Functional analysis of (pro)renin receptor in the genesis of pancreatic cancer

• Project/Area Number: 16K14610
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kagawa University
• Principal Investigator: Shibayama Yuki 香川大学, 医学部, 博士研究員 (90401190)
• Research Collaborator: NISHIYAMA Akira ; YASUDA Jun ; YACHIDA Shinichi ; KIYOMOTO Hideyasu ; MASAKI Tsutomu ; YUZAWA Yukio ; TAKAI Shinji ; TAKAHASHI Kazuo ; YAMAGUCHI Hisateru ; FUJISAWA Yoshihide ; YAMAZAKI Daisuke ; RAHMAN Asadur ; FUJIMORI Takayuki
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: (プロ)レニン受容体 / 膵臓がん / ゲノム不安定性 / 発がん / クロマチンリモデリング / （P)RR / 癌 / ゲノム

Outline of Final Research Achievements

The aim of this study is to elucidate whether (pro)renin receptor [(P)RR] is involved in the genesis of pancreatic ductal adenocarcinoma (PDAC). Human whole-genome analysis revealed that aberrant (P)RR expression induced massive chromosomal rearrangements and enhanced the total number of somatic mutations at the global level in human pancreatic ductal epithelial (HPDE) cells, which are capable of transforming into PDAC. (P)RR-expressing HPDE cell population engrafted into the renal subcapsules of immunodeficient mice showed the biological characters of malignant tumour such as atypical cells including abnormal nuclear shapes. (P)RR overexpression also resulted in the failure of genomic stability pathways such as DNA replication, DNA repair and telomere maintenance. In conclusion, our findings demonstrate that aberrant (P)RR expression induces genomic instability by the disorder of genomic stability pathways.

Research Products

• [Journal Article] High glucose augments angiotensinogen in human renal proximal tubular cells through hepatocyte nuclear factor-5. (2017)
  • Author(s): Wang J, Shibayama Y, Kobori H, Liu Y, Kobara H, Masaki T, Wang Z, Nishiyama A.
  • Journal Title: PLoS One Volume: 12 Issue: 10 Pages: e0185600-e0185600
  • DOI: 10.1371/journal.pone.0185600
  • Peer Reviewed / Open Access
• [Journal Article] IBMX protects human proximal tubular epithelial cells from hypoxic stress through suppressing hypoxia-inducible factor-1α expression (2017)
  • Author(s): Hasan Arif Ul、Kittikulsuth Wararat、Yamaguchi Fuminori、Musarrat Ansary Tuba、Rahman Asadur、Shibayama Yuki、Nakano Daisuke、Hitomi Hirofumi、Tokuda Masaaki、Nishiyama Akira
  • Journal Title: Experimental Cell Research Volume: 358 Issue: 2 Pages: 343-351
  • DOI: 10.1016/j.yexcr.2017.07.007
  • Peer Reviewed
• [Journal Article] Letter to the Editor. Expression of tissue (pro)renin receptor and concentrations of its soluble form in CSF in adult diffuse gliomas response (2017)
  • Author(s): Kouchi M, Shibayama Y, Ogawa D, Miyake K, Nishiyama A, Tamiya T
  • Journal Title: J Neurosurg Volume: 127 Issue: 4 Pages: 962-964
  • DOI: 10.3171/2017.2.jns17254
  • Peer Reviewed
• [Journal Article] (Pro)renin receptor is crucial for glioma development via the Wnt/β-catenin signaling pathway. (2016)
  • Author(s): Kochi m. Shibayama Y, Ogawa D, Miyake K, Nishiyama A, Tamiya T
  • Journal Title: J Neurosurg Volume: epub Issue: 4 Pages: 1-10
  • DOI: 10.3171/2016.9.jns16431
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Aberration of (pro)renin receptor induces genomic instability in human pancreatic ductal epithelial cells (2017)
  • Author(s): Shibayama, Y., Yasuda, J., Yamazaki, D., Rahman, A., Yachida, S., Nishiyama, A.
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] 膵臓癌治療の新たなアプローチ (2017)
  • Author(s): 西山 成、谷内田真一、柴山弓季
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] (プロ)レニン受容体発現の亢進は、ヒト膵管上皮細胞のゲノム不安定性を生じる (2017)
  • Author(s): 柴山弓季、安田純、谷内田真一、西山 成
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] (プロ)レニン受容体発現の増大によって生じるゲノム不安定性の分子メカニズム (2017)
  • Author(s): 柴山弓季、西山 成
  • Organizer: ConsBio2017
• [Presentation] 高血糖はヒト近位尿細管細胞のアンジオテンシノーゲンの発現をhepatocyte nuclear factor-5を介して亢進する (2017)
  • Author(s): 西山 成、柴山弓季、小堀浩幸、Wang, J.
  • Organizer: 第90回日本薬理学会年会
• [Presentation] (Pro)renin receptor promotes colorectal cancer through Wnt/be-ta catenin pathway despite of constructive mutations (2017)
  • Author(s): Wang, J., Shibayama, Y., Nishiyama, A.
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] (プロ)レニン受容体過剰発現で生じるヒト膵管上皮細胞のゲノム不安定性 (2016)
  • Author(s): 柴山弓季、安田 純、西山 成
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] 膵臓がんにおける(プロ)レニン受容体とWnt/β-catenin経路を介した腫瘍進展 (2016)
  • Author(s): 柴山弓季、谷内田真一、西山 成
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] Role of (Pro)renin receptor in the activation of Wnt/β-catenin pathway in colon cancer (2016)
  • Author(s): Wang, J., Shibayama,Y., Nakano, D. Hitomi, H. and Nishiyama, A.
  • Organizer: HYPERTENSION SEOUL. 26th Scientific Meeting of the ISH.
  • Place of Presentation: Corex, Seoul, Korea
  • Year and Date: 2016-09-24
  • Int'l Joint Research
• [Presentation] 神経膠腫におけるWnt/β-catenin を介した（pro）renin receptorの発現と役割 (2016)
  • Author(s): 河内雅章、柴山弓季、小川大輔、三宅啓介、西山 成、田宮 隆
  • Organizer: 第17回日本分子脳神経外科学会
  • Place of Presentation: 帝京大学板橋キャンパス
  • Year and Date: 2016-08-26
• [Presentation] (Pro)renin receptor is pivotal for Wnt/β-catenin-dependent genesis of pancreatic ductal adenocarcinoma (2016)
  • Author(s): Shibayama, Y., Yachida, S., Rahman, A. and Nishiyama, A.
  • Organizer: 第47回日本膵臓学会・第20回国際膵臓学会・第6回アジアオセアニア膵臓学会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-08-04
  • Int'l Joint Research / Invited
• [Presentation] 大腸がんの病態における(プロ)レニン受容体の関与 (2016)
  • Author(s): 西山 成、柴山弓季、Wang Juan
  • Organizer: 第53回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2016-04-15