Exploring a novel therapy of hormone-resistant breast cancer by short RNA

• Project/Area Number: 24591920
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Kyoto University
• Principal Investigator: OHE Kenji 京都大学, 健康長寿社会の総合医療開発ユニット, 特定講師 (30419527)
• Co-Investigator(Kenkyū-buntansha): UTSUMI Toshiaki 藤田保健衛生大学, 医学部乳腺外科, 教授 (10176711)
• Co-Investigator(Renkei-kenkyūsha): MAYEDA Akila 藤田保健衛生大学, 総合医科学研究所, 教授 (50212204)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 乳腺外科学 / エストロゲン受容体 / 癌遺伝子産物 / 選択的スプライシング / RNA結合蛋白質 / RNAスプライシング / 乳癌

Outline of Final Research Achievements

We have found HMGA1a binds to RNA in a sequence-specific manner and induces alternative splicing. While investigating this function in the estrogen-receptor alpha(ERα)gene, we found a “decoy RNA” of HMGA1a reverses its effect on ERα when stable transfectants of MCF-7 mammary carcinoma cells form tumors in nude mice. Since the expression of miR-16, which is known to downregulate HMGA1a, is decreased in these tumors, and has a strong homology to HMGA1a RNA binding sequence in its seed sequence, we hypothesized HMGA1a regulates its own regulating micro-RNA by its sequence-specific RNA binding function. This implies a positive feedback mechanism of HMGA1a which is known as oncogenic protein product.

Research Products

• [Journal Article] HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. (2013)
  • Author(s): Rahman, M. A., Masuda, A., Ohe, K., Ito, M. , Hutchinson, D. O., Mayeda, A., Engel, A. G. and Ohno, K.
  • Journal Title: Sci. Rep. Volume: 3 Issue: 1 Pages: 2931-2931
  • DOI: 10.1038/srep02931
  • Peer Reviewed
• [Journal Article] Intronic and exonic nucleotide variations that affect RNA splicing in humans. (2013)
  • Author(s): K. Ohe, A. Masuda & K. Ohno.
  • Journal Title: iConcept Press. Sequence and Genome Analysis I Volume: in press
  • Peer Reviewed
• [Journal Article] Nested introns in an intron : Evidence of multi-step splicing in a large intron of the human dystrophin pre-mRNA. (2013)
  • Author(s): Suzuki, H., Kameyama, T., Ohe, K. Tsukahara, T., Mayeda, A.
  • Journal Title: FEBS Letters Volume: 587 Issue: 6 Pages: 555-561
  • DOI: 10.1016/j.febslet.2013.01.057
  • Peer Reviewed
• [Presentation] Sequence-specific RNA-binding of HMGA1a may play a role in acquired resistance of estrogen receptor-positive breast carcinoma (2013)
  • Author(s): Kenji Ohe, Shinsuke Miyajima, Kanako Kuwasako, Yutaka Muto, Toshiaki Utsumi, Masatoshi Hagiwara, Akila Mayeda
  • Organizer: 2013 CSHL Meeting on Eukaryotic mRNA Processing
  • Place of Presentation: コールドスプリングハーバー、ニューヨーク、米国
• [Presentation] HMGA1に対する「おとり」RNAは、 エストロゲン受容体アルファ-46（ERα46）の選択的スプライシング改変により腫瘍増殖を促進する (2012)
  • Author(s): 大江賢治、宮島慎介、内海俊明
  • Organizer: 第85回 日本内分泌学会学術総会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] 乳癌における癌遺伝子産物HMGA1aによるERα46 の発現調節機構 (2012)
  • Author(s): 宮島慎介、大江賢治、牛窓かおり、引地理浩、小林尚美、前田明、内海俊明
  • Organizer: 第20回 日本乳癌学会学術総会
  • Place of Presentation: 熊本市民会館
• [Book] BIO Clinica BIOLOGY TOPICS 選択的スプライシングを標的とした低分子化合物の医薬品開発 (2014)
  • Author(s): 大江賢治、萩原正敏
  • Total Pages: 6
  • Publisher: 北隆館
• [Remarks] ReaD&Researchmap
  • URL: http://researchmap.jp/ohekenji/