Tumor Biology

, Volume 34, Issue 5, pp 2835–2842 | Cite as

Ataxia–telangiectasia group D complementing gene (ATDC) upregulates matrix metalloproteinase 9 (MMP-9) to promote lung cancer cell invasion by activating ERK and JNK pathways

  • Zhong-Ping Tang
  • Quan-Zhe Cui
  • Qian-Ze Dong
  • Ke Xu
  • En-Hua Wang
Research Article


Although the expression pattern and biological functions of ataxia–telangiectasia group D complementing gene (ATDC) had been implicated in several types of cancer, the roles and potential mechanisms of ATDC in lung cancer cell invasion are still ambiguous. In this study, we used gain- and loss-of-function analyses to explore the roles and potential mechanisms of ATDC in lung cancer cell invasion. siRNA knockdown of ATDC impaired cell invasion in A549 and H1299 cell lines, and its overexpression promoted cell invasion in HBE cell line. ATDC may contribute to the invasive ability of lung cancer cells by promoting the expression of invasion-related matrix metalloproteinase 9 (MMP-9). In addition, ATDC increased activating protein 1 (AP-1) reporter luciferase activity and the protein and mRNA levels of c-Jun and c-Fos. We further demonstrated that the roles of ATDC on cell invasion, MMP-9 upregulation, and AP-1 activation were dependent on extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) pathway activation, and ERK inhibitor U0126 or JNK inhibitor SP600125 blocked these effects of ATDC. These results suggested that ATDC upregulates MMP-9 to promote lung cancer cell invasion by activating ERK and JNK pathways.





This study was supported by the National Natural Science Foundation of China (NSFC nos. 81071905, 81272606).

