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01.09.2013 | Original Article

Plakophilin-associated RNA-binding proteins in prostate cancer and their implications in tumor progression and metastasis

verfasst von: Cheng Yang, Philipp Ströbel, Alexander Marx, Ilse Hofmann

Erschienen in: Virchows Archiv | Ausgabe 3/2013

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Abstract

Both plakophilins (PKP) 1 and 3 play a role in the progression of prostate cancer. The RNA-binding proteins (RBPs) GAP-SH3-binding protein (G3BP), fragile-X-related protein 1 (FXR1), poly(A)-binding protein, cytoplasmic 1 (PABPC1), and up-frameshift factor 1 (UPF1) are associated with PKP3. All these RBPs have an impact on RNA metabolism. Until recently, the PKP-associated RBPs have not been analyzed in prostate cancer. In the current study, we showed by affinity purification that the PKP3-associated RBPs were also binding partners of PKP1. We examined the expression of PKP1/3-associated RBPs and PKP1/3 in prostate cell lines, tumor-free prostate, and 136 prostatic adenocarcinomas by immunofluorescence and immunoblot. All four RBPs G3BP, FXR1, UPF1, and PABPC1 were expressed in the glandular epithelium of the normal prostate. PKP1 and FXR1 were strongly reduced in tumor tissues with Gleason score >7 and diminished expression of PKP1 and FXR1 also appeared to be associated with a metastatic phenotype. Additionally, the predominant nuclear localization of UPF1 in normal glandular cells and low grade tumors was switched to a more cytoplasmic pattern in carcinomas with Gleason score >7. Our findings suggest that PKP1 and FXR1 may have a tumor-suppressive function and are downregulated in more aggressive tumors. Collectively, PKP1/3-associated RBPs FXR1 and UPF1 may have a functional role in prostate cancer progression and metastasis and highlight the potential importance of posttranscriptional regulation of gene expression and nonsense-mediated decay in cancer.

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Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917PubMedCrossRef

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedCrossRef

Jackson RJ, Hellen CU, Pestova TV (2008) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11(2):113–127CrossRef

Glisovic T, Bachorik JL, Yong J, Dreyfuss G (2008) RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett 582(14):1977–1986PubMedCrossRef

Jeanes A, Gottardi CJ, Yap AS (2008) Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27(55):6920–6929PubMedCrossRef

Vasioukhin V, Fuchs E (2001) Actin dynamics and cell–cell adhesion in epithelia. Curr Opin Cell Biol 13(1):76–84PubMedCrossRef

Bass-Zubek AE, Godsel LM, Delmar M, Green KJ (2009) Plakophilins: multifunctional scaffolds for adhesion and signaling. Curr Opin Cell Biol 21(5):708–716PubMedCrossRef

Neuber S, Muhmer M, Wratten D, Koch PJ, Moll R, Schmidt A (2010) The desmosomal plaque proteins of the plakophilin family. Dermatol Res Pract 2010:101452PubMed

Breuninger S, Reidenbach S, Sauer CG, Strobel P, Pfitzenmaier J, Trojan L, Hofmann I (2010) Desmosomal plakophilins in the prostate and prostatic adenocarcinomas: implications for diagnosis and tumor progression. Am J Pathol 176(5):2509–2519PubMedCrossRef

10.

Valenta T, Hausmann G, Basler K (2012) The many faces and functions of beta-catenin. EMBO J 31(12):2714–2736PubMedCrossRef

11.

Hofmann I, Casella M, Schnolzer M, Schlechter T, Spring H, Franke WW (2006) Identification of the junctional plaque protein plakophilin 3 in cytoplasmic particles containing RNA-binding proteins and the recruitment of plakophilins 1 and 3 to stress granules. Mol Biol Cell 17(3):1388–1398PubMedCrossRef

12.

Irvine K, Stirling R, Hume D, Kennedy D (2004) Rasputin, more promiscuous than ever: a review of G3BP. Int J Dev Biol 48(10):1065–1077PubMedCrossRef

13.

Vasudevan S, Steitz JA (2007) AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128(6):1105–1118PubMedCrossRef

14.

Siomi MC, Siomi H, Sauer WH, Srinivasan S, Nussbaum RL, Dreyfuss G (1995) FXR1, an autosomal homolog of the fragile X mental retardation gene. EMBO J 14(11):2401–2408PubMed

15.

Khera TK, Dick AD, Nicholson LB (2010) Fragile X-related protein FXR1 controls post-transcriptional suppression of lipopolysaccharide-induced tumour necrosis factor-alpha production by transforming growth factor-beta1. FEBS J 277(13):2754–2765PubMedCrossRef

16.

