Tumor Biology

, Volume 36, Issue 12, pp 9567–9577 | Cite as

Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression

  • Cheng Yang
  • Regina Fischer-Kešo
  • Tanja Schlechter
  • Philipp Ströbel
  • Alexander Marx
  • Ilse Hofmann
Research Article

Abstract

Plakophilin (PKP) 1 is frequently downregulated in prostate cancer and therefore may play a tumor-suppressive role. In the present study, we stably knocked down PKP1 in the non-neoplastic, prostatic BPH-1 cell line. In the PKP1-deficient cells, the expression of keratin 14 was lost, and the apoptosis rate was significantly reduced indicating that the cells acquired new biological capabilities. Moreover, we analyzed the gene expression profile of the PKP1-deficient BPH-1 cells. Among the genes that were significantly altered upon PKP1 knockdown, we noticed several extracellular matrix (ECM)-related genes and identified sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1/testican-1) as a gene of interest. SPOCK1 is a component of the ECM and belongs to a matricellular protein family named secreted protein, acidic, cysteine-rich (SPARC). The role of SPOCK1 in prostate cancer has not been clearly elucidated. We analyzed SPOCK1 mRNA expression levels in different cancer databases and characterized its expression in 136 prostatic adenocarcinomas by immunohistochemistry and western blot. SPOCK1 revealed a cytoplasmic localization in the glandular epithelium of the prostate and showed a significant upregulation of mRNA and protein in prostate tumor samples. Our findings support the hypothesis that PKP1 may have a tumor-suppressive function and suggest an important role of SPOCK1 in prostate tumor progression. Collectively, altered expression of PKP1 and SPOCK1 appears to be a frequent and critical event in prostate cancer.

Keywords

Prostate cancer PKP1 SPOCK1 Extracellular matrix Testican-1 

Notes

Acknowledgments

This study was funded by grants from the German Cancer Aid (109248) and the “Deutsche Forschungsgemeinschaft” (HO 2455/3-1). Cheng Yang obtained a fellowship from the Chinese Scholarship Council (CSC). We thank the microarray unit of the DKFZ Genomics and Proteomics Core Facility for providing the Illumina Whole-Genome Expression Beadchips and related services.

Conflicts of interest

None

Supplementary material

13277_2015_3628_MOESM1_ESM.docx (22 kb)
ESM 1 (DOCX 21 kb)
13277_2015_3628_MOESM2_ESM.docx (24 kb)
ESM 2 (DOCX 23 kb)

