A molecular analysis in colorectal poorly differentiated adenocarcinoma and its clinical application

• Project/Area Number: 19K08398
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Aoki Hironori 札幌医科大学, 医学部, 訪問研究員 (40749496)
• Co-Investigator(Kenkyū-buntansha): 山本 英一郎 札幌医科大学, 医学部, 訪問研究員 (60567915)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 早期大腸がん / 低分化腺がん / 浸潤・転移 / トランスクリプトーム / 早期大腸低分化腺がん / 微小環境 / 浸潤 / 腫瘍関連マクロファージ / SAA1 / 大腸低分化腺癌 / 大腸低分化腺がん

Outline of Research at the Start

早期大腸がんにおける低分化成分の存在は、リンパ節転移と密接に関連することが知られている。今回臨床検体を対象としたトランスクリプトーム解析から、低分化腺がんにおいて特異的に高発現している遺伝子Aに着目した。本研究では、大腸がんにおける遺伝子Aの機能を解明し、新規診断・治療法の開発につなげることを目指す。

Outline of Final Research Achievements

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues, and detected significant upregulation of SAA1 in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. We also found that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. Immunohistochemical analysis of primary T1 CRCs showed accumulation of macrophages at SAA1-positive invasive front regions. Our data suggest that macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1, and that SAA1 may be a predictive marker and a therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

我々は早期大腸低分化腺がんの解析から、SAA1が浸潤先進部の低分化成分に極めて特異的に発現することを見いだした。低分化腺がんは著しく進行が早いために早期で発見することは困難である。本研究は、最先端の消化管内視鏡診断技術をもつ専門施設と強力に連携することで初めて可能となった、独自性の高い研究である。本研究から、SAA1が早期大腸がんの予後予測マーカーや、治療標的となりうる可能性が示された。

Research Products

• [Journal Article] A Case of Pedunculated Esophageal Neuroendocrine Tumor G1 (2022)
  • Author(s): Aoki Hironori、Omori Yuko、Katanuma Akio
  • Journal Title: Clinical Gastroenterology and Hepatology Volume: 20 Issue: 4 Pages: e651-e652
  • DOI: 10.1016/j.cgh.2021.02.039
  • Peer Reviewed
• [Journal Article] Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β‐serum amyloid A1 axis (2021)
  • Author(s): Sudo Gota、Aoki Hironori、Yamamoto Eiichiro、Takasawa Akira、Niinuma Takeshi、Yoshido Ayano、Kitajima Hiroshi、Yorozu Akira、Kubo Toshiyuki、Harada Taku、Ishiguro Kazuya、Kai Masahiro、Katanuma Akio、Yamano Hiro‐o、Osanai Makoto、Nakase Hiroshi、Suzuki Hiromu
  • Journal Title: Cancer Science Volume: 112 Issue: 10 Pages: 4151-4165
  • DOI: 10.1111/cas.15080
  • Peer Reviewed / Open Access
• [Journal Article] An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST (2021)
  • Author(s): NIINUMA TAKESHI、KITAJIMA HIROSHI、YAMAMOTO EIICHIRO、MARUYAMA REO、AOKI HIRONORI、HARADA TAKU、ISHIGURO KAZUYA、SUDO GOTA、TOYOTA MUTSUMI、YOSHIDO AYANO、KAI MASAHIRO、NAKASE HIROSHI、SUGAI TAMOTSU、SUZUKI HIROMU
  • Journal Title: Anticancer Research Volume: 41 Issue: 6 Pages: 2817-2828
  • DOI: 10.21873/anticanres.15062
  • Peer Reviewed / Open Access
• [Journal Article] The continuum of transformation of TSA to low‐grade neoplasia and cancer with BRAF mutation ? A case with molecular analysis (2021)
  • Author(s): Aoki Hironori、Adachi Yasushi、Yamamoto Eiichiro、Yoshida Yukinari、Ishii Yoshifumi、Yamano Hiro‐o、Suzuki Hiromu、Endo Takao
  • Journal Title: Pathology International Volume: － Issue: 5 Pages: 368-370
  • DOI: 10.1111/pin.13078
  • Peer Reviewed
• [Journal Article] Histopathologic features and fragmentation of polyps with cold snare defect protrusions (2021)
  • Author(s): Ishii Tatsuya、Harada Taku、Tanuma Tokuma、Yamazaki Hajime、Tachibana Yasuhiro、Aoki Hironori、Shinohara Toshiya、Katanuma Akio
  • Journal Title: Gastrointestinal Endoscopy Volume: 93 Issue: 4 Pages: 952-959
  • DOI: 10.1016/j.gie.2020.07.040
  • Peer Reviewed
• [Presentation] 活性化マクロファージはIL-1β-SAA1 axisを介して早期大腸がんの浸潤を促進する． (2021)
  • Author(s): 須藤豪太，山本英一郎，青木敬則，髙澤啓，新沼猛，久保俊之，萬顕，吉戸文乃，北嶋洋志，甲斐正広，小山内誠，仲瀬裕志，鈴木拓．
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] SMOC1 の大腸腫瘍診断マーカーとしての臨床的有用性の検討 (2020)
  • Author(s): 青木 敬則、山本 英一郎、高澤 啓、新沼 猛、山野 泰穂、萬 顕、北嶋 洋志、甲斐 正広、小山内 誠、仲瀬 裕志、菅井 有、鈴木 拓
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 大腸鋸歯状腺腫の発育進展に関わるSMOC1メチル化異常の検討 (2020)
  • Author(s): 青木敬則, 山本英一郎, 高澤啓, 山野泰穂, 原田拓, 松下 弘雄, 菅井有, 鈴木拓
  • Organizer: 第16回日本消化管学会総会学術集会
• [Presentation] Clinical usefulness of SMOC1 as a diagnostic marker of colorectal precancerous lesions (2019)
  • Author(s): Hironori Aoki, Eiichiro Yamamoto, Akira Takasawa, Takeshi Niinuma, Hiro-o Yamano, Akira Yorozu, Hiroshi Kitajima, Masahiro Kai, Makoto Osanai, Hiroshi Nakase, Tamotsu Sugai, Hiromu Suzuki
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Clinical usefulness of SMOC1 as a diagnostic marker for colorectal serrated lesions and colorectal precancerous lesions (2019)
  • Author(s): Hironori Aoki, Eiichiro Yamamoto, Akira Takasawa, Hiro-o Yamano, Taku Harada, Tamotsu Sugai, Hiromu Suzuki
  • Organizer: ACG2019
  • Int'l Joint Research