Skip to main content
SpringerLink
Log in

Biglycan promotes the chemotherapy resistance of colon cancer by activating NF-κB signal transduction

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Biglycan (BGN) is overexpressed in cancer stem cells of colon cancer and induces the activation of NF-κB pathway which contributes to the chemotherapy resistance of diverse cancer types. Therefore, we hypothesized that the overexpression of BGN also promoted the development of multiple drug resistance (MDR) in colon cancer via NF-κB pathway. The expression of BGN was bilaterally modulated in colon cancer cell lines HT-29 and SW-480 and the effect of treatments on the cell proliferation and resistance to 5-FU was assessed. Moreover, the role of NF-κB signaling in the BGN-mediated formation of MDR was further investigated by subjecting BGN-overexpressed SW-480 cells to the co-treatment of chemo-agents and NF-κB inhibitor, PDTC. The inhibition of BGN expression decreased the proliferation potential of HT-29 cells while the induction of BGN expression increased the potential of SW-480 cells. BGN knockdown increased HT-29 cells’ sensitivity to 5-FU, represented by the lower colony number and higher apoptotic rate. To the contrary, BGN overexpression promoted the resistance of SW-480 cells to 5-FU. The effect of BGN modulation on colon cancer cells was associated with the changes in apoptosis and NF-κB pathways: BGN inhibition increased the expressions of pro-apoptosis indicators and suppressed NF-κB pathway activity while BGN overexpression had the opposite effect. It was also found that the BGN-mediated formation of MDR was impaired when NF-κB pathway was blocked. Findings outlined in the current study showed that BGN contributed to the formation of chemotherapy resistance in colon cancer cells by activating NF-κB signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gill S, Thomas RR, Goldberg RM (2003) Review article: colorectal cancer chemotherapy. Aliment Pharmacol Ther 18:683–692

    Article  CAS  PubMed  Google Scholar 

  2. Hu T, Fei Li L, Shen J, Zhang L, Hin Cho C (2015) Chronic inflammation and colorectal cancer: the role of vascular endothelial growth factor. Curr Pharm Des 21(21):2960–2967

    Article  CAS  PubMed  Google Scholar 

  3. Li LF, Chan RLY, Lu L, Shen J, Zhang L, Wu WKK, Wang L, Hu T, Li MX, Cho CH (2014) Cigarette smoking and gastrointestinal diseases: the causal relationship and underlying molecular mechanisms. Int J Mol Med 34(2):372–380

    Article  CAS  PubMed  Google Scholar 

  4. Center MM, Jemal A, Smith RA, Ward E (2009) Worldwide variations in colorectal cancer. CA 59(6):366–378

    PubMed  Google Scholar 

  5. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N (2010) Colorectal cancer. Lancet 375:1030–1047

    Article  PubMed  Google Scholar 

  6. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA 60(5):277–300

    PubMed  Google Scholar 

  7. Van Cutsem EJ (2008) Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 19(2):21–22

    Google Scholar 

  8. Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, Buren GV, Samuel S, Kim MP, Lim SJ, Ellis LM (2009) Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res 69(5):1951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Thomas H, Coley HM (2003) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 10(2):159

    Article  PubMed  Google Scholar 

  10. Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, Salto-Tellez M (2010) CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol 23(3):450–457

    Article  CAS  PubMed  Google Scholar 

  11. Ward RJ, Dirks PB (2007) Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol 2(2):175–189

    Article  CAS  PubMed  Google Scholar 

  12. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115

    Article  CAS  PubMed  Google Scholar 

  13. Fang DD, Kim YJ, Lee CN, Aggarwal S, McKinnon K, Mesmer D, Norton J, Birse CE, He T, Ruben SM (2010) Expansion of CD133 + colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery. Br J Cancer 102(8):1265–1275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xing X, Gu X, Ma T, Ye H (2015) Biglycan up-regulated vascular endothelial growth factor (VEGF) expression and promoted angiogenesis in colon cancer. Tumor Biol 36(3):1773–1780

    Article  CAS  Google Scholar 

  15. Xing X, Gu X, Ma T (2015) Knockdown of biglycan expression by RNA interference inhibits the proliferation and invasion of, and induces apoptosis in, the HCT116 colon cancer cell line. Mol Med Rep 12(5):7538–7544