Gorgoni B, Richardson WA, Burgess HM, Anderson RC, Wilkie GS, Gautier P, Martins JP, Brook M, Sheets MD, Gray NK (2011) Poly(A)-binding proteins are functionally distinct and have essential roles during vertebrate development. Proc Natl Acad Sci U S A 108(19):7844–7849PubMedCrossRef

17.

Brook M, Gray NK (2012) The role of mammalian poly(A)-binding proteins in co-ordinating mRNA turnover. Biochem Soc Trans 40(4):856–864PubMedCrossRef

18.

Mangus DA, Evans MC, Jacobson A (2003) Poly(A)-binding proteins: multifunctional scaffolds for the post-transcriptional control of gene expression. Genome Biol 4(7):223PubMedCrossRef

19.

Amrani N, Ghosh S, Mangus DA, Jacobson A (2008) Translation factors promote the formation of two states of the closed-loop mRNP. Nature 453(7199):1276–1280PubMedCrossRef

20.

Cosson B, Berkova N, Couturier A, Chabelskaya S, Philippe M, Zhouravleva G (2002) Poly(A)-binding protein and eRF3 are associated in vivo in human and Xenopus cells. Biol Cell 94(4–5):205–216PubMedCrossRef

21.

Ivanov PV, Gehring NH, Kunz JB, Hentze MW, Kulozik AE (2008) Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. EMBO J 27(5):736–747PubMedCrossRef

22.

Nicholson P, Yepiskoposyan H, Metze S, Zamudio Orozco R, Kleinschmidt N, Muhlemann O (2010) Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol Life Sci 67(5):677–700PubMedCrossRef

23.

Czaplinski K, Weng Y, Hagan KW, Peltz SW (1995) Purification and characterization of the Upf1 protein: a factor involved in translation and mRNA degradation. RNA 1(6):610–623PubMed

24.

Lukong KE, Chang KW, Khandjian EW, Richard S (2008) RNA-binding proteins in human genetic disease. Trends Genet 24(8):416–425PubMedCrossRef

25.

Silvera D, Formenti SC, Schneider RJ (2010) Translational control in cancer. Nat Rev Cancer 10(4):254–266PubMedCrossRef

26.

Wurth L (2012) Versatility of RNA-binding proteins in cancer. Comp Funct Genom 2012:178525CrossRef

27.

Silvera D, Arju R, Darvishian F, Levine PH, Zolfaghari L, Goldberg J, Hochman T, Formenti SC, Schneider RJ (2009) Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer. Nat Cell Biol 11(7):903–908PubMedCrossRef

28.

Wendel HG, Silva RL, Malina A, Mills JR, Zhu H, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Teruya-Feldstein J, Pelletier J, Lowe SW (2007) Dissecting eIF4E action in tumorigenesis. Genes Dev 21(24):3232–3237PubMedCrossRef

29.

Abdelmohsen K, Gorospe M (2010) Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA 1(2):214–229PubMedCrossRef

30.

Hinman MN, Lou H (2008) Diverse molecular functions of Hu proteins. Cell Mol Life Sci 65(20):3168–3181PubMedCrossRef

31.

Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL (2005) The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 29(9):1228–1242PubMedCrossRef

32.

Hayward SW, Dahiya R, Cunha GR, Bartek J, Deshpande N, Narayan P (1995) Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1. Vitro Cell Dev Biol Anim 31(1):14–24CrossRef

33.

Stone KR, Mickey DD, Wunderli H, Mickey GH, Paulson DF (1978) Isolation of a human prostate carcinoma cell line (DU 145). Int J Cancer 21(3):274–281PubMedCrossRef

34.

Hofmann I, Kuhn C, Franke WW (2008) Protein p0071, a major plaque protein of non-desmosomal adhering junctions, is a selective cell-type marker. Cell Tissue Res 334(3):381–399PubMedCrossRef

35.

Kirkpatrick LL, McIlwain KA, Nelson DL (1999) Alternative splicing in the murine and human FXR1 genes. Genomics 59(2):193–202PubMedCrossRef

36.

Dube M, Huot ME, Khandjian EW (2000) Muscle specific fragile X related protein 1 isoforms are sequestered in the nucleus of undifferentiated myoblast. BMC Genet 1:4PubMedCrossRef

37.

Schmidt A, Langbein L, Rode M, Pratzel S, Zimbelmann R, Franke WW (1997) Plakophilins 1a and 1b: widespread nuclear proteins recruited in specific epithelial cells as desmosomal plaque components. Cell Tissue Res 290(3):481–499PubMedCrossRef

38.

