Tumor-suppressive effects and mechanism of a novel PPAR gamma agonist in esophageal caner

• Project/Area Number: 25462028
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: YOSHIDA Naoya 熊本大学, 大学院生命科学研究部(医), 講師 (60467983)
• Co-Investigator(Kenkyū-buntansha): BABA Yoshifumi 熊本大学, 大学院生命科学研究部, 講師 (20599708) ; IMAMURA Yu 熊本大学, 大学院生命科学研究部, 講師 (70583045) ; WATANABE Masayuki 公益財団法人がん研究会, 有明病院 消化器外科, 食道担当部長 (80254639)
• Research Collaborator: SAWAYAMA Hiroshi 熊本大学, 医学部附属病院, 非常勤診療医師 (40594875)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: PPARγ / 新規PPARγ agonist / 食道扁平上皮癌 / cetuximab / p21 / Akt / EGFR / agonist / 低分子化合物 / 予後因子 / Cetuximab

Outline of Final Research Achievements

The novel third-generation thiazolidinedione peroxisome proliferator-activated receptor gamma(PPARγ) agonist,previously demonstrated an anti-tumor effect in patients with advanced cancers.PPARγ expression was found to decrease in the tumors of esophageal squamous cell carcinoma(ESCC) patients,and its expression exhibited an inverse relationship with the expression of Ki-67.The novel PPARγ agonist can inhibit the proliferation ESCC cell lines both in vitro and in vivo.The PPARγ agonist was revealed to upregulate the p21 protein level in the nucleus by inactivating the AKT pathway and dephosphorylating p21 at Thr145.Treatment with the PPARγ agonist led to phosphorylate the EGFR and the MAPK pathway.The combination of the PPARγ agonist with cetuximab exerted synergetic anti-proliferative effects by negatively regulating EGFR.Our findings suggest that the novel PPARγ agonist can be used both alone and in combination with cetuximab as a potential therapeutic approach for ESCC.

Research Products

• [Journal Article] Reconstruction Using a Pedunculated Gastric Tube with Duodenal Transection After Esophagectomy and Pharyngolaryngectomy. (2015)
  • Author(s): Yoshida N, Baba Y, Oda E, Kosumi K, Ishimoto T, Watanabe M, Hiyoshi Y, Iwagami S, Kurashige J, Sakamoto Y, Miyamoto Y, Sugihara H, Eto K, Harada K, Baba H.
  • Journal Title: Ann Surg Oncol Volume: 22(13) Issue: 13 Pages: 4352-4352
  • DOI: 10.1245/s10434-015-4427-1
  • Peer Reviewed / Open Access
• [Journal Article] Duration of Smoking Cessation and Postoperative Morbidity After Esophagectomy for Esophageal Cancer: How Long Should Patients Stop Smoking Before Surgery? (2015)
  • Author(s): Yoshida N, Baba Y, Hiyoshi Y, Shigaki H, Kurashige J, Sakamoto Y, Miyamoto Y, Iwatsuki M, Ishimoto T, Kosumi K, Sugihara H, Harada K, Tokunaga R, Izumi D, Watanabe M, Baba H.
  • Journal Title: World J Surg Volume: 40(1) Issue: 1 Pages: 142-7
  • DOI: 10.1007/s00268-015-3236-9
  • Peer Reviewed / Open Access
• [Journal Article] Reviews of Recent Advances in Research and Treatment for Gastroenterological Malignancies Cancer metabolism in gastrointestinal cancer. (2015)
  • Author(s): Hiroshi Sawayama , Nobutomo Miyanari , Hideo Baba.
  • Journal Title: J Cancer Metastasis Treat Volume: 1 Issue: 3 Pages: 172-82
  • DOI: 10.4103/2394-4722.165533
  • Peer Reviewed / Open Access
• [Journal Article] Triangulating Stapling Technique Covered with the Pedicled Omental Flap for Esophagogastric Anastomosis: A Safe Anastomosis with Fewer Complications (2015)
  • Author(s): Yoshida N, Baba Y, Watanabe M, Hiyoshi Y, Ishimoto T, Iwagami S, Kurashige J, Sakamoto Y, Miyamoto Y, Baba H
  • Journal Title: J Am Coll Surg Volume: 220(2) Issue: 2 Pages: e13-e16
  • DOI: 10.1016/j.jamcollsurg.2014.10.015
  • Peer Reviewed
• [Journal Article] An original scoring system for predicting postoperative morbidity after esophagectomy for esophageal cancer (2015)
  • Author(s): Yoshida N, Baba Y, Watanabe M, Ida S, Ishimoto T, Karashima R, Iwagami S, Imamura Y, Sakamoto Y, Miyamoto Y, Baba H
  • Journal Title: Surg Today Volume: 45(3) Issue: 3 Pages: 346-54
  • DOI: 10.1007/s00595-014-0958-5
  • Peer Reviewed
• [Journal Article] Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer. (2014)
  • Author(s): Sawayama H, Ishimoto T, Watanabe M, Yoshida N, Sugihara H, Kurashige J, Hirashima K, Iwatsuki M, Baba Y, Oki E, Morita M, Shiose Y, Baba H
  • Journal Title: Cancer Res Volume: 74 Issue: 2 Pages: 575-585
  • DOI: 10.1158/0008-5472.can-13-1836
  • Peer Reviewed
• [Journal Article] High expression of glucose transporter 1 on primary lesions of esophageal squamous cell carcinoma is associated with hematogenous recurrence (2014)
  • Author(s): Sawayama H, Ishimoto T, Watanabe M, Yoshida N, Baba Y, Sugihara H, Izumi D, Kurashige J, Baba H
  • Journal Title: Ann Surg Oncol Volume: 21(5) Issue: 5 Pages: 1756-62
  • DOI: 10.1245/s10434-013-3371-1
  • Peer Reviewed
• [Journal Article] Influence of preoperative docetaxel, cisplatin, and 5-fluorouracil on the incidence of complication after esophagectomy for resectable advanced esophageal cancer (2014)
  • Author(s): 108 Yoshida N., Watanabe M., Baba Y., Ishimoto T., Iwagami S., Sakamoto Y., Miyamoto Y., Karashima R., Baba H
  • Journal Title: Dis Esophagus Volume: 27 Issue: 4 Pages: 374-379
  • DOI: 10.1111/dote.12117
  • Peer Reviewed
• [Presentation] 食道扁平上皮癌におけるGlut1の発現とMicrovessel densityに関する検討 (2014)
  • Author(s): 澤山 浩
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-03 – 2014-04-05