Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis

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Dysregulated cell–cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell–cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell–cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Vyšlo v časopise: Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis. PLoS Genet 6(10): e32767. doi:10.1371/journal.pgen.1001168
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001168

Souhrn

Zdroje

1. CooperGM

1995 Oncogenes Boston Jones and Bartlett Publishers xv, 384

2. AlamM

RatnerD

2001 Cutaneous squamous-cell carcinoma. N Engl J Med 344 975 983

3. HunterKD

ParkinsonEK

HarrisonPR

2005 Profiling early head and neck cancer. Nat Rev Cancer 5 127 135

4. FuchsE

RaghavanS

2002 Getting under the skin of epidermal morphogenesis. Nat Rev Genet 3 199 209

5. GreenKJ

GaudryCA

2000 Are desmosomes more than tethers for intermediate filaments? Nat Rev Mol Cell Biol 1 208 216

6. YinT

GreenKJ

2004 Regulation of desmosome assembly and adhesion. Semin Cell Dev Biol 15 665 677

7. ChidgeyM

2002 Desmosomes and disease: an update. Histol Histopathol 17 1179 1192

8. NoseA

NagafuchiA

TakeichiM

1988 Expressed recombinant cadherins mediate cell sorting in model systems. Cell 54 993 1001

9. NagafuchiA

ShirayoshiY

OkazakiK

YasudaK

TakeichiM

1987 Transformation of cell adhesion properties by exogenously introduced E-cadherin cDNA. Nature 329 341 343

10. OzawaM

BaribaultH

KemlerR

1989 The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J 8 1711 1717

11. RimmDL

KoslovER

KebriaeiP

CianciCD

MorrowJS

1995 Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex. Proc Natl Acad Sci U S A 92 8813 8817

12. VleminckxK

VakaetLJr

MareelM

FiersW

van RoyF

1991 Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66 107 119

13. FrixenUH

BehrensJ

SachsM

EberleG

VossB

1991 E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113 173 185

14. BatlleE

SanchoE

FranciC

DominguezD

MonfarM

2000 The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2 84 89

15. MoodySE

PerezD

PanTC

SarkisianCJ

PortocarreroCP

2005 The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8 197 209

16. SchipperJH

FrixenUH

BehrensJ

UngerA

JahnkeK

1991 E-cadherin expression in squamous cell carcinomas of head and neck: inverse correlation with tumor dedifferentiation and lymph node metastasis. Cancer Res 51 6328 6337

17. PerlAK

WilgenbusP

DahlU

SembH

ChristoforiG

1998 A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392 190 193

18. DerksenPW

LiuX

SaridinF

van der GuldenH

ZevenhovenJ

2006 Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10 437 449

19. DavisMA

ReynoldsAB

2006 Blocked acinar development, E-cadherin reduction, and intraepithelial neoplasia upon ablation of p120-catenin in the mouse salivary gland. Dev Cell 10 21 31

20. Perez-MorenoM

SongW

PasolliHA

WilliamsSE

FuchsE

2008 Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer. Proc Natl Acad Sci U S A 105 15399 15404

21. VasioukhinV

BauerC

DegensteinL

WiseB

FuchsE

2001 Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin. Cell 104 605 617

22. KobielakA

FuchsE

2006 Links between alpha-catenin, NF-kappaB, and squamous cell carcinoma in skin. Proc Natl Acad Sci U S A 103 2322 2327

23. ChitaevNA

TroyanovskySM

1997 Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion. J Cell Biol 138 193 201

24. TselepisC

ChidgeyM

NorthA

GarrodD

1998 Desmosomal adhesion inhibits invasive behavior. Proc Natl Acad Sci U S A 95 8064 8069

25. SyedSE

TrinnamanB

MartinS

MajorS

HutchinsonJ

2002 Molecular interactions between desmosomal cadherins. Biochem J 362 317 327

26. MathurM

GoodwinL

CowinP

1994 Interactions of the cytoplasmic domain of the desmosomal cadherin Dsg1 with plakoglobin. J Biol Chem 269 14075 14080

27. TroyanovskySM

TroyanovskyRB

EshkindLG

LeubeRE

FrankeWW

1994 Identification of amino acid sequence motifs in desmocollin, a desmosomal glycoprotein, that are required for plakoglobin binding and plaque formation. Proc Natl Acad Sci U S A 91 10790 10794

28. HatzfeldM

HaffnerC

SchulzeK

VinzensU

2000 The function of plakophilin 1 in desmosome assembly and actin filament organization. J Cell Biol 149 209 222

29. ChenX

BonneS

HatzfeldM

van RoyF

GreenKJ

2002 Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling. J Biol Chem 277 10512 10522

30. BonneS

GilbertB

HatzfeldM

ChenX

GreenKJ

2003 Defining desmosomal plakophilin-3 interactions. J Cell Biol 161 403 416

31. KowalczykAP

HatzfeldM

BornslaegerEA

KoppDS

BorgwardtJE

1999 The head domain of plakophilin-1 binds to desmoplakin and enhances its recruitment to desmosomes. Implications for cutaneous disease. J Biol Chem 274 18145 18148

