Elucidation of mechanism underlying ectopic ACTH producing pheochromocytoma

• Project/Area Number: 17K16160
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Endocrinology
• Research Institution: Chiba University
• Principal Investigator: SAKUMA Ikki 千葉大学, 医学部附属病院, 特任助教 (70791721)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ACTH / 褐色細胞腫 / 内科 / クッシング病

Outline of Final Research Achievements

The molecular mechanism of ACTH production has not been fully elucidated in ectopic ACTH syndrome. In this study, I examined POMC methylation deregulation, upstream signals of POMC regulation, and onset origin of tumor in ectopic ACTH producing pheochromocytoma. I found that demethylation of POMC promoter region was important for POMC expression in ectopic ACTH production syndrome. In addition, analysis of RNA-sequencing using ectopic ACTH secreting pheochromocytoma tumor.

Academic Significance and Societal Importance of the Research Achievements

褐色細胞腫はカテコラミンを自律分泌するクロム親和性細胞由来の腫瘍である。稀にACTHを異所性に産生することが報告されているが、その発症機構は十分に明らかにされていない。本研究では、異所性ACTH産生症候群において、POMC発現の機能性獲得に、POMC promoter領域の脱メチル化が重要であることが示された。本研究の成果が、異所性ACTH産生症候群の新たな治療薬への臨床応用に展開するための基盤になることが期待される。

