Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Oncogene volume 37, pages 1205–1219 (2018)Cite this article

Subjects

Abstract

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 investigate the role of Hic-5 in CAFs, we isolated CAFs and the control counterpart normal fibroblasts (NFs) from human colorectal cancer and non-cancerous regions, respectively. Hic-5 was highly expressed in isolated human CAFs and strongly induced in NFs in culture by the supernatant from cultured colorectal cancer cells as well as cytokines such as TGF-β, IL-1β and stromal cell-derived factor 1 (SDF-1/CXCL12). Furthermore, tumor growth was inhibited in a co-culture assay with Hic-5 knockdown fibroblasts compared with control fibroblasts. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Levental I, Levental KR, Klein EA, Assoian R, Miller RT, Wells RG, et al. A simple indentation device for measuring micrometer-scale tissue stiffness. J Phys Condens Matter 2010;22:194120.

    Article  CAS  Google Scholar 

  2. Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech 2011;4:165–78.

    Article  CAS  Google Scholar 

  3. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 2001;1:46–54.

    Article  CAS  Google Scholar 

  4. Csiszar K. Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol 2001;70:1–32.

    Article  CAS  Google Scholar 

  5. Kagan HM, Li W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 2003;88:660–72.

    Article  CAS  Google Scholar 

  6. Cox TR, Rumney RM, Schoof EM, Perryman L, Hoye AM, Agrawal A, et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 2015;522:106–10.

    Article  CAS  Google Scholar 

  7. Baker AM, Bird D, Lang G, Cox TR, Erler JT. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene 2013;32:1863–8.

    Article  CAS  Google Scholar 

  8. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009;139:891–906.

    Article  CAS  Google Scholar 

  9. Shibanuma M, Kim-Kaneyama JR, Ishino K, Sakamoto N, Hishiki T, Yamaguchi K, et al. Hic-5 communicates between focal adhesions and the nucleus through oxidant-sensitive nuclear export signal. Mol Biol Cell 2003;14:1158–71.

    Article  CAS  Google Scholar 

  10. Lei XF, Fu W, Kim-Kaneyama JR, Omoto T, Miyazaki T, Li B, et al. Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice. J Hepatol 2016;64:110–7.

    Article  CAS  Google Scholar 

  11. Arita-Okubo S, Kim-Kaneyama JR, Lei XF, Fu WG, Ohnishi K, Takeya M, et al. Role of Hic-5 in the formation of microvilli-like structures and the monocyte-endothelial interaction that accelerates atherosclerosis. Cardiovasc Res 2015;105:361–71.

    Article  CAS  Google Scholar 

  12. Lei XF, Kim-Kaneyama JR, Arita-Okubo S, Offermanns S, Itabe H, Miyazaki T, et al. Identification of Hic-5 as a novel scaffold for the MKK4/p54 JNK pathway in the development of abdominal aortic aneurysms. J Am Heart Assoc 2014;3:e000747.

    Article  Google Scholar 

  13. Jamba A, Kondo S, Urushihara M, Nagai T, Kim-Kaneyama JR, Miyazaki A, et al. Hydrogen peroxide-inducible clone-5 regulates mesangial cell proliferation in proliferative glomerulonephritis in mice. PLoS One 2015;10:e0122773.

    Article  Google Scholar 

  14. Varney SD, Betts CB, Zheng R, Wu L, Hinz B, Zhou J, et al. Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation. J Cell Sci 2016;129:774–87.

    Article  CAS  Google Scholar 

  15. Solomon JD, Heitzer MD, Liu TT, Beumer JH, Parise RA, Normolle DP, et al. VDR activity is differentially affected by Hic-5 in prostate cancer and stromal cells. Mol Cancer Res 2014;12:1166–80.

    Article  CAS  Google Scholar 

  16. Kim-Kaneyama JR, Takeda N, Sasai A, Miyazaki A, Sata M, Hirabayashi T, et al. Hic-5 deficiency enhances mechanosensitive apoptosis and modulates vascular remodeling. J Mol Cell Cardiol 2011;50:77–86.

    Article  CAS  Google Scholar 

  17. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–67.

    Article  CAS  Google Scholar 

  18. Zhou L, Yang K, Andl T, Wickett RR, Zhang Y. Perspective of Targeting Cancer-Associated Fibroblasts in Melanoma. J Cancer 2015;6:717–26.

    Article  CAS  Google Scholar 

  19. Vasudev NS, Reynolds AR. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 2014;17:471–94.

    Article  CAS  Google Scholar 

  20. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010;330:827–30.

