Skip to main content

Biglycan up-regulated vascular endothelial growth factor (VEGF) expression and promoted angiogenesis in colon cancer

Tumor Biology volume 36, pages 1773–1780 (2015)Cite this article

Abstract

Biglycan is an important component of the extracellular matrix, which belongs to the small leucine-rich proteoglycan family. Recent studies have shown that biglycan expression is elevated in many tumor tissues and implies poor prognosis, such as colon cancer. However, the molecular mechanism of biglycan in colon cancer has not been investigated. The present study aimed to investigate the effects of biglycan on vascular endothelial growth factor (VEGF) expression in colon cancer cells and on tumor angiogenesis in vivo. Biglycan overexpression vectors were constructed, and the stable biglycan overexpression in human colon cancer cell lines (HCT116 cells) was established by G418 screening. The stable cell clones were subsequently used to initiate tumor xenografts in nude mice. Our results showed that biglycan overexpression notably up-regulated the levels of VEGF in colon cancer cells, which was further confirmed by immunohistochemistry analysis in the xenograft colon tumors. Moreover, high levels of biglycan promoted angiogenesis and colon tumor growth, as evidenced by the increased cell viability, colon tumor size, and weight, as well as the CD34 expression. Additionally, we found that the extracellular signal-regulated kinase (ERK) signaling pathway was activated by biglycan in colon cancer cells. The ERK inhibitor PD98059 dramatically reversed the increased expression of VEGF induced by biglycan. Taken together, our results indicated that biglycan up-regulated VEGF expression in colon cancer cells and promoted tumor angiogenesis. Biglycan-mediated VEGF regulation may correlate with the activation of the ERK signaling pathway. Therefore, biglycan may be a promising target for anti-angiogenic therapy for cancer.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679–95.

    CAS  Article  PubMed  Google Scholar 

  2. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol: Off J Am Soc Clin Oncol. 2005;23:1011–27.

    CAS  Article  Google Scholar 

  3. Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Semin Cancer Biol. 2009;19:329–37.

    CAS  Article  PubMed  Google Scholar 

  4. Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010;468:829–33.

    CAS  Article  PubMed  Google Scholar 

  5. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    CAS  Article  PubMed  Google Scholar 

  6. Wadhwa S, Embree MC, Bi Y, Young MF. Regulation, regulatory activities, and function of biglycan. Crit Rev Eukaryot Gene Expr. 2004;14:301–15.

    CAS  Article  PubMed  Google Scholar 

  7. Nishino R, Honda M, Yamashita T, Takatori H, Minato H, Zen Y, et al. Identification of novel candidate tumour marker genes for intrahepatic cholangiocarcinoma. J Hepatol. 2008;49:207–16.

    CAS  Article  PubMed  Google Scholar 

  8. Pan S, Cheng L, White JT, Lu W, Utleg AG, Yan X, et al. Quantitative proteomics analysis integrated with microarray data reveals that extracellular matrix proteins, catenins, and p53 binding protein 1 are important for chemotherapy response in ovarian cancers. Omics: J Integr Biol. 2009;13:345–54.

    CAS  Article  Google Scholar 

  9. Liu Y, Li W, Li X, Tai Y, Lu Q, Yang N, et al. Expression and significance of biglycan in endometrial cancer. Arch Gynecol Obstet. 2014;289:649–55.

    CAS  Article  PubMed  Google Scholar 

  10. Aprile G, Avellini C, Reni M, Mazzer M, Foltran L, Rossi D, et al. Biglycan expression and clinical outcome in patients with pancreatic adenocarcinoma. Tumour Biol: J Int Soc Oncodev Biol Med. 2013;34:131–7.

    CAS  Article  Google Scholar 

  11. Hu L, Duan YT, Li JF, Su LP, Yan M, Zhu ZG, Liu BY, Yang QM: Biglycan enhances gastric cancer invasion by activating fak signaling pathway. Oncotarget 2014.

  12. Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the united states 2003 to 2007. Crit Care Med. 2012;40:754–61.

    Article  PubMed  Google Scholar 

  13. Wang B, Li GX, Zhang SG, Wang Q, Wen YG, Tang HM, et al. Biglycan expression correlates with aggressiveness and poor prognosis of gastric cancer. Exp Biol Med (Maywood). 2011;236:1247–53.

    CAS  Article  Google Scholar 

  14. Troup S, Njue C, Kliewer EV, Parisien M, Roskelley C, Chakravarti S, et al. Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2003;9:207–14.

    CAS  Google Scholar 

  15. Yamamoto K, Ohga N, Hida Y, Maishi N, Kawamoto T, Kitayama K, et al. Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells. Br J Cancer. 2012;106:1214–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS. Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer. J Surg Res. 2007;143:58–65.