Conflicts of interest



  1. 1.
    Minna JD, Roth JA, Gazdar AF. Focus on lung cancer. Cancer Cell. 2002;1:49–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Xu J, et al. Cancer statistics. CA Cancer J Clin. 2010;60:277–300.CrossRefPubMedGoogle Scholar
  3. 3.
    Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature. 1980;283:139–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Reymond A, Meroni G, Fantozzi A, et al. The tripartite motif family identifies cell compartments. EMBO J. 2001;20:2140–51.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Borden KL. RING fingers and B-boxes: zinc-binding protein–protein interaction domains. Biochem Cell Biol. 1998;76:351–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Reddy BA, Etkin LD, Freemont PS. A novel zinc finger coiled-coil domain in a family of nuclear proteins. Trends Biochem Sci. 1992;17:344–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhao G, Ke D, Vu T, et al. Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces. PLoS Pathog. 2011;7:e1002009.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Oliveira NM, Trikha R, McKnight A. A novel envelope mediated post entry restriction of murine leukaemia virus in human cells is Ref1/TRIM5α independent. Retrovirology. 2010;7:81.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Wang L, Heidt DG, Lee CJ, et al. Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell. 2009;15:207–19.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Hawthorn L, Stein L, Panzarella J, et al. Characterization of cell-type specific profiles in tissues and isolated cells from squamous cell carcinomas of the lung. Lung Cancer. 2006;53:129–42.CrossRefPubMedGoogle Scholar
  12. 12.
    Kosaka Y, Inoue H, Ohmachi T, et al. Tripartite motif-containing 29 (TRIM29) is a novel marker for lymph node metastasis in gastric cancer. Ann Surg Oncol. 2007;14:2543–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Dyrskjot L, Kruhoffer M, Thykjaer T, et al. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 2004;64:4040–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Glebov OK, Rodriguez LM, Soballe P, et al. Gene expression patterns distinguish colonoscopically isolated human aberrant crypt foci from normal colonic mucosa. Cancer Epidemiol Biomarkers Prev. 2006;15:2253–62.CrossRefPubMedGoogle Scholar
  15. 15.
    Ohmachi T, Tanaka F, Mimori K, et al. Clinical significance of TROP2 expression in colorectal cancer. Clin Cancer Res. 2006;12:3057–63.CrossRefPubMedGoogle Scholar
  16. 16.
    Santin AD, Zhan F, Bellone S, et al. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer. 2004;112:14–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Mutter GL, Baak JP, Fitzgerald JT, et al. Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol Oncol. 2001;83:177–85.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhan F, Hardin J, Kordsmeier B, et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood. 2002;99:1745–57.CrossRefPubMedGoogle Scholar
  19. 19.
    Smith AP, Hoek K, Becker D. Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas. Cancer Biol Ther. 2005;4:1018–29.CrossRefPubMedGoogle Scholar
  20. 20.
    Nacht M, Ferguson AT, Zhang W, et al. Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer. Cancer Res. 1999;59:5464–70.PubMedGoogle Scholar
  21. 21.
    Zhang P, Zhang Z, Zhou X, et al. Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line. BMC Cancer. 2006;6:224.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    LaTulippe E, Satagopan J, Smith A, et al. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res. 2002;62:4499–506.PubMedGoogle Scholar
  23. 23.
    Luo J, Duggan DJ, Chen Y, et al. Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. Cancer Res. 2001;61:4683–8.PubMedGoogle Scholar
  24. 24.
    Yu YP, Landsittel D, Jing L, et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol. 2004;22:2790–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Yuan Z, Villagra A, Peng L, et al. The ATDC (TRIM29) protein binds p53 and antagonizes p53-mediated functions. Mol Cell Biol. 30:3004–15.Google Scholar
  26. 26.
    Brzoska PM, Chen H, Zhu Y, et al. The product of the ataxia-telangiectasia group D complementing gene, ATDC, interacts with a protein kinase C substrate and inhibitor. Proc Natl Acad Sci U S A. 1995;92:7824–8.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Vincenti MP. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol. 2001;151:121–48.PubMedGoogle Scholar
  28. 28.
    Westermarck J, Kahari VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 1999;13:781–92.PubMedGoogle Scholar
  29. 29.
    Chen PN, Hsieh YS, Chiou HL, et al. Silibinin inhibits cell invasion through inactivation of both PI3K-Akt and MAPK signaling pathways. Chem Biol Interact. 2005;156:141–50.CrossRefPubMedGoogle Scholar
  30. 30.
    Huang C, Ma WY, Young MR, et al. Shortage of mitogen-activated protein kinase is responsible for resistance to AP-1 transactivation and transformation in mouse JB6 cells. Proc Natl Acad Sci U S A. 1998;95:156–61.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A. 2001;98:10983–5.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Leonhardt EA, Kapp LN, Young BR, et al. Nucleotide sequence analysis of a candidate gene for ataxia-telangiectasia group D (ATDC). Genomics. 1994;19:130–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Sardiello M, Cairo S, Fontanella B, et al. Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties. BMC Evol Biol. 2008;8:225.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Johnsen M, Lund LR, Romer J, et al. Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol. 1998;10:667–71.CrossRefPubMedGoogle Scholar
  35. 35.
    Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res. 1991;51:5054s–9.PubMedGoogle Scholar
  36. 36.
    Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.CrossRefPubMedGoogle Scholar
  37. 37.
    Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Iizasa T, Fujisawa T, Suzuki M, et al. Elevated levels of circulating plasma matrix metalloproteinase 9 in non-small cell lung cancer patients. Clin Cancer Res. 1999;5:149–53.PubMedGoogle Scholar
  39. 39.
    Shiraga M, Yano S, Yamamoto A, et al. Organ heterogeneity of host-derived matrix metalloproteinase expression and its involvement in multiple-organ metastasis by lung cancer cell lines. Cancer Res. 2002;62:5967–73.PubMedGoogle Scholar
  40. 40.
    Ylisirnio S, Hoyhtya M, Turpeenniemi-Hujanen T. Serum matrix metalloproteinases −2, -9 and tissue inhibitors of metalloproteinases −1, -2 in lung cancer—TIMP-1 as a prognostic marker. Anticancer Res. 2000;20:1311–6.PubMedGoogle Scholar
  41. 41.
    Baruch RR, Melinscak H, Lo J, et al. Altered matrix metalloproteinase expression associated with oncogene-mediated cellular transformation and metastasis formation. Cell Biol Int. 2001;25:411–20.CrossRefPubMedGoogle Scholar
  42. 42.
    Sehgal I, Thompson TC. Novel regulation of type IV collagenase (matrix metalloproteinase-9 and −2) activities by transforming growth factor-beta1 in human prostate cancer cell lines. Mol Biol Cell. 1999;10:407–16.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Hess J, Angel P, Schorpp-Kistner M. AP-1 subunits: quarrel and harmony among siblings. J Cell Sci. 2004;117:5965–73.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Zhong-Ping Tang
    • 1
  • Quan-Zhe Cui
    • 1
  • Qian-Ze Dong
    • 1
  • Ke Xu
    • 2
  • En-Hua Wang
    • 1
  1. 1.Department of Pathology, the First Affiliated Hospital and College of Basic Medical SciencesChina Medical UniversityShenyangChina
  2. 2.Department of Radiology, the First Affiliated HospitalChina Medical UniversityShenyangChina

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