    Article  CAS  Google Scholar 

  21. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005;121:335–48.

    Article  CAS  Google Scholar 

  22. Takai K, Le A, Weaver VM, Werb Z. Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget 2016;7:82889–901.

    PubMed  PubMed Central  Google Scholar 

  23. Allaoui R, Bergenfelz C, Mohlin S, Hagerling C, Salari K, Werb Z, et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nat Commun 2016;7:13050.

    Article  CAS  Google Scholar 

  24. Deakin NO, Turner CE. Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis. Mol Biol Cell 2011;22:327–41.

    Article  CAS  Google Scholar 

  25. Wu JR, Hu CT, You RI, Pan SM, Cheng CC, Lee MC, et al. Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression. Oncotarget 2015;6:32526–44.

    PubMed  PubMed Central  Google Scholar 

  26. Shola DT, Wang H, Wahdan-Alaswad R, Danielpour D. Hic-5 controls BMP4 responses in prostate cancer cells through interacting with Smads 1, 5 and 8. Oncogene 2012;31:2480–90.

    Article  CAS  Google Scholar 

  27. Drori S, Girnun GD, Tou L, Szwaya JD, Mueller E, Xia K, et al. Hic-5 regulates an epithelial program mediated by PPARgamma. Genes Dev 2005;19:362–75.

    Article  CAS  Google Scholar 

  28. Goreczny GJ, Ouderkirk-Pecone JL, Olson EC, Krendel M, Turner CE. Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene. 2017;36:2693–2703.

    Article  Google Scholar 

  29. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2014;15:786–801.

    Article  CAS  Google Scholar 

  30. Dabiri G, Tumbarello DA, Turner CE, Van de Water L. Hic-5 promotes the hypertrophic scar myofibroblast phenotype by regulating the TGF-beta1 autocrine loop. J Invest Dermatol 2008;128:2518–25.

    Article  CAS  Google Scholar 

  31. Wang TH, Hsia SM, Shieh TM. Lysyl oxidase and the tumor microenvironment. Int J Mol Sci. 2016;18: pii: E62.

  32. Voloshenyuk TG, Landesman ES, Khoutorova E, Hart AD, Gardner JD. Induction of cardiac fibroblast lysyl oxidase by TGF-beta1 requires PI3K/Akt, Smad3, and MAPK signaling. Cytokine 2011;55:90–97.

    Article  CAS  Google Scholar 

  33. Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 2013;4:2612.

    Article  Google Scholar 

  34. Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet 2015;47:320–9.

    Article  CAS  Google Scholar 

  35. Isella C, Terrasi A, Bellomo SE, Petti C, Galatola G, Muratore A, et al. Stromal contribution to the colorectal cancer transcriptome. Nat Genet 2015;47:312–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research (26461149 to J-rK-K; 16K10553 to TO; 17K10713 to X-FL) from Japan Society for the Promotion of Science, a research grant from Japan-China Medical Association (to J-rK-K), a research grant from Takeda Science Foundation (to J-rK-K and X-FL) and Private University Research Branding Project. This work was also supported in part by the MEXT (Ministry of Education, Culture, Sports, Science and Technology)-Supported Program for the Strategic Research Foundation at Private Universities, 2012-2016.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan

    Tomokatsu Omoto, Joo-ri Kim-Kaneyama, Xiao-Feng Lei, Aya Miyauchi, Shuo Li, Lin Gao, Shogo Haraguchi, Takuro Miyazaki & Akira Miyazaki

  2. Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan

    Akira Orimo

  3. Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan

    Koji Ohnishi & Motohiro Takeya

  4. Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Kosuke Yoshihara

  5. Department of Gastroenterological and General Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan

    Takahiro Umemoto & Junichi Tanaka

  6. Digestive Disease Center, Showa University Northern Yokohama Hospital, Tsuzuki-ku, Yokohama, Japan

    Kenta Nakahara, Fumio Ishida & Shin-ei Kudo

Authors
  1. Tomokatsu Omoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joo-ri Kim-Kaneyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Feng Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akira Orimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koji Ohnishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kosuke Yoshihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aya Miyauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shuo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lin Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takahiro Umemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Junichi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kenta Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Motohiro Takeya
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fumio Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shin-ei Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shogo Haraguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Takuro Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Akira Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joo-ri Kim-Kaneyama.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Omoto, T., Kim-Kaneyama, Jr., Lei, XF. et al. The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling. Oncogene 37, 1205–1219 (2018). https://doi.org/10.1038/s41388-017-0033-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-017-0033-y

This article is cited by

Search

Advanced search

Quick links