    CAS  Article  PubMed  Google Scholar 

  17. Liang D, Li F, Fu Y, Cao Y, Song X, Wang T, et al. Thymol inhibits LPS-stimulated inflammatory response via down-regulation of Nf-kappab and MAPK signaling pathways in mouse mammary epithelial cells. Inflammation. 2014;37:214–22.

    CAS  Article  PubMed  Google Scholar 

  18. Gu X, Ma Y, Xiao J, Zheng H, Song C, Gong Y, et al. Up-regulated biglycan expression correlates with the malignancy in human colorectal cancers. Clin Exp Med. 2012;12:195–9.

    CAS  Article  PubMed  Google Scholar 

  19. Hu L, Duan YT, Li JF, Su LP, Yan M, Zhu ZG, et al. Biglycan enhances gastric cancer invasion by activating FAK signaling pathway. Oncotarget. 2014;5:1885–96.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Folkman J, Hanahan D. Switch to the angiogenic phenotype during tumorigenesis. Princess Takamatsu Symp. 1991;22:339–47.

    CAS  PubMed  Google Scholar 

  21. Gangenahalli GU, Singh VK, Verma YK, Gupta P, Sharma RK, Chandra R, et al. Hematopoietic stem cell antigen CD34: role in adhesion or homing. Stem Cells Dev. 2006;15:305–13.

    CAS  Article  PubMed  Google Scholar 

  22. Ajili F, Kacem M, Tounsi H, Darouiche A, Enayfer E, Chebi M, et al. Prognostic impact of angiogenesis in nonmuscle invasive bladder cancer as defined by microvessel density after immunohistochemical staining for CD34. Ultrastruct Pathol. 2012;36:336–42.

    Article  PubMed  Google Scholar 

  23. Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med. 2011;17:347–62.

    CAS  Article  PubMed  Google Scholar 

  24. Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, et al. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res. 1999;247:495–504.

    CAS  Article  PubMed  Google Scholar 

  25. Lin P, Sankar S, Shan S, Dewhirst MW, Polverini PJ, Quinn TQ, et al. Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ: Mol Biol J Am Assoc Cancer Res. 1998;9:49–58.

    CAS  Google Scholar 

  26. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995;55:3964–8.

    CAS  PubMed  Google Scholar 

  27. Berendsen AD, Pinnow EL, Maeda A, Brown AC, McCartney-Francis N, Kram V, et al. Biglycan modulates angiogenesis and bone formation during fracture healing. Matrix Biol: J Int Soc Matrix Biol. 2014;35:223–31.

    CAS  Article  Google Scholar 

  28. Mavria G, Vercoulen Y, Yeo M, Paterson H, Karasarides M, Marais R, et al. ERK-MAPK signaling opposes rho-kinase to promote endothelial cell survival and sprouting during angiogenesis. Cancer Cell. 2006;9:33–44.

    CAS  Article  PubMed  Google Scholar 

  29. Meadows KN, Bryant P, Pumiglia K. Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J Biol Chem. 2001;276:49289–98.

    CAS  Article  PubMed  Google Scholar 

  30. Wang X, Harimoto K, Xie S, Cheng H, Liu J, Wang Z. Matrix protein biglycan induces osteoblast differentiation through extracellular signal-regulated kinase and smad pathways. Biol Pharm Bull. 2010;33:1891–7.

    CAS  Article  PubMed  Google Scholar 

  31. Weber CK, Sommer G, Michl P, Fensterer H, Weimer M, Gansauge F, et al. Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines. Gastroenterology. 2001;121:657–67.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 81201968), the Natural Science Foundation of Liaoning Province (No. 201102111), and the Doctoral Starting Foundation of Liaoning Province (No. 20091045).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Cancer Prevention and Treatment Office, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People’s Republic of China

    Xiaojing Xing & Tianfei Ma

  2. Department of Surgical Oncology, Liaoning Cancer Hospital and Institute, Shenyang, 110042, People’s Republic of China

    Xiaohu Gu

  3. Department of Internal Oncology, Liaoning Cancer Hospital and Institute, Shenyang, 110042, People’s Republic of China

    Xiaojing Xing & Huinan Ye

Authors
  1. Xiaojing Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaohu Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianfei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huinan Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaojing Xing.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xing, X., Gu, X., Ma, T. et al. Biglycan up-regulated vascular endothelial growth factor (VEGF) expression and promoted angiogenesis in colon cancer. Tumor Biol. 36, 1773–1780 (2015). https://doi.org/10.1007/s13277-014-2779-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2779-y

Keywords

  • Biglycan
  • Colon cancer
  • VEGF
  • ERK signaling pathway