32. KowalczykAP

BornslaegerEA

BorgwardtJE

PalkaHL

DhaliwalAS

1997 The amino-terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin-plakoglobin complexes. J Cell Biol 139 773 784

33. BornslaegerEA

CorcoranCM

StappenbeckTS

GreenKJ

1996 Breaking the connection: displacement of the desmosomal plaque protein desmoplakin from cell-cell interfaces disrupts anchorage of intermediate filament bundles and alters intercellular junction assembly. J Cell Biol 134 985 1001

34. GreenKJ

SimpsonCL

2007 Desmosomes: new perspectives on a classic. J Invest Dermatol 127 2499 2515

35. YashiroM

NishiokaN

HirakawaK

2006 Decreased expression of the adhesion molecule desmoglein-2 is associated with diffuse-type gastric carcinoma. Eur J Cancer 42 2397 2403

36. RoepmanP

WesselsLF

KettelarijN

KemmerenP

MilesAJ

2005 An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nat Genet 37 182 186

37. PapagerakisS

ShabanaAH

PollockBH

PapagerakisP

DepondtJ

2009 Altered desmoplakin expression at transcriptional and protein levels provides prognostic information in human oropharyngeal cancer. Hum Pathol 40 1320 1329

38. DepondtJ

ShabanaAH

Florescu-ZorilaS

GehannoP

ForestN

1999 Down-regulation of desmosomal molecules in oral and pharyngeal squamous cell carcinomas as a marker for tumour growth and distant metastasis. Eur J Oral Sci 107 183 193

39. FurukawaC

DaigoY

IshikawaN

KatoT

ItoT

2005 Plakophilin 3 oncogene as prognostic marker and therapeutic target for lung cancer. Cancer Res 65 7102 7110

40. ChenYJ

ChangJT

LeeL

WangHM

LiaoCT

2007 DSG3 is overexpressed in head neck cancer and is a potential molecular target for inhibition of oncogenesis. Oncogene 26 467 476

41. KurzenH

MunzingI

HartschuhW

2003 Expression of desmosomal proteins in squamous cell carcinomas of the skin. J Cutan Pathol 30 621 630

42. AttardiLD

ReczekEE

CosmasC

DemiccoEG

McCurrachME

2000 PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev 14 704 718

43. IhrieRA

MarquesMR

NguyenBT

HornerJS

PapazogluC

2005 Perp is a p63-regulated gene essential for epithelial integrity. Cell 120 843 856

44. JiangW

AnanthaswamyHN

MullerHK

KripkeML

1999 p53 protects against skin cancer induction by UV-B radiation. Oncogene 18 4247 4253

45. IndraAK

LiM

BrocardJ

WarotX

BornertJM

2000 Targeted somatic mutagenesis in mouse epidermis. Horm Res 54 296 300

46. MetzgerD

LiM

ChambonP

2005 Targeted somatic mutagenesis in the mouse epidermis. Methods Mol Biol 289 329 340

47. IhrieRA

ReczekE

HornerJS

KhachatrianL

SageJ

2003 Perp is a mediator of p53-dependent apoptosis in diverse cell types. Curr Biol 13 1985 1990

48. HakemR

HakemA

DuncanGS

HendersonJT

WooM

1998 Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94 339 352

49. JozaN

SusinSA

DaugasE

StanfordWL

ChoSK

2001 Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410 549 554

50. ZieglerA

JonasonAS

LeffellDJ

SimonJA

SharmaHW

1994 Sunburn and p53 in the onset of skin cancer. Nature 372 773 776

51. BornslaegerEA

GodselLM

CorcoranCM

ParkJK

HatzfeldM

2001 Plakophilin 1 interferes with plakoglobin binding to desmoplakin, yet together with plakoglobin promotes clustering of desmosomal plaque complexes at cell-cell borders. J Cell Sci 114 727 738

52. KalluriR

WeinbergRA

2009 The basics of epithelial-mesenchymal transition. J Clin Invest 119 1420 1428

53. TusherVG

TibshiraniR

ChuG

2001 Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98 5116 5121

54. BlumbergH

DinhH

TruebloodES

PretoriusJ

KuglerD

2007 Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J Exp Med 204 2603 2614

55. GebhardtC

NemethJ

AngelP

HessJ

2006 S100A8 and S100A9 in inflammation and cancer. Biochem Pharmacol 72 1622 1631

56. SalamaI

MalonePS

MihaimeedF

JonesJL

2008 A review of the S100 proteins in cancer. Eur J Surg Oncol 34 357 364

57. EurichK

SegawaM

Toei-ShimizuS

MizoguchiE

2009 Potential role of chitinase 3-like-1 in inflammation-associated carcinogenic changes of epithelial cells. World J Gastroenterol 15 5249 5259

58. BeiderK

AbrahamM

BeginM

WaldH

WeissID

2009 Interaction between CXCR4 and CCL20 pathways regulates tumor growth. PLoS One 4 e5125 doi:10.1371/journal.pone.0005125

