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ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis

Oncogene volume 33, pages 2273–2278 (2014)Cite this article

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Abstract

Tumor suppressors with extracellular function are likely to have advantages as targets for cancer therapy, but few are known. Here, we focused on angiopoietin-like 4 (ANGPTL4), which is a secreted glycoprotein involved in lipoprotein metabolism and angiogenesis, is methylation-silenced in human cancers, but has unclear roles in cancer development and progression. We found a deletion mutation in its coiled-coil domain at its N-terminal in human gastric cancers, in addition to hypermethylation of the ANGPTL4 promoter CpG islands. Forced expression of wild-type ANGPTL4, but not ANGPTL4 with the deletion, at physiological levels markedly suppressed in vivo tumorigenicity and tumor angiogenesis, indicating that the latter caused the former. Tumor-derived ANGPTL4 suppressed in vitro vascular tube formation and proliferation of human umbilical vascular endothelial cells, partly due to suppression of ERK signaling. These showed that ANGPTL4 is a genetically and epigenetically inactivated secreted tumor suppressor that inhibits tumor angiogenesis.

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References

  1. Knudson AG . Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001; 1: 157–162.

    Article  CAS  PubMed  Google Scholar 

  2. Baylin SB, Jones PA . A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011; 11: 726–734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kishore R, Losordo DW . Gene therapy for restenosis: biological solution to a biological problem. J Mol Cell Cardiol 2007; 42: 461–468.

    Article  CAS  PubMed  Google Scholar 

  4. Lane DP, Cheok CF, Lain S . p53-based cancer therapy. Cold Spring Harb Perspect Biol 2010; 2: a001222.

    PubMed  PubMed Central  Google Scholar 

  5. Levine AJ, Oren M . The first 30 years of p53: growing ever more complex. Nat Rev Cancer 2009; 9: 749–758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 2004; 36: 417–422.

    Article  CAS  PubMed  Google Scholar 

  7. Shi Y, He B, You L, Jablons DM . Roles of secreted frizzled-related proteins in cancer. Acta Pharmacol Sin 2007; 28: 1499–1504.

    Article  CAS  PubMed  Google Scholar 

  8. Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T . Identification of silencing of nine genes in human gastric cancers. Cancer Res 2002; 62: 6645–6650.

    PubMed  Google Scholar 

  9. Hattori N, Okochi-Takada E, Kikuyama M, Wakabayashi M, Yamashita S, Ushijima T . Methylation silencing of angiopoietin-like 4 in rat and human mammary carcinomas. Cancer Sci 2011; 102: 1337–1343.

    Article  CAS  PubMed  Google Scholar 

  10. Miida T, Hirayama S . Impacts of angiopoietin-like proteins on lipoprotein metabolism and cardiovascular events. Curr Opin Lipidol 2010; 21: 70–75.

    Article  CAS  PubMed  Google Scholar 

  11. Yang YH, Wang Y, Lam KS, Yau MH, Cheng KK, Zhang J et al. Suppression of the Raf/MEK/ERK signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4. Arterioscler Thromb Vasc Biol 2008; 28: 835–840.

    Article  CAS  PubMed  Google Scholar 

  12. Ito Y, Oike Y, Yasunaga K, Hamada K, Miyata K, Matsumoto S et al. Inhibition of angiogenesis and vascular leakiness by angiopoietin-related protein 4. Cancer Res 2003; 63: 6651–6657.

    CAS  PubMed  Google Scholar 

  13. Chomel C, Cazes A, Faye C, Bignon M, Gomez E, Ardidie-Robouant C et al. Interaction of the coiled-coil domain with glycosaminoglycans protects angiopoietin-like 4 from proteolysis and regulates its antiangiogenic activity. FASEB J 2009; 23: 940–949.

    Article  CAS  PubMed  Google Scholar 

  14. Hermann LM, Pinkerton M, Jennings K, Yang L, Grom A, Sowders D et al. Angiopoietin-like-4 is a potential angiogenic mediator in arthritis. Clin Immunol 2005; 115: 93–101.

    Article  CAS  PubMed  Google Scholar 

  15. Ma T, Jham BC, Hu J, Friedman ER, Basile JR, Molinolo A et al. Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma. Proc Natl Acad Sci USA 2010; 107: 14363–14368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li KQ, Li WL, Peng SY, Shi XY, Tang HL, Liu YB . Anti-tumor effect of recombinant retroviral vector-mediated human ANGPTL4 gene transfection. Chin Med J (Engl) 2004; 117: 1364–1369.

    CAS  Google Scholar 

  17. Galaup A, Cazes A, Le Jan S, Philippe J, Connault E, Le Coz E et al. Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc Natl Acad Sci USA 2006; 103: 18721–18726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008; 133: 66–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M et al. Angiopoietin-like 4 protein elevates the prosurvival intracellular O2-:H2O2 ratio and confers anoikis resistance to tumors. Cancer Cell 2011; 19: 401–415.

    Article  CAS  PubMed  Google Scholar 

  20. Nakayama T, Hirakawa H, Shibata K, Abe K, Nagayasu T, Taguchi T . Expression of angiopoietin-like 4 in human gastric cancer: ANGPTL4 promotes venous invasion. Oncol Rep 2010; 24: 599–606.

