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Human chorionic gonadotropin β induces cell motility via ERK1/2 and MMP-2 activation in human glioblastoma U87MG cells

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Abstract

Human chorionic gonadotropin β (hCGβ) promotes tumorigenesis in a variety of tumors including glioblastoma, breast and prostate cancer cells, etc. However, the involved mechanisms remain elusive. Distinct from the other tumors, glioblastoma is a highly invasive brain tumor; invasion causes high recurrence and mortality. Characterization of hCGβ signaling is to determine therapeutic targets to inhibit invasion and lower recurrence. Through both a stable cell line over-expressing hCGβ and hCGβ standards, we tested hCGβ signaling, migration and invasion in human glioblastoma U87MG cells. ELISA showed that hCGβ secreted into culture medium at an amount of 237.8 ± 7.8 ng/107 cells in hCGβ transfected stable cells after the cells were grown for 24 h. Through Western blot and Gelatin zymography, we found that hCGβ standards phosphorylated ERK1/2 and upregulated MMP-2 expression in dose- and time-dependent manners. Meanwhile, overexpressed hCGβ phosphorylated ERK1/2, and upregulated MMP-2 expression and activity, whereas ERK1/2 blocker PD98059 (25 μM) significantly decreased both ERK1/2 and MMP-2 expression and activity. In addition, in the same conditions as the signaling test, hCGβ promoted cell migration and invasion, whereas the PD98059 diminished these effects. These findings demonstrated that hCGβ phosphorylated ERK1/2 upregulating MMP-2 expression and activity leading to cell migration and invasion, suggesting that hCGβ, ERK1/2 and MMP-2 are the potential targets to inhibit glioblastoma invasion.

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References

  1. Stenman UH, Alfthan H, Hotakainen K (2004) Human chorionic gonadotropin in cancer. Clin Biochem 37(7):549–561

    Article  PubMed  CAS  Google Scholar 

  2. Iles RK, Delves PJ, Butler SA (2010) Does hCG or hCGbeta play a role in cancer cell biology? Mol Cell Endocrinol 329(1–2):62–70

    Article  PubMed  CAS  Google Scholar 

  3. Acevedo HF, Hartsock RJ, Maroon JC (1997) Detection of membrane-associated human chorionic gonadotropin and its subunits on human cultured cancer cells of the nervous system. Cancer Detect Prev 21(4):295–303

    PubMed  CAS  Google Scholar 

  4. Ruddon RW, Bryan AH, Meade-Cobun KS, Pollack VA (1980) Production of human chorionic gonadotropin and its subunits by human tumors growing in nude mice. Cancer Res 40(11):4007–4012

    PubMed  CAS  Google Scholar 

  5. Hotakainen K, Ljungberg B, Paju A, Rasmuson T, Alfthan H, Stenman UH (2002) The free beta-subunit of human chorionic gonadotropin as a prognostic factor in renal cell carcinoma. Br J Cancer 86(2):185–189

    Article  PubMed  CAS  Google Scholar 

  6. Lundin M, Nordling S, Lundin J, Alfthan H, Stenman UH, Haglund C (2001) Tissue expression of human chorionic gonadotropin beta predicts outcome in colorectal cancer: a comparison with serum expression. Int J Cancer 95(1):18–22

    Article  PubMed  CAS  Google Scholar 

  7. Djurdjevic S, Maksimovic M, Pantelic M, Golubovic A, Curcic A (2011) Usefulness of beta hCG as tumor marker in the diagnosis and follow up of patients with ovarian cancer. J BUON 16(4):715–721

    PubMed  CAS  Google Scholar 

  8. Sheaff MT, Martin JE, Badenoch DF, Baithun SI (1996) Beta hCG as a prognostic marker in adenocarcinoma of the prostate. J Clin Pathol 49(4):329–332

    Article  PubMed  CAS  Google Scholar 

  9. Venyo AK, Herring D, Greenwood H, Maloney DJ (2010) The expression of beta human chorionic gonadotrophin (beta-hCG) in human urothelial carcinoma. Pan Afr Med J 7:20

    PubMed  Google Scholar 

  10. Oberg K, Wide L (1981) hCG and hCG subunits as tumour markers in patients with endocrine pancreatic tumours and carcinoids. Acta Endocrinol (Copenh) 98(2):256–260