    Article  CAS  PubMed  Google Scholar 

  16. Frantz C, Stewart KM, Weaver VM (2010) The extracellular matrix at a glance. J Cell Sci 123(24):4195–4200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pan S, Cheng L, White JT, Lu W, Utleg AG, Yan X, Urban ND, Drescher CW, Hood L, Lin B (2009) 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 13(4):345–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mintz MB, Sowers R, Brown KM, Hilmer SC, Mazza B, Huvos AG, Meyers PA, LaFleur B, McDonough WS, Henry MM (2005) An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Res 65(5):1748–1754

    Article  CAS  PubMed  Google Scholar 

  19. Song R, Ao L, Zhao K-s, Zheng D, Venardos N, Fullerton DA, Meng X (2014) Soluble biglycan induces the production of ICAM-1 and MCP-1 in human aortic valve interstitial cells through TLR2/4 and the ERK1/2 pathway. Inflamm Res 63(9):703–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rajamannan NM (2006) Calcific aortic stenosis: a disease ready for prime time. Circulation 114(19):2007

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li F, Sethi G (2010) Targeting transcription factor NF-κB to overcome chemoresistance and radioresistance in cancer therapy. BBA-Rev Cancer 1805(2):167–180

    CAS  Google Scholar 

  22. Sakamoto K, Maeda S (2010) Targeting NF-κB for colorectal cancer. Expert Opin Ther Targets 14(6):593–601

    Article  CAS  PubMed  Google Scholar 

  23. Sui H, Zhou LH, Zhang YL, Huang JP, Liu X, Ji Q, Fu XL, Wen HT, Chen ZS, Deng WL (2016) Evodiamine suppresses ABCG2 mediated drug resistance by inhibiting p50/p65 NF-κB pathway in colorectal cancer. J Cell Biochem 117(6):1471–1481

    Article  CAS  PubMed  Google Scholar 

  24. Dick JE (2009) Looking ahead in cancer stem cell research. Nat Biotechnol 27(1):44–46

    Article  CAS  PubMed  Google Scholar 

  25. Yamamoto K, Ohga N, Hida Y, Maishi N, Kawamoto T, Kitayama K, Akiyama K, Osawa T, Kondoh M, Matsuda K (2012) Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells. Br J Cancer 106(6):1214–1223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Westermann D, Mersmann J, Melchior A, Freudenberger T, Petrik C, Schaefer L, Lüllmann-Rauch R, Lettau O, Jacoby C, Schrader J (2008) Biglycan is required for adaptive remodeling after myocardial infarction. Circulation 117(10):1269–1276

    Article  CAS  PubMed  Google Scholar 

  27. Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, Bruckner P, Pfeilschifter J, Schaefer RM, Gröne H-J (2009) Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem 284(36):24035–24048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mohan H, Krumbholz M, Sharma R, Eisele S, Junker A, Sixt M, Newcombe J, Wekerle H, Hohlfeld R, Lassmann H (2010) Extracellular matrix in multiple sclerosis lesions: fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells. Brain Pathol 20(5):966–975

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Song R, Zeng Q, Ao L, Jessica AY, Cleveland JC, Zhao K-s, Fullerton DA, Meng X (2012) Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor-2. Arterioscler Thromb Vasc Biol 32(11):2711–2720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shatz M, Menendez D, Resnick MA (2012) The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells. Cancer Res 72(16):3948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA (2017) TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis. Cytokine 89:127

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Grants from the Foundation of Department of Science and Technology, Liaoning Province (No. 2015020254) and the Wu Jieping Medical Foundation (No. 320.6750.17250).

Author information

Authors and Affiliations

  1. Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People’s Republic of China

    Bin Liu, Tonghong Xu, Xinning Xu, Yuzhu Cui & Xiaojing Xing

Authors
  1. Bin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tonghong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinning Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuzhu Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaojing Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaojing Xing.

Ethics declarations

Conflict of interest

The authors disclose no conflict of 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

Liu, B., Xu, T., Xu, X. et al. Biglycan promotes the chemotherapy resistance of colon cancer by activating NF-κB signal transduction. Mol Cell Biochem 449, 285–294 (2018). https://doi.org/10.1007/s11010-018-3365-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3365-1

Keywords

Search

Navigation