References

  1. 1.
    Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012;61(6):1079–92.CrossRefPubMedGoogle Scholar
  2. 2.
    Peifer M, Berg S, Reynolds AB. A repeating amino acid motif shared by proteins with diverse cellular roles. Cell. 1994;76(5):789–91.CrossRefPubMedGoogle Scholar
  3. 3.
    Neuber S, Muhmer M, Wratten D, Koch PJ, Moll R, Schmidt A. The desmosomal plaque proteins of the plakophilin family. Dermatol Res Pract. 2010;2010:101452.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Garrod D, Chidgey M. Desmosome structure, composition and function. Biochim Biophys Acta. 2008;1778(3):572–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Bass-Zubek AE, Godsel LM, Delmar M, Green KJ. Plakophilins: multifunctional scaffolds for adhesion and signaling. Curr Opin Cell Biol. 2009;21(5):708–16.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wolf A, Krause-Gruszczynska M, Birkenmeier O, Ostareck-Lederer A, Huttelmaier S, Hatzfeld M. Plakophilin 1 stimulates translation by promoting eIF4A1 activity. J Cell Biol. 2010;188(4):463–71.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fischer-Keso R, Breuninger S, Hofmann S, Henn M, Rohrig T, Strobel P, et al. Plakophilins 1 and 3 bind to FXR1 and thereby influence the mRNA stability of desmosomal proteins. Mol Cell Biol. 2014;34(23):4244–56.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sobolik-Delmaire T, Katafiasz D, Keim SA, Mahoney MG, Wahl 3rd JK. Decreased plakophilin-1 expression promotes increased motility in head and neck squamous cell carcinoma cells. Cell Commun Adhes. 2007;14(2–3):99–109.CrossRefPubMedGoogle Scholar
  9. 9.
    Papagerakis S, Shabana AH, Depondt J, Gehanno P, Forest N. Immunohistochemical localization of plakophilins (PKP1, PKP2, PKP3, and p0071) in primary oropharyngeal tumors: correlation with clinical parameters. Hum Pathol. 2003;34(6):565–72.CrossRefPubMedGoogle Scholar
  10. 10.
    Kaz AM, Luo Y, Dzieciatkowski S, Chak A, Willis JE, Upton MP, et al. Aberrantly methylated PKP1 in the progression of Barrett’s esophagus to esophageal adenocarcinoma. Gene Chrom Cancer. 2012;51(4):384–93.CrossRefGoogle Scholar
  11. 11.
    Schwarz J, Ayim A, Schmidt A, Jager S, Koch S, Baumann R, et al. Differential expression of desmosomal plakophilins in various types of carcinomas: correlation with cell type and differentiation. Hum Pathol. 2006;37(5):613–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Moll I, Kurzen H, Langbein L, Franke WW. The distribution of the desmosomal protein, plakophilin 1, in human skin and skin tumors. J Invest Dermatol. 1997;108(2):139–46.CrossRefPubMedGoogle Scholar
  13. 13.
    Furukawa C, Daigo Y, Ishikawa N, Kato T, Ito T, Tsuchiya E, et al. Plakophilin 3 oncogene as prognostic marker and therapeutic target for lung cancer. Cancer Res. 2005;65(16):7102–10.CrossRefPubMedGoogle Scholar
  14. 14.
    Aigner K, Descovich L, Mikula M, Sultan A, Dampier B, Bonne S, et al. The transcription factor ZEB1 (deltaEF1) represses plakophilin 3 during human cancer progression. FEBS Lett. 2007;581(8):1617–24.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Valladares-Ayerbes M, Diaz-Prado S, Reboredo M, Medina V, Lorenzo-Patino MJ, Iglesias-Diaz P, et al. Evaluation of plakophilin-3 mRNA as a biomarker for detection of circulating tumor cells in gastrointestinal cancer patients. Cancer Epidemiol Biomarkers Prev. 2010;19(6):1432–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Demirag GG, Sullu Y, Gurgenyatagi D, Okumus NO, Yucel I. Expression of plakophilins (PKP1, PKP2, and PKP3) in gastric cancers. Diagn Pathol. 2011;6:1.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Demirag GG, Sullu Y, Yucel I. Expression of plakophilins (PKP1, PKP2, and PKP3) in breast cancers. Med Oncol. 2012;29(3):1518–22.CrossRefPubMedGoogle Scholar
  18. 18.
    Takahashi H, Nakatsuji H, Takahashi M, Avirmed S, Fukawa T, Takemura M, et al. Up-regulation of plakophilin-2 and down-regulation of plakophilin-3 are correlated with invasiveness in bladder cancer. Urology. 2012;79(1):240. e1–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Yang C, Strobel P, Marx A, Hofmann I. Plakophilin-associated RNA-binding proteins in prostate cancer and their implications in tumor progression and metastasis. Virchows Arch. 2013;463(3):379–90.CrossRefPubMedGoogle Scholar