Atkin AL, Altamura N, Leeds P, Culbertson MR (1995) The majority of yeast UPF1 co-localizes with polyribosomes in the cytoplasm. Mol Biol Cell 6(5):611–625PubMedCrossRef

39.

Singh G, Jakob S, Kleedehn MG, Lykke-Andersen J (2007) Communication with the exon-junction complex and activation of nonsense-mediated decay by human Upf proteins occur in the cytoplasm. Mol Cell 27(5):780–792PubMedCrossRef

40.

Thomas MG, Martinez Tosar LJ, Loschi M, Pasquini JM, Correale J, Kindler S, Boccaccio GL (2005) Staufen recruitment into stress granules does not affect early mRNA transport in oligodendrocytes. Mol Biol Cell 16(1):405–420PubMedCrossRef

41.

Buchan JR, Parker R (2009) Eukaryotic stress granules: the ins and outs of translation. Mol Cell 36(6):932–941PubMedCrossRef

42.

Anderson P, Kedersha N (2008) Stress granules: the Tao of RNA triage. Trends Biochem Sci 33(3):141–150PubMedCrossRef

43.

Sobolik-Delmaire T, Katafiasz D, Keim SA, Mahoney MG, Wahl JK 3rd (2007) Decreased plakophilin-1 expression promotes increased motility in head and neck squamous cell carcinoma cells. Cell Commun Adhes 14(2–3):99–109PubMedCrossRef

44.

Papagerakis S, Shabana AH, Depondt J, Gehanno P, Forest N (2003) Immunohistochemical localization of plakophilins (PKP1, PKP2, PKP3, and p0071) in primary oropharyngeal tumors: correlation with clinical parameters. Hum Pathol 34(6):565–572PubMedCrossRef

45.

Kaz AM, Luo Y, Dzieciatkowski S, Chak A, Willis JE, Upton MP, Leidner RS, Grady WM (2012) Aberrantly methylated PKP1 in the progression of Barrett’s esophagus to esophageal adenocarcinoma. Gene Chromosome Cancer 51(4):384–393CrossRef

46.

Schwarz J, Ayim A, Schmidt A, Jager S, Koch S, Baumann R, Dunne AA, Moll R (2006) Differential expression of desmosomal plakophilins in various types of carcinomas: correlation with cell type and differentiation. Hum Pathol 37(5):613–622PubMedCrossRef

47.

Moll I, Kurzen H, Langbein L, Franke WW (1997) The distribution of the desmosomal protein, plakophilin 1, in human skin and skin tumors. J Invest Dermatol 108(2):139–146PubMedCrossRef

48.

Furukawa C, Daigo Y, Ishikawa N, Kato T, Ito T, Tsuchiya E, Sone S, Nakamura Y (2005) Plakophilin 3 oncogene as prognostic marker and therapeutic target for lung cancer. Cancer Res 65(16):7102–7110PubMedCrossRef

49.

Aigner K, Descovich L, Mikula M, Sultan A, Dampier B, Bonne S, van Roy F, Mikulits W, Schreiber M, Brabletz T, Sommergruber W, Schweifer N, Wernitznig A, Beug H, Foisner R, Eger A (2007) The transcription factor ZEB1 (deltaEF1) represses plakophilin 3 during human cancer progression. FEBS Lett 581(8):1617–1624PubMedCrossRef

50.

Valladares-Ayerbes M, Diaz-Prado S, Reboredo M, Medina V, Lorenzo-Patino MJ, Iglesias-Diaz P, Haz M, Pertega S, Santamarina I, Blanco M, Quindos-Varela M, Figueroa A, Anton-Aparicio LM (2010) Evaluation of plakophilin-3 mRNA as a biomarker for detection of circulating tumor cells in gastrointestinal cancer patients. Cancer Epidemiol Biomarkers Prev 19(6):1432–1440PubMedCrossRef

51.

Demirag GG, Sullu Y, Gurgenyatagi D, Okumus NO, Yucel I (2011) Expression of plakophilins (PKP1, PKP2, and PKP3) in gastric cancers. Diagn Pathol 6:1PubMedCrossRef

52.

Demirag GG, Sullu Y, Yucel I (2012) Expression of plakophilins (PKP1, PKP2, and PKP3) in breast cancers. Med Oncol 29(3):1518–1522PubMedCrossRef

53.

Takahashi H, Nakatsuji H, Takahashi M, Avirmed S, Fukawa T, Takemura M, Fukumori T, Kanayama H (2012) Up-regulation of plakophilin-2 and down-regulation of plakophilin-3 are correlated with invasiveness in bladder cancer. Urology 79(1):240.e1–240.e8CrossRef

54.