Research Products

• [Journal Article] Ceritinib Aggravates Glycemic Control in Insulin-treated Patients with Diabetes and Metastatic ALK-positive Lung Cancer (2019)
  • Author(s): Sakuma Ikki、Nagano Hidekazu、Yoshino Ichiro、Yokote Koutaro、Tanaka Tomoaki
  • Journal Title: Internal Medicine Volume: 58 Issue: 6 Pages: 817-820
  • DOI: 10.2169/internalmedicine.1870-18
  • NAID: 130007614396
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-03-15
  • Peer Reviewed / Open Access
• [Journal Article] A Unique Case of Renovascular Hypertension due to Fibromuscular Dysplasia in an Extra-renal Artery (2018)
  • Author(s): Sakuma Ikki、Saito Jun、Matsuzawa Yoko、Omura Masao、Matsui Seiji、Nishikawa Tetsuo
  • Journal Title: Internal Medicine Volume: 57 Issue: 18 Pages: 2689-2694
  • DOI: 10.2169/internalmedicine.0023-17
  • NAID: 130007484304
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-09-15
• [Journal Article] p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells. (2018)
  • Author(s): Nagano H, Hashimoto N, Nakayama A, Suzuki S, Miyabayashi Y, Yamato A, Higuchi S, Fujimoto M, Sakuma I, Beppu M, Yokoyama M, Suzuki Y, Sugano S, Ikeda K, Tatsuno I, Manabe I, Yokote K, Inoue S, Tanaka T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 115 Issue: 33 Pages: 8370-8375
  • DOI: 10.1073/pnas.1804243115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glucagonoma with necrolytic migratory erythema: metabolic profile and detection of biallelic inactivation of DAXX gene. (2018)
  • Author(s): ①Tamura A, Ogasawara T, Fujii Y, Kaneko H, Nakayama A, Higuchi S, Hashimoto N, Miyabayashi Y, Fujimoto M, Komai E, Kono T, Sakuma I, Nagano H, Suzuki S, Koide H, Yokote K, Iseki K, Oguma R, Matsue H, Nojima H, Sugiura K, Yoshitomi H, Ohtsuka M, Rahmutulla B, Kaneda A, Inoshita N, Ogawa S, Tanaka T.
  • Journal Title: J Clin Endocrinol Metab. Volume: 23 Issue: 7 Pages: 1-4
  • DOI: 10.1210/jc.2017-02646
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prednisolone-responsive Postpartum IgG4-related Hypophysitis (2018)
  • Author(s): Koide H, Shiga A, Komai E, Yamato A, Fujimoto M, Tamura A, Kono T, Nakayama A, Takiguchi T, Higuchi S, Sakuma I, Nagano H, Hashimoto N, Suzuki S, Takeda Y, Shibuya M, Nishioka H, Yamada S, Inoshita N, Ishiwatari N, Horiguchi K, Yokote K, Tanaka T.
  • Journal Title: Internal Medicine Volume: 57 Issue: 3 Pages: 367-375
  • DOI: 10.2169/internalmedicine.8446-16
  • NAID: 130006329476
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] CONGESTIVE HEART FAILURE SECONDARY TO A TSH-SECRETING PITUITARY ADENOMA AGGRAVATED BY TAKOTSUBO CARDIOMYOPATHY IN AN ELDERLY PATIENT (2018)
  • Author(s): Sakuma Ikki、Koide Hisashi、Yoshida Tomohiko、Yamato Azusa、Fujimoto Masanori、Tamura Ai、Komai Eri、Kono Takashi、Nagano Hidekazu、Horiguchi Kentaro、Yokote Koutaro、Tanaka Tomoaki
  • Journal Title: AACE Clinical Case Reports Volume: 4 Issue: 2 Pages: 115-123
  • DOI: 10.4158/ep171968.cr
  • Peer Reviewed / Open Access
• [Journal Article] SEVEN FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA CASES IN THREE UNRELATED JAPANESE FAMILIES AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ANALYSIS OF THE THYROXINE BINDING PROFILE. (2017)
  • Author(s): Nagano H, Nakagawa Y, Ishikawa N, Watanabe H, Miyabayashi Y, Nakayama A, Fujimoto M, Komai E, Shiga A, Tamura A, Kono T, Takiguchi T, Higuchi S, Sakuma I, Hashimoto N, Suzuki S, Koide H, Yokote K, Tanaka T.
  • Journal Title: Endocr Pract. Volume: 23 Issue: 11 Pages: 1325-1332
  • DOI: 10.4158/ep171964.or
  • Peer Reviewed / Open Access
• [Journal Article] Multihormonal pituitary adenoma concomitant with Pit-1 and Tpit lineage cells causing acromegaly associated with subclinical Cushing's disease: a case report. (2017)
  • Author(s): Takiguchi T, Koide H, Nagano H, Nakayama A, Fujimoto M, Tamura A, Komai E, Shiga A, Kono T, Higuchi S, Sakuma I, Hashimoto N, Suzuki S, Miyabayashi Y, Ishiwatari N, Horiguchi K, Nakatani Y, Yokote K, Tanaka T.
  • Journal Title: BMC Endocr Disord. Volume: 17 Issue: 1 Pages: 54-54
  • DOI: 10.1186/s12902-017-0203-5
  • Peer Reviewed / Open Access
• [Presentation] Characterization and Categorization Based on Genotype-Biochemical Phenotype Association in Fructose-1,6-Bisphosphatase Deficiency (2019)
  • Author(s): Ikki Sakuma, Yue Yao, Masanori Fujimoto, Hidekazu Nagano, Koutaro Yokote and Tomoaki Tanaka
  • Organizer: ENDO2019
  • Int'l Joint Research
• [Presentation] FBPase欠損症におけるミスセンス変異の分子病態の解明 (2018)
  • Author(s): 佐久間一基、 姚躍、 藤本真徳、永野秀和、横手幸太郎、田中知明
  • Organizer: 第28回臨床内分泌代謝Update
• [Presentation] p53下流遺伝子FDXRによる鉄代謝依存的ROS制御を介した肝糖新生の調節機構 (2018)
  • Author(s): 佐久間一基、姚躍、横手幸太郎、田中知明
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] FBPase欠損症における新規FBP1変異の同定と機能解析 (2018)
  • Author(s): 佐久間一基、 姚躍、 藤本真徳、永野秀和、横手幸太郎、田中知明
  • Organizer: 第91回日本内分泌学会学術総会
• [Presentation] 症例から学ぶ副腎性高血圧症の病理と遺伝子変異 副腎静脈サンプリングで機能性を確認しえたアルドステロン産生腺腫合併の無症候性褐色細胞腫 (2017)
  • Author(s): 佐久間一基, 山崎 有人, 笹野 公伸, 横手 幸太郎, 田中 知明
  • Organizer: 第40回日本高血圧学会総会
  • Invited
• [Presentation] FBPase欠損症の成人例で同定されたFBP1新規変異とその機能解析 (2017)
  • Author(s): 佐久間一基, 藤本真徳、大和梓、田村愛、駒井絵里、志賀明菜、河野貴史、中山哲俊、永野秀和、鈴木佐和子、小出尚史、田中知明、横手幸太郎
  • Organizer: 第90回日本内分泌学会学術総会
• [Presentation] セリチニブ投与後に血糖コントロール悪化を認めた2型糖尿病の1例 (2017)
  • Author(s): 佐久間一基、石田 晶子, 吉井 聡美, 出口 ハンナ, 大和 梓, 藤本 真徳, 田村 愛, 駒井 絵里, 河野 貴史, 永野 秀和, 小出 尚史, 田中 知明, 横手 幸太郎
  • Organizer: 第27回臨床内分泌代謝Update
• [Presentation] FBPase欠損症の成人例で同定されたFBP1新規変異とその機能解析 (2017)
  • Author(s): 佐久間一基、藤本 真徳, 大和 梓, 田村 愛, 駒井 絵里, 志賀 明菜, 河野 貴史, 中山 哲俊, 永野 秀和, 鈴木 佐和子, 小出 尚史, 田中 知明, 横手 幸太郎
  • Organizer: 第60回日本糖尿病学会年次学術集会