    Article  CAS  PubMed  Google Scholar 

  21. Issa JP . CpG island methylator phenotype in cancer. Nat Rev Cancer 2004; 4: 988–993.

    Article  CAS  PubMed  Google Scholar 

  22. Ushijima T . Epigenetic field for cancerization. J Biochem Mol Biol 2007; 40: 142–150.

    CAS  PubMed  Google Scholar 

  23. Hato T, Tabata M, Oike Y . The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc Med 2008; 18: 6–14.

    Article  CAS  PubMed  Google Scholar 

  24. Oike Y, Akao M, Kubota Y, Suda T . Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy. Trends Mol Med 2005; 11: 473–479.

    Article  CAS  PubMed  Google Scholar 

  25. Ge H, Yang G, Huang L, Motola DL, Pourbahrami T, Li C . Oligomerization and regulated proteolytic processing of angiopoietin-like protein 4. J Biol Chem 2004; 279: 2038–2045.

    Article  CAS  PubMed  Google Scholar 

  26. Yin W, Romeo S, Chang S, Grishin NV, Hobbs HH, Cohen JC . Genetic variation in ANGPTL4 provides insights into protein processing and function. J Biol Chem 2009; 284: 13213–13222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mei R, Galipeau PC, Prass C, Berno A, Ghandour G, Patil N et al. Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res 2000; 10: 1126–1137.

    Article  CAS  PubMed  Google Scholar 

  28. Hoglund M, Gorunova L, Andren-Sandberg A, Dawiskiba S, Mitelman F, Johansson B . Cytogenetic and fluorescence in situ hybridization analyses of chromosome 19 aberrations in pancreatic carcinomas: frequent loss of 19p13.3 and gain of 19q13.1-13.2. Genes Chromosomes Cancer 1998; 21: 8–16.

    Article  CAS  PubMed  Google Scholar 

  29. Trojan J, Brieger A, Raedle J, Esteller M, Zeuzem S . 5′-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut 2000; 47: 272–276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sobottka SB, Haase M, Fitze G, Hahn M, Schackert HK, Schackert G . Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain. J Neurooncol 2000; 49: 187–195.

    Article  CAS  PubMed  Google Scholar 

  31. Tanner JE, Forte A, Panchal C . Nucleosomes bind fibroblast growth factor-2 for increased angiogenesis in vitro and in vivo. Mol Cancer Res 2004; 2: 281–288.

    CAS  PubMed  Google Scholar 

  32. Zhu H, Zhang L, Wu S, Teraishi F, Davis JJ, Jacob D et al. Induction of S-phase arrest and p21 overexpression by a small molecule 2[[3-(2,3-dichlorophenoxy) propyl] amino]ethanol in correlation with activation of ERK. Oncogene 2004; 23: 4984–4992.

    Article  CAS  PubMed  Google Scholar 

  33. Asada K, Ando T, Niwa T, Nanjo S, Watanabe N, Okochi-Takada E et al. FHL1 on chromosome X is a single-hit gastrointestinal tumor-suppressor gene and contributes to the formation of an epigenetic field defect. Oncogene 2012; 32: 2140–2149.

    Article  PubMed  Google Scholar 

  34. Ando T, Yoshida T, Enomoto S, Asada K, Tatematsu M, Ichinose M et al. DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. Int J Cancer 2009; 124: 2367–2374.

    Article  CAS  PubMed  Google Scholar 

  35. Enomoto S, Maekita T, Tsukamoto T, Nakajima T, Nakazawa K, Tatematsu M et al. Lack of association between CpG island methylator phenotype in human gastric cancers and methylation in their background non-cancerous gastric mucosae. Cancer Sci 2007; 98: 1853–1861.

    Article  CAS  PubMed  Google Scholar 

  36. Ota N, Kawakami K, Okuda T, Takehara A, Hiranuma C, Oyama K et al. Prognostic significance of p16INK4a hypermethylation in non-small cell lung cancer is evident by quantitative DNA methylation analysis. Anticancer Res 2006; 26: 3729–3732.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr Masabumi Shibuya, Tokyo Medical and Dental University, for his expert advice. This study was supported by the Third-term Comprehensive Cancer Control Strategy from the Ministry of Health, Labour and Welfare, Japan and by National Cancer Center Research and Development Fund. YN is a recipient of a Research Resident Fellowships from the Foundation for Promotion of Cancer Research.

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Authors and Affiliations

  1. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan

    E Okochi-Takada, N Hattori, T Ando, M Wakabayashi, Y Nobeyama & T Ushijima

  2. Oncological Pathology Division, Aichi Cancer Center Research Institute, Nagoya, Japan

    T Tsukamoto

  3. Division of Molecular Oncology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kureshi, Japan

    K Miyamoto

  4. Third Department of Internal Medicine, University of Toyama, Toyama, Japan

    T Ando

  5. Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan

    S Ito & Y Yamamura

  6. Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan

    Y Nobeyama

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  1. E Okochi-Takada
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Correspondence to T Ushijima.

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Okochi-Takada, E., Hattori, N., Tsukamoto, T. et al. ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis. Oncogene 33, 2273–2278 (2014). https://doi.org/10.1038/onc.2013.174

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