    CAS  Google Scholar 

  11. Wu W, Walker AM (2006) Human chorionic gonadotropin beta (hCGbeta) down-regulates E-cadherin and promotes human prostate carcinoma cell migration and invasion. Cancer 106(1):68–78

    Article  PubMed  CAS  Google Scholar 

  12. Srisuparp S, Strakova Z, Brudney A, Mukherjee S, Reierstad S, Hunzicker-Dunn M, Fazleabas AT (2003) Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells. Biol Reprod 68(2):457–464

    Article  PubMed  CAS  Google Scholar 

  13. Maymo JL, Perez Perez A, Sanchez-Margalet V, Duenas JL, Calvo JC, Varone CL (2009) Up-regulation of placental leptin by human chorionic gonadotropin. Endocrinology 150(1):304–313

    Article  PubMed  CAS  Google Scholar 

  14. Huang C, Jacobson K, Schaller MD (2004) MAP kinases and cell migration. J Cell Sci 117(Pt 20):4619–4628

    Article  PubMed  CAS  Google Scholar 

  15. Coutts AS, Murphy LC (1998) Elevated mitogen-activated protein kinase activity in estrogen-nonresponsive human breast cancer cells. Cancer Res 58(18):4071–4074

    PubMed  CAS  Google Scholar 

  16. Adeyinka A, Nui Y, Cherlet T, Snell L, Watson PH, Murphy LC (2002) Activated mitogen-activated protein kinase expression during human breast tumorigenesis and breast cancer progression. Clin Cancer Res 8(6):1747–1753

    PubMed  CAS  Google Scholar 

  17. Lin HC, Song TY, Hu ML (2009) S-Adenosylhomocysteine promotes the invasion of C6 glioma cells via increased secretion of matrix metalloproteinase-2 in murine microglial BV2 cells. Toxicol Sci 112(2):322–330

    Article  PubMed  CAS  Google Scholar 

  18. Bergman MR, Cheng S, Honbo N, Piacentini L, Karliner JS, Lovett DH (2003) A functional activating protein 1 (AP-1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and JunB-FosB heterodimers. Biochem J 369(Pt 3):485–496

    Article  PubMed  CAS  Google Scholar 

  19. Yao J, Xiong S, Klos K, Nguyen N, Grijalva R, Li P, Yu D (2001) Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells. Oncogene 20(56):8066–8074

    Article  PubMed  CAS  Google Scholar 

  20. Bauvois B (2012) New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 1825(1):29–36

    PubMed  CAS  Google Scholar 

  21. Gialeli C, Theocharis AD, Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278(1):16–27

    Article  PubMed  CAS  Google Scholar 

  22. Chang MC, Chen CA, Chen PJ, Chiang YC, Chen YL, Mao TL, Lin HW, Lin Chiang WH, Cheng WF (2012) Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways. Biochem J 442(2):293–302

    Article  PubMed  CAS  Google Scholar 

  23. Watanabe T, Yasue A, Fujihara S, Tanaka E (2012) PERIOSTIN regulates MMP-2 expression via the alphavbeta3 integrin/ERK pathway in human periodontal ligament cells. Arch Oral Biol 57(1):52–59

    Article  PubMed  CAS  Google Scholar 

  24. Hu B, Jarzynka MJ, Guo P, Imanishi Y, Schlaepfer DD, Cheng SY (2006) Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the alphavbeta1 integrin and focal adhesion kinase signaling pathway. Cancer Res 66(2):775–783

    Article  PubMed  CAS  Google Scholar 

  25. Fluhr H, Bischof-Islami D, Krenzer S, Licht P, Bischof P, Zygmunt M (2008) Human chorionic gonadotropin stimulates matrix metalloproteinases-2 and -9 in cytotrophoblastic cells and decreases tissue inhibitor of metalloproteinases-1, -2, and -3 in decidualized endometrial stromal cells. Fertil Steril 90(4 Suppl):1390–1395

    Article  PubMed  CAS  Google Scholar 

  26. Chueh FS, Chen YY, Huang AC, Ho HC, Liao CL, Yang JS, Kuo CL, Chung JG (2011) Bufalin-inhibited migration and invasion in human osteosarcoma U-2 OS cells is carried out by suppression of the matrix metalloproteinase-2, ERK, and JNK signaling pathways. Environ Toxicol. doi:10.1002/tox.20769