Parker F, Maurier F, Delumeau I, Duchesne M, Faucher D, Debussche L, Dugue A, Schweighoffer F, Tocque B (1996) A Ras-GTPase-activating protein SH3-domain-binding protein. Mol Cell Biol 16(6):2561–2569PubMed

55.

Gorlach M, Burd CG, Dreyfuss G (1994) The mRNA poly(A)-binding protein: localization, abundance, and RNA-binding specificity. Exp Cell Res 211(2):400–407PubMedCrossRef

56.

Kennedy D, French J, Guitard E, Ru K, Tocque B, Mattick J (2001) Characterization of G3BPs: tissue specific expression, chromosomal localisation and rasGAP(120) binding studies. J Cell Biochem 84(1):173–187PubMedCrossRef

57.

Siomi MC, Zhang Y, Siomi H, Dreyfuss G (1996) Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them. Mol Cell Biol 16(7):3825–3832PubMed

58.

Garnon J, Lachance C, Di Marco S, Hel Z, Marion D, Ruiz MC, Newkirk MM, Khandjian EW, Radzioch D (2005) Fragile X-related protein FXR1P regulates proinflammatory cytokine tumor necrosis factor expression at the post-transcriptional level. J Biol Chem 280(7):5750–5763PubMedCrossRef

59.

Caudy AA, Myers M, Hannon GJ, Hammond SM (2002) Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev 16(19):2491–2496PubMedCrossRef

60.

Jin P, Zarnescu DC, Ceman S, Nakamoto M, Mowrey J, Jongens TA, Nelson DL, Moses K, Warren ST (2004) Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat Neurosci 7(2):113–117PubMedCrossRef

61.

Mortensen RD, Serra M, Steitz JA, Vasudevan S (2011) Posttranscriptional activation of gene expression in Xenopus laevis oocytes by microRNA-protein complexes (microRNPs). Proc Natl Acad Sci U S A 108(20):8281–8286PubMedCrossRef

62.

Xu XL, Zong R, Li Z, Biswas MH, Fang Z, Nelson DL, Gao FB (2011) FXR1P but not FMRP regulates the levels of mammalian brain-specific microRNA-9 and microRNA-124. J Neurosci 31(39):13705–13709PubMedCrossRef

63.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Disc 2(5):401–404CrossRef

64.

Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18(1):11–22PubMedCrossRef

65.

Comtesse N, Keller A, Diesinger I, Bauer C, Kayser K, Huwer H, Lenhof HP, Meese E (2007) Frequent overexpression of the genes FXR1, CLAPM1 and EIF4G located on amplicon 3q26–27 in squamous cell carcinoma of the lung. Int J Cancer 120(12):2538–2544PubMedCrossRef

66.

Lykke-Andersen J, Shu MD, Steitz JA (2000) Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell 103(7):1121–1131PubMedCrossRef

67.

Mendell JT, ap Rhys CM, Dietz HC (2002) Separable roles for rent1/hUpf1 in altered splicing and decay of nonsense transcripts. Science 298(5592):419–422PubMedCrossRef

68.

Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318(5851):798–801PubMedCrossRef

69.

Chawla R, Redon S, Raftopoulou C, Wischnewski H, Gagos S, Azzalin CM (2011) Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication. EMBO J 30(19):4047–4058PubMedCrossRef

70.

Perrin-Vidoz L, Sinilnikova OM, Stoppa-Lyonnet D, Lenoir GM, Mazoyer S (2002) The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons. Hum Mol Genet 11(23):2805–2814PubMedCrossRef

71.

Gardner LB (2010) Nonsense-mediated RNA decay regulation by cellular stress: implications for tumorigenesis. Mol Cancer Res 8(3):295–308PubMedCrossRef

72.

Wang D, Zavadil J, Martin L, Parisi F, Friedman E, Levy D, Harding H, Ron D, Gardner LB (2011) Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol Cell Biol 31(17):3670–3680PubMedCrossRef

Titel: Plakophilin-associated RNA-binding proteins in prostate cancer and their implications in tumor progression and metastasis
verfasst von: Cheng Yang
Philipp Ströbel
Alexander Marx
Ilse Hofmann
Publikationsdatum: 01.09.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Virchows Archiv / Ausgabe 3/2013
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-013-1452-y

Springer Medizin

Plakophilin-associated RNA-binding proteins in prostate cancer and their implications in tumor progression and metastasis

Abstract

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie

Springer Medizin

Abstract

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