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Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer

Clinical & Experimental Metastasis volume 29, pages 915–925 (2012)Cite this article

Abstract

We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (A)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed A-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in HT29 cells. Reduction of hepatic ATG production by cholesterol-conjugated antisense S-oligodeoxynucleotide suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and A-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated angiotensin activation enhances liver metastasis of CRC and may therefore provide a possible target for antimetastatic therapy in CRC.

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Abbreviations

CRC:

Colorectal cancer

ATG:

Angiotensinogen

A-I:

Angiotensin I

A-II:

Angiotensin II

ATR-1:

Angiotensin II type 1 receptor

ACE:

Angiotensin converting enzyme

MAPK:

Mitogen-activated protein kinase

ODN:

Oligodeoxynucleotide

ARB:

Angiotensin II type 1 receptor blocker

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, Japan.

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Affiliations

  1. Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Takasumi Shimomoto, Hitoshi Ohmori, Yi Luo, Yoshitomo Chihara, Ayumi Denda, Tomonori Sasahira, Kiyomu Fujii & Hiroki Kuniyasu

  2. Department of Surgery, Miyoshi Central Hospital, Miyoshi, Japan

    Naokuni Tatsumoto

Authors
  1. Takasumi Shimomoto
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  2. Hitoshi Ohmori
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  3. Yi Luo
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  4. Yoshitomo Chihara
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  5. Ayumi Denda
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  6. Tomonori Sasahira
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  7. Naokuni Tatsumoto
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  8. Kiyomu Fujii
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  9. Hiroki Kuniyasu
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Correspondence to Hiroki Kuniyasu.

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Shimomoto, T., Ohmori, H., Luo, Y. et al. Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer. Clin Exp Metastasis 29, 915–925 (2012). https://doi.org/10.1007/s10585-012-9480-6

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  • DOI: https://doi.org/10.1007/s10585-012-9480-6

Keywords

  • Angiotensin
  • Angiotensinogen
  • Renin
  • Chymase
  • Colorectal cancer
  • Liver metastasis