    Google Scholar 

  27. Ma CY, Ji WT, Chueh FS, Yang JS, Chen PY, Yu CC, Chung JG (2011) Butein inhibits the migration and invasion of SK-HEP-1 human hepatocarcinoma cells through suppressing the ERK, JNK, p38, and uPA signaling multiple pathways. J Agric Food Chem 59(16):9032–9038

    Article  PubMed  CAS  Google Scholar 

  28. Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25(1):9–34

    Article  PubMed  CAS  Google Scholar 

  29. Gessi S, Sacchetto V, Fogli E, Merighi S, Varani K, Baraldi PG, Tabrizi MA, Leung E, Maclennan S, Borea PA (2010) Modulation of metalloproteinase-9 in U87MG glioblastoma cells by A3 adenosine receptors. Biochem Pharmacol 79(10):1483–1495

    Article  PubMed  CAS  Google Scholar 

  30. Bandopadhyaya G, Arora G, Shukla J, Ghosh S (2012) Recognition based hormonal 95 kDa monoclonal antibody on three human cancer cell lines for developing targeted radio-immuno-imaging and therapy. Hellenic J Nuc Med 15(2):108

    Google Scholar 

  31. Cole LA (2009) Human chorionic gonadotropin and associated molecules. Expert Rev Mol Diagn 9(1):51–73

    Article  PubMed  CAS  Google Scholar 

  32. Kim EK (1802) Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 4:396–405

    Google Scholar 

  33. Meng XL, Rennert OM, Chan WY (2007) Human chorionic gonadotropin induces neuronal differentiation of PC12 cells through activation of stably expressed lutropin/choriogonadotropin receptor. Endocrinology 148(12):5865–5873

    Article  PubMed  CAS  Google Scholar 

  34. Hua H, Li M, Luo T, Yin Y, Jiang Y (2011) Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci 68(23):3853–3868

    Article  PubMed  CAS  Google Scholar 

  35. Rucci N, Sanita P, Angelucci A (2011) Roles of metalloproteases in metastatic niche. Curr Mol Med 11(8):609–622

    Article  PubMed  CAS  Google Scholar 

  36. Li R, Li G, Deng L, Liu Q, Dai J, Shen J, Zhang J (2010) IL-6 augments the invasiveness of U87MG human glioblastoma multiforme cells via up-regulation of MMP-2 and fascin-1. Oncol Rep 23(6):1553–1559

    PubMed  CAS  Google Scholar 

  37. Kesanakurti D, Chetty C, Dinh DH, Gujrati M, Rao JS (2012) Role of MMP-2 in the regulation of IL-6/Stat3 survival signaling via interaction with alpha5beta1 integrin in glioma. Oncogene. doi:10.1038/onc.2012.52

    Google Scholar 

  38. Deshane J, Garner CC, Sontheimer H (2003) Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem 278(6):4135

    Article  PubMed  CAS  Google Scholar 

  39. Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3(5):362–374

    Article  PubMed  CAS  Google Scholar 

  40. Wolf K, Mazo I, Leung H, Engelke K, Von Andrian UH, Deryugina EI, Strongin AY, Bröcker EB, Friedl P (2003) Compensation mechanism in tumor cell migration. J Cell Biol 160(2):267–277

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are very grateful to Dr. Ameae Walker, University of California at Riverside for her assistance in the experiments. This work was supported by National Natural Science Foundation of China (Grant No: 81272843).

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None to declare.

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This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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Authors and Affiliations

  1. Department of Epidemiology and Health Statistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, 100069, China

    Zongwen Li, Lianlian Du, Chunliu Li & Wei Wu

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Wei Wu

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  1. Zongwen Li
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  2. Lianlian Du
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Correspondence to Wei Wu.

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Li, Z., Du, L., Li, C. et al. Human chorionic gonadotropin β induces cell motility via ERK1/2 and MMP-2 activation in human glioblastoma U87MG cells. J Neurooncol 111, 237–244 (2013). https://doi.org/10.1007/s11060-012-1017-y

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  • DOI: https://doi.org/10.1007/s11060-012-1017-y

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