  20. 20.
    Breuninger S, Reidenbach S, Sauer CG, Strobel P, Pfitzenmaier J, Trojan L, et al. Desmosomal plakophilins in the prostate and prostatic adenocarcinomas: implications for diagnosis and tumor progression. Am J Pathol. 2010;176(5):2509–19.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Schaefer L, Schaefer RM. Proteoglycans: from structural compounds to signaling molecules. Cell Tissue Res. 2010;339(1):237–46.CrossRefPubMedGoogle Scholar
  22. 22.
    Jarvelainen H, Sainio A, Koulu M, Wight TN, Penttinen R. Extracellular matrix molecules: potential targets in pharmacotherapy. Pharmacol Rev. 2009;61(2):198–223.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Egeblad M, Rasch MG, Weaver VM. Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol. 2010;22(5):697–706.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Mott JD, Werb Z. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol. 2004;16(5):558–64.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bode W, Huber R. Proteinase-protein inhibitor interaction. In: Sies H, Flohé L, Zimmer G, editors. Molecular aspects of inflammation. Colloquium der gesellschaft für biologische chemie 11–13 April 1991 in Mosbach/Baden. Heidelberg: Springer Berlin; 1991. p. 103–15.Google Scholar
  26. 26.
    Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123(Pt 24):4195–200.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Bradshaw AD. Diverse biological functions of the SPARC family of proteins. Int J Biochem Cell Biol. 2012;44(3):480–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Tai IT, Tang MJ. SPARC in cancer biology: its role in cancer progression and potential for therapy. Drug Resist Updat. 2008;11(6):231–46.CrossRefPubMedGoogle Scholar
  29. 29.
    Li Y, Chen L, Chan TH, Liu M, Kong KL, Qiu JL, et al. SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice. Gastroenterology. 2013;144(1):179–91. e4.CrossRefPubMedGoogle Scholar
  30. 30.
    Leja J, Essaghir A, Essand M, Wester K, Oberg K, Totterman TH, et al. Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas. Mod Pathol. 2009;22(2):261–72.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim HP, Han SW, Song SH, Jeong EG, Lee MY, Hwang D, et al. Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer. Oncogene. 2014;33(25):3334–41.CrossRefPubMedGoogle Scholar
  32. 32.
    Wlazlinski A, Engers R, Hoffmann MJ, Hader C, Jung V, Muller M, et al. Downregulation of several fibulin genes in prostate cancer. Prostate. 2007;67(16):1770–80.CrossRefPubMedGoogle Scholar
  33. 33.
    Epstein JI, Allsbrook Jr WC, Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol. 2005;29(9):1228–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Hayward SW, Dahiya R, Cunha GR, Bartek J, Deshpande N, Narayan P. Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1. In Vitro Cell Dev Biol Anim. 1995;31(1):14–24.CrossRefPubMedGoogle Scholar
  35. 35.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):l1.CrossRefGoogle Scholar
  36. 36.
    Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol. 2003;200(4):448–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Krojer T, Garrido-Franco M, Huber R, Ehrmann M, Clausen T. Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine. Nature. 2002;416(6879):455–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Clements J, Hooper J, Dong Y, Harvey T. The expanded human kallikrein (KLK) gene family: genomic organisation, tissue-specific expression and potential functions. Biol Chem. 2001;382(1):5–14.CrossRefPubMedGoogle Scholar
  39. 39.
    Rawlings ND, Tolle DP, Barrett AJ. Evolutionary families of peptidase inhibitors. Biochem J. 2004;378(Pt 3):705–16.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Bobek LA, Levine MJ. Cystatins—inhibitors of cysteine proteinases. Crit Rev Oral Biol Med. 1992;3(4):307–32.CrossRefPubMedGoogle Scholar
  41. 41.
    Itano N, Kimata K. Mammalian hyaluronan synthases. IUBMB Life. 2002;54(4):195–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRefPubMedGoogle Scholar
  43. 43.
    Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007;9(2):166–80.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. Oncomine: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A. 2004;101(3):811–6.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefPubMedGoogle Scholar
  48. 48.
    Green KJ, Simpson CL. Desmosomes: new perspectives on a classic. J Invest Dermatol. 2007;127(11):2499–515.CrossRefPubMedGoogle Scholar
  49. 49.
    Dusek RL, Attardi LD. Desmosomes: new perpetrators in tumour suppression. Nat Rev Cancer. 2011;11(5):317–23.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Chidgey M, Dawson C. Desmosomes: a role in cancer? Br J Cancer. 2007;96(12):1783–7.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    van Leenders GJ, Aalders TW, de Kaa CA H-v, Ruiter DJ, Schalken JA. Expression of basal cell keratins in human prostate cancer metastases and cell lines. J Pathol. 2001;195(5):563–70.CrossRefPubMedGoogle Scholar
  52. 52.
    Okada H, Tsubura A, Okamura A, Senzaki H, Naka Y, Komatz Y, et al. Keratin profiles in normal/hyperplastic prostates and prostate carcinoma. Virchows Arch A Pathol Anat Histopathol. 1992;421(2):157–61.CrossRefPubMedGoogle Scholar
  53. 53.
    Ke XS, Li WC, Hovland R, Qu Y, Liu RH, McCormack E, et al. Reprogramming of cell junction modules during stepwise epithelial to mesenchymal transition and accumulation of malignant features in vitro in a prostate cell model. Exp Cell Res. 2011;317(2):234–47.CrossRefPubMedGoogle Scholar
  54. 54.
    Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196(4):395–406.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Alliel PM, Perin JP, Jolles P, Bonnet FJ. Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour. Eur J Biochem. 1993;214(1):347–50.CrossRefPubMedGoogle Scholar
  56. 56.
    Wight TN, Kinsella MG, Qwarnstrom EE. The role of proteoglycans in cell adhesion, migration and proliferation. Curr Opin Cell Biol. 1992;4(5):793–801.CrossRefPubMedGoogle Scholar
  57. 57.
    Manon-Jensen T, Itoh Y, Couchman JR. Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. 2010;277(19):3876–89.CrossRefPubMedGoogle Scholar
  58. 58.
    Edgell CJ, BaSalamah MA, Marr HS. Testican-1: a differentially expressed proteoglycan with protease inhibiting activities. Int Rev Cytol. 2004;236:101–22.CrossRefPubMedGoogle Scholar
  59. 59.
    Bocock JP, Edgell CJ, Marr HS, Erickson AH. Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin L. Eur J Biochem. 2003;270(19):4008–15.CrossRefPubMedGoogle Scholar
  60. 60.
    Marr HS, Edgell CJ. Testican-1 inhibits attachment of Neuro-2a cells. Matrix Biol. 2003;22(3):259–66.CrossRefPubMedGoogle Scholar
  61. 61.
    Miao L, Wang Y, Xia H, Yao C, Cai H, Song Y. SPOCK1 is a novel transforming growth factor-β target gene that regulates lung cancer cell epithelial-mesenchymal transition. Biochem Biophys Res Commun. 2013;440(4):792–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Pieters T, van Roy F, van Hengel J. Functions of p120ctn isoforms in cell-cell adhesion and intracellular signaling. Front Biosci. 2012;17:1669–94.CrossRefGoogle Scholar
  63. 63.
    Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J. 2012;31(12):2714–36.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.CrossRefPubMedGoogle Scholar
  65. 65.
    Aparicio LA, Abella V, Valladares M, Figueroa A. Posttranscriptional regulation by RNA-binding proteins during epithelial-to-mesenchymal transition. Cell Mol Life Sci. 2013;70(23):4463–77.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Cheng Yang
    • 1
    • 2
    • 5
  • Regina Fischer-Kešo
    • 1
    • 2
  • Tanja Schlechter
    • 1
    • 2
  • Philipp Ströbel
    • 3
  • Alexander Marx
    • 4
  • Ilse Hofmann
    • 1
    • 2
  1. 1.Division of Vascular Oncology and MetastasisGerman Cancer Research Center, DKFZ-ZMBH AllianceHeidelbergGermany
  2. 2.Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  3. 3.Institute of PathologyUniversity Medical Center GöttingenGöttingenGermany
  4. 4.Institute of Pathology, University Medical Center MannheimHeidelberg UniversityMannheimGermany
  5. 5.Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina

Personalised recommendations