Functional analysis of PHLDA3 in neuroendocrine tumor

• Project/Area Number: 17H07378
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Endocrinology
• Research Institution: National Cancer Center Japan
• Principal Investigator: TAKIKAWA Masahiro 国立研究開発法人国立がん研究センター, 研究所, 特任研究員 (80807834)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経内分泌腫瘍 / p53 / PHLDA3遺伝子 / PHLDA1遺伝子 / PHLDA3 / PHLDA1 / 内分泌学 / 遺伝子

Outline of Final Research Achievements

PHLDA3 is a target gene of p53. Inactivation of PHLDA3 by loss of heterozygosity (LOH) in PHLDA3 locus is frequently observed in pancreatic and lung neuroendocrine tumors (NETs) (Cell 2009, PNAS 2014). We hypothesized that neuroendocrine tumors arisen in every organ might harbor genetic alterations in PHLDA3. To investigate the relationship between PHLDA3 alterations and cancer malignancy, we collected several kinds of clinical samples and constructed NET model mice.
We found that PHLDA1, another PHLDA family gene, acts as a repressor for cell proliferation via competitive interaction to PIPs leading to Akt inhibition.

Academic Significance and Societal Importance of the Research Achievements

神経内分泌腫瘍（neuroendocrine tumor; NET）は、毎年の発症率が10万人あたり6人未満の希少がんであり、サンプルの収集が困難であることから研究が遅れていた。神経内分泌細胞は全身の諸臓器に分布していることが知られている。肺と膵臓のNETで高頻度な遺伝子異常を示したPHLDA3が、全身の神経内分泌腫瘍に関連する可能性を明らかにすることで、現在使用されている抗がん剤の適応拡大や、NET悪性化の診断に基盤的な知見を得ることが期待できる。また、がん抑制遺伝子PHLDA3と同様の働きを示すPHLDA1の機能を明らかにし、がん悪性化メカニズムの解明を行った。

Research Products

• [Journal Article] PHLDA1, another PHLDA family protein that inhibits Akt. (2018)
  • Author(s): Chen, Y., Takikawa, M., Tsutsumi, S., Yamaguchi, Y., Okabe, A., Shimada, M., Kawase, T., Sada, A., Ezawa, I., Takano, Y., Nagata, K. Suzuki, Y., Semba, K., Aburatani, H., and Ohki, R.
  • Journal Title: Cancer Sci Volume: 109 Issue: 11 Pages: 3532-3542
  • DOI: 10.1111/cas.13796
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A vicious partnership between AKT and PHLDA3 to facilitate neuroendocrine tumors (2017)
  • Author(s): Masahiro Takikawa and Rieko Ohki
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 6 Pages: 1101-1108
  • DOI: 10.1111/cas.13235
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Remarks] p53標的遺伝子であり、がん抑制遺伝子であるPHLDA3の機能解析
  • URL: https://www.ncc.go.jp/jp/ri/division/fundamental_oncology/project/020/index.html