59. HasanL

MazzucchelliL

LiebiM

LisM

HungerRE

2006 Function of liver activation-regulated chemokine/CC chemokine ligand 20 is differently affected by cathepsin B and cathepsin D processing. J Immunol 176 6512 6522

60. PunjV

MattaH

SchamusS

YangT

ChangY

2009 Induction of CCL20 production by Kaposi sarcoma-associated herpesvirus: role of viral FLICE inhibitory protein K13-induced NF-kappaB activation. Blood 113 5660 5668

61. Ben-BaruchA

2006 The multifaceted roles of chemokines in malignancy. Cancer Metastasis Rev 25 357 371

62. O'SheaJJ

MurrayPJ

2008 Cytokine signaling modules in inflammatory responses. Immunity 28 477 487

63. GrivennikovSI

GretenFR

KarinM

2010 Immunity, inflammation, and cancer. Cell 140 883 899

64. PinkusGS

PinkusJL

1991 Myeloperoxidase: a specific marker for myeloid cells in paraffin sections. Mod Pathol 4 733 741

65. RibattiD

VaccaA

NicoB

CrivellatoE

RoncaliL

2001 The role of mast cells in tumour angiogenesis. Br J Haematol 115 514 521

66. CoussensLM

RaymondWW

BergersG

Laig-WebsterM

BehrendtsenO

1999 Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13 1382 1397

67. Ch'ngS

WallisRA

YuanL

DavisPF

TanST

2006 Mast cells and cutaneous malignancies. Mod Pathol 19 149 159

68. MeiningerCJ

1995 Mast cells and tumor-associated angiogenesis. Chem Immunol 62 239 257

69. MaltbyS

KhazaieK

McNagnyKM

2009 Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 1796 19 26

70. BashkinP

RazinE

EldorA

VlodavskyI

1990 Degranulating mast cells secrete an endoglycosidase that degrades heparan sulfate in subendothelial extracellular matrix. Blood 75 2204 2212

71. VlodavskyI

EldorA

Haimovitz-FriedmanA

MatznerY

Ishai-MichaeliR

1992 Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 12 112 127

72. NavaP

LaukoetterMG

HopkinsAM

LaurO

Gerner-SmidtK

2007 Desmoglein-2: a novel regulator of apoptosis in the intestinal epithelium. Mol Biol Cell 18 4565 4578

73. DusekRL

GetsiosS

ChenF

ParkJK

AmargoEV

2006 The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes. J Biol Chem 281 3614 3624

74. NaikE

MichalakEM

VillungerA

AdamsJM

StrasserA

2007 Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J Cell Biol 176 415 424

75. AndreuP

JohanssonM

AffaraNI

PucciF

TanT

2010 FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17 121 134

76. CuiW

FowlisDJ

BrysonS

DuffieE

IrelandH

1996 TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86 531 542

77. PierceAM

Schneider-BroussardR

Gimenez-ContiIB

RussellJL

ContiCJ

1999 E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model. Mol Cell Biol 19 6408 6414

78. MarquesMR

HornerJS

IhrieRA

BronsonRT

AttardiLD

2005 Mice lacking the p53/p63 target gene Perp are resistant to papilloma development. Cancer Res 65 6551 6556

79. KempCJ

DonehowerLA

BradleyA

BalmainA

1993 Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell 74 813 822

80. BenjaminCL

UllrichSE

KripkeML

AnanthaswamyHN

2008 p53 tumor suppressor gene: a critical molecular target for UV induction and prevention of skin cancer. Photochem Photobiol 84 55 62

81. BruinsW

ZwartE

AttardiLD

IwakumaT

HoogervorstEM

2004 Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389. Mol Cell Biol 24 8884 8894

82. MelnikovaVO

AnanthaswamyHN

2005 Cellular and molecular events leading to the development of skin cancer. Mutat Res 571 91 106

83. LozanoG

ZambettiGP

2005 What have animal models taught us about the p53 pathway? J Pathol 205 206 220

84. HemannMT

ZilfouJT

ZhaoZ

BurgessDJ

HannonGJ

2004 Suppression of tumorigenesis by the p53 target PUMA. Proc Natl Acad Sci U S A 101 9333 9338

85. ArmstrongBK

KrickerA

2001 The epidemiology of UV induced skin cancer. J Photochem Photobiol B 63 8 18

86. 2009 Detailed Guide: Esophagus Cancer. American Cancer Society

87. KashiwagiS

YashiroM

TakashimaT

NomuraS

NodaS

2010 Significance of E-cadherin expression in triple-negative breast cancer. Br J Cancer 103 249 255

88. MellLK

MeyerJJ

TretiakovaM

KhramtsovA

GongC

2004 Prognostic significance of E-cadherin protein expression in pathological stage I-III endometrial cancer. Clin Can Res 10 5546 5553

89. LuthraR

WuTT

LuthraMG

IzzoJ

Lopez-AlvarezE

2006 Gene expression profiling of localized esophageal carcinomas: association with pathologic response to preoperative chemoradiation. J Clin Oncol 24 259 267

90. HarradineKA

RiddK

SaunierEF

ClermontFF

Perez-LosadaJ

2009 Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients. Clin Cancer Res 15 5101 5107