The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling.

• Project/Area Number: 16K10553
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Showa University
• Principal Investigator: Omoto Tomokastu 昭和大学, 医学部, 特別研究生 (10515456)
• Co-Investigator(Kenkyū-buntansha): 金山 朱里 昭和大学, 医学部, 准教授 (10338535)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Hic-5 / 大腸がん / がん関連線維芽細胞 / 細胞外微小環境制御 / 大腸癌 / 癌関連線維芽細胞 / 線維芽細胞

Outline of Final Research Achievements

Carcinoma-associated fibroblasts (CAFs) influence tumor initiation, progression and metastasis within the tumor-associated stroma. This suggests that CAFs would be a potential target for tumor therapy. Here we found that Hydrogen peroxide-inducible clone-5 (Hic-5), also named transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was strongly induced in CAFs found in human colorectal cancer. To clarify the function and significance of Hic-5 in colorectal cancer in vivo, we utilized a mouse model of azoxymethane (AOM)-induced colorectal cancer using Hic-5 deficient mice. Lack of Hic-5 in CAFs completely prevented AOM-induced colorectal cancer development in the colon tissues of mice. Mechanistic investigation revealed that Hic-5 promoted the expression of lysyl oxidase and collagen I in human control counterpart fibroblasts. Taken together, these results demonstrate that Hic-5 in CAFs is responsible for orchestrating or generating a tumor-promoting stroma.

Academic Significance and Societal Importance of the Research Achievements

大腸癌は近年増加が著しい悪性腫瘍で，従来の治療に加えて予防的なアプローチも重要性を増している．そこで現状の癌細胞そのものをターゲットにした治療概念にとらわれない、新しい治療ターゲット分子が提唱可能になったと考える．

Research Products

• [Journal Article] Excessive mechanical loading promotes osteoarthritis through the gremlin-1?NF-κB pathway (2019)
  • Author(s): Chang Song Ho、Mori Daisuke、Kobayashi Hiroshi、Mori Yoshifumi、Nakamoto Hideki、Okada Keita、Taniguchi Yuki、Sugita Shurei、Yano Fumiko、Chung Ung-il、Kim-Kaneyama Joo-ri、Yanagita Motoko、Economides Aris、Canalis Ernesto、Chen Di、Tanaka Sakae、Saito Taku
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1442-1442
  • DOI: 10.1038/s41467-019-09491-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toll‐Like Receptor 9 Plays a Pivotal Role in Angiotensin II Induced Atherosclerosis (2019)
  • Author(s): Fukuda Daiju、Nishimoto Sachiko、Aini Kunduziayi、Tanaka Atsushi、Nishiguchi Tsuyoshi et al.
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 7
  • DOI: 10.1161/jaha.118.010860
  • NAID: 120006602927
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial calpain systems orchestrate myofibroblast differentiation during wound healing. (2019)
  • Author(s): Miyazaki T, Haraguchi S, Kim-Kaneyama JR, Miyazaki A.
  • Journal Title: FASEB Journal Volume: 33 Issue: 2 Pages: 2037-2046
  • DOI: 10.1096/fj.201800588rr
  • Peer Reviewed
• [Journal Article] Expression of steroidogenic enzymes and metabolism of steroids in COS-7 cells known as non-steroidogenic cells. (2018)
  • Author(s): Nozaki M, Haraguchi S, Miyazaki T, Shigeta D, Kano N, Lei XF, Kim-Kaneyama JR, Minakata H, Miyazaki A, Tsutsui K.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 2167-2167
  • DOI: 10.1038/s41598-018-20226-2
  • Peer Reviewed / Open Access
• [Journal Article] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling. (2018)
  • Author(s): Omoto T, Kim-Kaneyama JR, Lei XF, Orimo A, Ohnishi K, Yoshihara K, Miyauchi A, Li S, Gao L, Umemoto T, Tanaka J, Nakahara K, Takeya M, Ishida F, Kudo SE, Haraguchi S, Miyazaki T, Miyazaki A.
  • Journal Title: Oncogene. Volume: 37 Issue: 9 Pages: 1205-1219
  • DOI: 10.1038/s41388-017-0033-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity. (2017)
  • Author(s): Kim Y, Lim S, Ha T, Song YH, Sohn YI, Park DJ, Paik SS, Kim-Kaneyama JR, Song MR, Leung A, Levine EM, Kim IB, Goo YS, Lee SH, Kang KH, Kim JW.
  • Journal Title: Elife. Volume: 6
  • DOI: 10.7554/elife.21303
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Heterogeneity of Nadph Oxidases in Atherosclerotic and Aneurysmal Diseases (2017)
  • Author(s): Kigawa Y, Miyazaki T, Lei XF, Kim-Kaneyama JR, Miyazaki A.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 1 Pages: 1-13
  • DOI: 10.5551/jat.33431
  • NAID: 130005188266
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing. (2016)
  • Author(s): Miyazaki T, Tonami K, Hata S, Aiuchi T, Ohnishi K, Lei XF, Kim-Kaneyama JR, Takeya M, Itabe H, Sorimachi H, Kurihara H, Miyazaki A
  • Journal Title: J Clin Invest Volume: 126 Issue: 9 Pages: 3417-3432
  • DOI: 10.1172/jci85880
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The pathophysiological role of oxidized cholesterols in epicardial fat accumulation and cardiac dysfunction: a study in swine fed a high caloric diet with an inhibitor of intestinal cholesterol absorption, ezetimibe. (2016)
  • Author(s): Shimabukuro M, Okawa C, Yamada H, Yanagi S, Uematsu E, Sugasawa N, Kurobe H, Hirata Y, Kim-Kaneyama JR, Lei XF, Takao S, Tanaka Y, Fukuda D, Yagi S, Soeki T, Kitagawa T, Masuzaki H, Sato M, Sata M.
  • Journal Title: J Nutr Biochem. Volume: 35 Pages: 66-73
  • DOI: 10.1016/j.jnutbio.2016.05.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of paxillin family members in adhesion and ECM degradation coupling at invadosomes. (2016)
  • Author(s): Petropoulos C, Oddou C, Emadali A, Hiriart-Bryant E, Boyault C, Faurobert E, Vande Pol S, Kim-Kaneyama JR, Kraut A, Coute Y, Block M, Albiges-Rizo C, Destaing O.
  • Journal Title: J Cell Biol Volume: 213(5) Issue: 5 Pages: 585-99
  • DOI: 10.1083/jcb.201510036
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Hic-5 regulates the tumorigenesis of colorectal cancer through stromal remodeling (2018)
  • Author(s): Joo-ri Kim-kaneyama
  • Organizer: International Vascular Biology Meeting
  • Int'l Joint Research