and PP1γ downregulates ERK signaling and suppresses oncogene-induced cell transformation (2013)
  • Author(s): Nagasaka K, Seiki T, Yamashita A, Massimi P, Subbaiah VK, Thomas M, Kranjec C, Kawana K, Nakagawa S, Yano T, Taketani Y, Fujii T, Kozuma S, Banks L
  • Journal Title: PLosOne Volume: E-pub Issue: 1 Pages: 53752-53760
  • DOI: 10.1371/journal.pone.0053752
  • Peer Reviewed
• [Journal Article] Sequential effects of the proteasome inhibitor bortezomib and chemotherapeutic agents in uterine cervical cancer cell lines. (2013)
  • Author(s): Miyamoto Y, Nakagawa S, Wada-Hiraike O, Seiki T, Tanikawa M, Hiraike H, Sone K, Nagasaka K, Oda K, Kawana K, Nakagawa K, Fujii T, Yano T, Kozuma S, Taketani Y.
  • Journal Title: Oncol Rep. Volume: 29(1) Issue: 1 Pages: 51-7
  • DOI: 10.3892/or.2012.2072
  • Peer Reviewed
• [Journal Article] The prevalence of cervical regulatory T cells in HPV-related cervical intraepithelial neoplasia (CIN) correlates inversely with spontaneous regression of CIN (2013)
  • Author(s): Kojima S, Kawana K, Tomio K, Yamashita A, Taguchi A, Nagamatsu T, Nagasaka K, Matsumoto Y, Arimoto T, Oda K, Wada-Hiraike O, Yano T, Taketani Y, Fujii T, Schust DJ, Kozuma S
  • Journal Title: Am J Reprod Immunol, Volume: 69 Issue: 2 Pages: 134-144
  • DOI: 10.1111/aji.12030
  • Peer Reviewed
• [Journal Article] 性感染症の現状と治療の問題点 8. HPVワクチン (2012)
  • Author(s): 長阪一憲、川名敬
  • Journal Title: 化学療法の領域 5月号 Volume: 7 Pages: 97-104
• [Journal Article] ヒトパピローマウイルスワクチンの効果 (2012)
  • Author(s): 長阪一憲、川名敬
  • Journal Title: バムサジャーナル Volume: 2 Pages: 3-9
  • NAID: 40019386632
• [Presentation] HPV検査と細胞診の臨床的意義：HPV life cycleの視点から (2014)
  • Author(s): 長阪一憲
  • Organizer: 日本臨床細胞学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-11-02 – 2014-11-03
  • Invited
• [Presentation] CINから子宮頸癌への癌進展制御に関わるHPV由来の新規non-coding RNAの同定とその機能解析 (2014)
  • Author(s): 田口歩、川名敬、長阪一憲、橋本浩介、西田晴香、井上知子、松本陽子、有本貴英、平池修、織田克利、大須賀穣、藤井知行
  • Organizer: 日本産婦人科学会学術講演会
  • Place of Presentation: 東京
• [Presentation] HPV16 E6 interferes with hScrib regulation of ERK through protein phosphatase 1γ (2013)
  • Author(s): Kazunori Nagasaka
  • Organizer: DNA Tumour Virus Meeting 2013
  • Place of Presentation: Birmingham, UK
• [Presentation] Analysis of HPV-induced transcriptional network by deep-CAGE sequencing in different HPV16-positive cell-lines and cervical cancer specimens (2013)
  • Author(s): Kazunori Nagasaka
  • Organizer: DNA Tumour Virus Meeting 2013
  • Place of Presentation: Birmingham, UK
• [Presentation] 細胞極性決定因子hScribは脱リン酸化蛋白Protein phosphatase-1 gammaとの結合を介してERK系路を制御する (2012)
  • Author(s): 長阪一憲、川名敬、田口歩、清木孝之、山下亜紀、宮本雄一郎、曾根献文、松本陽子、平池修、織田克利、中川俊介、矢野哲、武谷雄二
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 札幌
• [Book] 臨床検査ガイド2015 (2015)
  • Author(s): 長阪一憲 矢野哲
  • Publisher: 文光堂
• [Book] 臨床検査ガイド2013-2014 ヒトパピローマウイルスDNA検査 (2013)
  • Author(s): 長阪一憲 矢野哲
  • Publisher: 文光堂