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教室で行われている基礎研究について、主な研究領域と最近の代表的な論文を紹介します

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消化器の発癌メカニズム

日本人の3人に1人が癌で亡くなる時代を迎え、その約半数が消化器癌とされています。遺伝子改変マウスによる膵癌関連遺伝子の解析、胃発癌機構の検討、大腸発癌における癌微小環境の解析、慢性肝疾患から肝発癌にいたる分子メカニズムの研究など、 広範な消化器癌のすべてを対象として、新しいコンセプトの提唱、新規治療標的の発掘を目指しています。

1. Ogawa S, et al. SETDB1 Inhibits p53-Mediated Apoptosis and is Required for Formation of Pancreatic Ductal Adenocarcinomas in Mice. Gastroenterology.(in press)
2. Nishikawa Y, et al. Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis. Oncogene. 2019 May;38(22):4283-4296.
3. Ikuta K, et al. Nardilysin suppresses pancreatic ductal adenocarcinoma initiation by inhibiting pancreatitis in mice. Gut.2019 May;68(5):882-892.
4. Eso Y, et al. MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development. Cancer Res. 2016 Aug 1;76(15):4383-93.
5. Sawai Y, et al. Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations. Cancer Res. 2015 Aug 15;75(16):3292-301.
6. Kanda K, et al. Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF-α. EMBO Mol Med. 2012 May;4(5):396-411.
7. Kawada M, et al. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene. 2012 Jun 28;31(26):3111-23.
8. Takai A, et al. Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation. Oncogene. 2012 Mar 29;31(13):1733-42.

消化器をつなぐ免疫ネットワーク

近年、消化器疾患の病態に、免疫、代謝などによる全身のネットワークが大きく影響を及ぼしていることが明らかになってきました。 炎症性腸疾患、IgG4関連疾患、非アルコール性脂肪性肝疾患など、様々な消化器疾患に対する全身の免疫、代謝ネットワークの影響を明らかにしていきます。

1. Shiokawa M, et al. Laminin 511 is a target antigen in autoimmune pancreatitis. Sci Transl Med. 2018 Aug 8;10(453).
2. Shiokawa M, et al. Pathogenicity of IgG in patients with IgG4-related disease. Gut. 2016 Aug;65(8):1322-32.
3. Honzawa Y, et al. Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn's disease. Gut. 2014 Dec;63(12):1902-12.
4. Maruoka R, et al. Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis. Gastroenterology. 2013 Jul;145(1):209-220.
5. Yamamoto S, et al. Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling. Am J Physiol. 2013 Aug 1;305(3):G241-9.
6. Shiokawa M, et al. Risk of cancer in patients with autoimmune pancreatitis. Am J Gastroenterol. 2013 Apr;108(4):610-7.
7. Tsuji Y, et al. Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis. Immunity. 2012 Aug 24;37(2):326-38.
8. Uza N, et al. SR-PSOX/CXCL16 plays a critical role in the progression of colonic inflammation. Gut. 2011 Nov;60(11):1494-505.

消化器の幹細胞とホメオスターシス

消化器臓器の恒常性維持や、消化器癌の発生、進展の過程で、幹細胞を頂点とする階層性と細胞の自在な可塑性が大きな役割を果たしています。遺伝子改変マウスや生体外３次元培養系において、多光子顕微鏡によるライブイメージングや細胞系譜解析を用いた「変化の見える」解析を行い、再生医療、副作用の少ない癌幹細胞標的治療を目指した創薬シーズの同定などを展開しています。

1. Goto N, et al. Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells. Proc Natl Acad Sci U S A.2019 Jun 25;116(26):12996-13005.
2. Yoshioka T, et al. Bmi1 marks gastric stem cells located in the isthmus in mice. J Pathol. 2019 Jun;248(2):179-190.
3. Hiramatsu Y, et al. Arid1a is essential for intestinal stem cells through Sox9 regulation. Proc Natl Acad Sci USA. 2019 Jan 29;116(5):1704-1713.
4. Tsuda M, et al. The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. J Clin Invest. 2018 Aug 1;128(8):3475-3489.
5. Kimura Y, et al. ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice. Gastroenterology. 2018 Jul;155(1):194-209.
6. Matsumoto T, et al. Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma. Cancer Res. 2017 Nov 15;77(22):6131-6143.
7. Goto N, et al. Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine. Cancer Res. 2017 Jul 1;77(13):3442-3454.
8. Takada Y, et al. Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling. Development. 2016 Oct 1;143(19):3532-3539.
9. Nakanishi Y, et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet. 2013 Jan;45(1):98-103.

消化器とそれをとりまくオミックス

消化器領域には、感染によって慢性炎症から発癌をおこす病原微生物がいくつかあります。代表的なものがヘリコバクター・ピロリ菌であり、B型肝炎ウイルスやC型肝炎ウイルスです。これらの細菌やウイルスと宿主＝ヒトの消化器臓器を対象として、次世代ならびに第三世代シーケンサーを用いた遺伝子解析や分子生物学的解析から、病態との関連や炎症発癌メカニズムの解明、さらには新規治療法の開発に取り組んでいます

1. Mizuguchi A, et al. Genetic features of multicentric/multifocal intramucosal gastric carcinoma. Int J Cancer. 2018 Oct 15;143(8):1923-1934.
2. Ki Kim S, et al. TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma. Int J Cancer. 2016 Dec 1;139(11):2512-8.
3. Takeda H, et al. Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing. Sci Rep. 2017 Mar 31;7:45605.
4. Shimizu T, et al. Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. Gastroenterology. 2014 Aug;147(2):407-17.
5. Kim SK, et al., A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations. Int J Cancer. 2014 Mar 1;134(5):1067-76.
6. Ikeda A, et al. Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma. Gastroenterology. 2014 Jan;146(1):222-32.

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