We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

VEGFR-1 activation-induced MMP-9-dependent invasion in hepatocellular carcinoma

    Tao Li

    Department of Infectious diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

    ,
    Yuhua Zhu

    Department of Infectious diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

    ,
    Lihui Han

    Department of Immunology, Shandong University School of Medicine, Jinan 250012, China

    ,
    Wanhua Ren

    Department of Infectious diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

    ,
    Hui Liu

    Department of Infectious diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

    &
    Chengyong Qin

    *Author for correspondence:

    E-mail Address: qchengy@163.com

    Department of Infectious diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

    Published Online:https://doi.org/10.2217/fon.15.263

    Aim: VEGFR-1 can promote invasion through epithelial–mesenchymal transition induction in hepatocellular carcinoma (HCC). This study aims to elucidate VEGFR-1 impact on proteolytic enzymes profile involved with invasion. Materials & methods: The effect on cell invasion was evaluated by invasive and migration assays with and without VEGFR-1 activation. The mechanism was investigated by real-time PCR, western blot and gelatin zymography using inhibitors for MMP-9. In total, 95 HCC patients were enrolled for its clinical value evaluation. Results: VEGFR-1 activation induced invasion in HCC cells with an increase in the expression and activity of MMP-9 and Snail. MMP-9 blockage effectively inhibited VEGFR-1-induced invasion. High coexpression of both in HCC predicted a worse clinical outcome. Conclusion: Data show a novel VEGFR-1 activation-to-MMP-9 mechanism promoting HCC invasion.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Huo TI, Lin HC, Huang YH et al. The model for end-stage liver disease-based Japan Integrated Scoring system may have a better predictive ability for patients with hepatocellular carcinoma undergoing locoregional therapy. Cancer 107(1), 141–148 (2006).
    • 2 Miyoshi A, Kitajima Y, Kido S et al. Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br. J. Cancer 92(2), 252–258 (2005).• Highlights that the upregulated MMPs expression induced by Snail can significantly promote the invasion of hepatocellular carcinoma.
    • 3 Sugimachi K, Tanaka S, Kameyama T et al. Transcriptional repressor snail and progression of human hepatocellular carcinoma. Clin. Cancer Res. 9(7), 2657–2664 (2003).•• Highlights that epithelial–mesenchymal transition is a critical mechanism in metastasis of hepatocellular carcinoma.
    • 4 Yang AD, Camp ER, Fan F et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 66(1), 46–51 (2006).
    • 5 Schwartz JD, Rowinsky EK, Youssoufian H, Pytowski B, Wu Y. Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1). Cancer 116(4 Suppl.), 1027–1032 (2010).•• An excellent review about the function and clinical value of VEGFR-1 in human cancer.
    • 6 Ng IO, Poon RT, Lee JM, Fan ST, Ng M, Tso WK. Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma. Am. J. Clin. Pathol. 116(6), 838–845 (2001).
    • 7 Wu Y, Hooper AT, Zhong Z et al. The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int. J. Cancer 119(7), 1519–1529 (2006).
    • 8 Price DJ, Miralem T, Jiang S, Steinberg R, Avraham H. Role of vascular endothelial growth factor in the stimulation of cellular invasion and signaling of breast cancer cells. Cell Growth Differ. 12(3), 129–135 (2001).
    • 9 Bates RC, Goldsmith JD, Bachelder RE et al. Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. Curr. Biol. 13(19), 1721–1727 (2003).
    • 10 Yi ZY, Feng LJ, Xiang Z et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in hepatocellular carcinoma cells. J. Invest. Surg. 24(2), 67–76 (2011).•• First paper to indicate that VEGFR-1 activation can induce epithelial–mesenchymal transition in hepatocellular carcinoma and promote its metastasis.
    • 11 Mira E, Mañes S, Lacalle RA, Márquez G, Martínez-A C. Insulin-like growth factor I-triggered cell migration and invasion are mediated by matrix metalloproteinase-9. Endocrinology 140(4), 1657–1664 (1999).
    • 12 Sun L, Diamond ME, Ottaviano AJ, Joseph MJ, Ananthanarayan V, Munshi HG. Transforming growth factor-beta 1 promotes matrix metalloproteinase-9-mediated oral cancer invasion through snail expression. Mol. Cancer Res. 6(1), 10–20 (2008).
    • 13 Zuo JH, Zhu W, Li MY et al. Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin. J. Cell Biochem. 112(9), 2508–2517 (2011).
    • 14 Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25(1), 9–34 (2006).
    • 15 Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2(3), 161–174 (2002).
    • 16 Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin. Cancer Biol. 10(6), 415–433 (2000).
    • 17 Bergers G, Brekken R, McMahon G et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2(10), 737–744 (2000).
    • 18 Hiratsuka S, Nakamura K, Iwai S et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2(4), 289–300 (2002).•• Highlights that MMP-9 expression induced by VEGFR-1 is involved in cancer metastasis.
    • 19 Zhang S, Li J, Jiang Y, Xu Y, Qin C. Programmed cell death 4 (PDCD4) suppresses metastastic potential of human hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res. 28, 71(2009).
    • 20 Chen R, Cui J, Xu C et al. The significance of MMP-9 Over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection. Ann. Surg. Oncol. 19(Suppl. 3), S375–S384 (2012).•• Highlights that MMP-9 rather than MMP-2 expression is closely involved with hepatocellular carcinoma invasion.
    • 21 Yung S, Davies M. Response of the human peritoneal mesothelial cell to injury: an in vitro model of peritoneal wound healing. Kidney Int. 54(6), 2160–2169 (1998).
    • 22 Ottaviano AJ, Sun L, Ananthanarayanan V, Munshi HG. Extracellular matrix-mediated membrane-type 1 matrix metalloproteinase expression in pancreatic ductal cells is regulated by transforming growth factor-beta1. Cancer Res. 66(14), 7032–7040 (2006).
    • 23 Jordà M, Olmeda D, Vinyals A et al. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J. Cell Sci. 118(Pt15), 3371–3385 (2005).
    • 24 Xu Y, Zhu M, Zhang S, Liu H, Li T, Qin C. Expression and prognostic value of PRL-3 in human intrahepatic cholangiocarcinoma. Pathol. Oncol. Res. 16(2), 169–175 (2010).
    • 25 Toi M, Bando H, Ogawa T, Muta M, Hornig C, Weich HA. Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer. Int. J. Cancer 98(1), 14–18 (2002).
    • 26 Tang J, Cui J, Chen R et al. A three-dimensional cell biology model of human hepatocellular carcinoma in vitro. Tumour Biol. 32(3), 469–479 (2011).
    • 27 Fukase K, Ohtsuka H, Onogawa T et al. Bile acids repress E-cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma. Cancer Sci. 99(9), 1785–1792 (2008).
    • 28 Hipp S, Walch A, Schuster T et al. Activation of epidermal growth factor receptor results in snail protein but not mRNA overexpression in endometrial cancer. J. Cell Mol. Med. 13(9B), 3858–3867 (2009).
    • 29 Wanami LS, Chen HY, Peiró S, García de Herreros A, Bachelder RE. Vascular endothelial growth factor-A stimulates Snail expression in breast tumor cells: implications for tumor progression. Exp. Cell Res. 314(13), 2448–2453 (2008).
    • 30 Amaoka N, Saio M, Nonaka K et al. Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma. Oncol. Rep. 16(1), 3–10 (2006).•• Highlights that VEGFR-1 was expressed in the hepatocellular carcinoma tissue and was confirmed as a functional receptor associated with histological grade.
    • 31 Jia JB, Zhuang PY, Sun HC et al. Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival. J. Cancer Res. Clin. Oncol. 135(6), 847–854 (2009).
    • 32 Wey JS, Fan F, Gray MJ et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104(2), 427–438 (2005).
    • 33 Kanda M, Nomoto S, Nishikawa Y et al. Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinico-pathological parameters. J. Surg. Oncol. 98(3), 190–196 (2008).
    • 34 Laird A, O'Mahony FC, Nanda J et al. Differential expression of prognostic proteomic markers in primary tumour, venous tumour thrombus and metastatic renal cell cancer tissue and correlation with patient outcome. PLoS ONE 8(4), e60483 (2013).•• Highlights that VEGFR-1 could serve as a prognostic marker for other type of malignancy.
    • 35 Fan F, Wey JS, McCarty MF et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24(16), 2647–2653 (2005).
    • 36 Libra M, Scalisi A, Vella N et al. Uterine cervical carcinoma: role of matrix metalloproteinases (review). Int. J. Oncol. 34(4), 897–903 (2009).
    • 37 Köhrmann A, Kammerer U, Kapp M et al. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature. BMC Cancer 9, 188 (2009).
    • 38 Lin CY, Tsai PH, Kandaswami CC et al. Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial-mesenchymal transition. Cancer Sci. 102(4), 815–827 (2011).