DeltaNp63 isoform-mediated beta-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma.

www.impactjournals.com/oncotarget/   Oncotarget,  Advance  Publications  2014

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patients  with  squamous  cell  carcinoma

0HJJ\6XDUH]&DUPRQD1,2,*_{,  Pascale  Hubert}1,*_{$UQDXG*RQ]DOH]}_{$QDHOOH'XUD\}4_,   Patrick   Roncarati1_{ &KDUORWWH (USLFXP}2_{,   Jacques   Boniver}1_{ 9LQFHQW &DVWURQRYR}_,   $JQqV 1RHO2_{ 6YHQ 6DXVVH]}4_{,   Olivier   Peulen}_{,   Philippe   Delvenne}1,**   _{and   Michael}   +HUIV1,**  

1 _{Laboratory  of  Experimental  Pathology,  GIGA-­Cancer,  University  of  Liege,  Liege,  Belgium}

2 _{Laboratory  of  Tumor  and  Developmental  Biology,  GIGA-­Cancer,  University  of  Liege,  Liege,  Belgium} 3 _{Metastasis  Research  Laboratory,  GIGA-­Cancer,  University  of  Liege,  Liege,  Belgium}

4 _{Laboratory  of  Anatomy,  Faculty  of  Medicine  and  Pharmacy,  University  of  Mons,  Mons,  Belgium} * _{These  authors  contributed  equally  to  this  work}

** _{These  authors  share  last  authorship}

Correspondence to: Michael Herfs, email: M.Herfs@ulg.ac.be

Keywords: p63, defensins, (lymph)angiogenesis, prognosis, squamous cell carcinoma

Received: January 17, 2014 Accepted: March 19, 2014 Published: March 21, 2014

This  is  an  open-­access  article  distributed  under  the  terms  of  the  Creative  Commons  Attribution  License,  which  permits  unrestricted  use,   distribution,  and  reproduction  in  any  medium,  provided  the  original  author  and  source  are  credited.  

ABSTRACT:

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INTRODUCTION

Member   of   the   p53   family,   TP63   gene   gives   rise   to   transcripts   that   encode   either   full-­length   isoforms   containing  an  amino-­transactivation  (TA)  domain  (TAp63)   RUWUXQFDWHGLVRIRUPVWKDWODFNVWKLV7$GRPDLQǻ1S %RWK7$DQGǻ1WUDQVFULSWVXQGHUJR&WHUPLQDODOWHUQDWLYH VSOLFLQJWR\LHOGVL[IXUWKHUFDUER[\OWHUPLQDOLVRW\SHVĮ ȕȖ>@,QWKHODVWGHFDGHWKHLPSOLFDWLRQRISSURWHLQV LQHSLWKHOLDOVWUDWL¿FDWLRQ>@GLIIHUHQWLDWLRQ>@DQGLQWKH maintenance   of   the   proliferative   potential   of   epithelial  

VWHPVFHOOV>@KDVEHHQZHOOHVWDEOLVKHG,QDGGLWLRQWR their   role   in   normal   development   and   homeostasis,   the   large   majority   of   squamous   malignancies   display   p63   immunoreactivity  suggesting  that,  similar  to  p53,  p63  is   DOVR DFWLQJ GXULQJ WXPRULJHQHVLV >@ +RZHYHU GXH WR both  the  complexity  of  the  gene  and  the  lack  of  reliable   antibodies  for  each  individual  isotype,  the  role  of  p63  in   FDQFHULVVWLOOFRQWURYHUVLDODQGVXEMHFWWRGHEDWH>@ Recent  data  suggested  that  p63FRXOGSOD\DGXDOIXQFWLRQ ,QGHHG VHYHUDO VWXGLHV KDYH KLJKOLJKWHG WKH RQFRJHQLF SRWHQWLDORIǻ1SĮ>@,QFRQWUDVWRWKHUGDWDVKRZ

that  the  p63  gene,  especially  TAp63  isoforms,  could  act  as   DWXPRUVXSSUHVVRU>@DOWKRXJKp63  is  rarely  mutated   in  human  cancer  in  contrast  to  classic  tumor  suppressor   JHQHV

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beta   receptor   system   is   highly   expressed   on   vascular   HQGRWKHOLDOFHOOV>@7KURXJK&'LPPXQRODEHOLQJ on   tumor   sections,   the   average   number   of   neoformed   blood  vessels  per  mm_{ZDVHYDOXDWHGE\LPDJHDQDO\VLV} $V VKRZQ LQ )LJXUH $% ZH REVHUYHG WKDW ǻ1S RYHUH[SUHVVLQJ 6&& DUH DVVRFLDWHG ZLWK D VLJQL¿FDQWO\ higher   tumor   vascularisation   compared   to   cancers   GLVSOD\LQJDZHDNO\SRVLWLYHǻ1SLPPXQRUHDFWLYLW\

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7KH LQÀXHQFH RI ǻ1SUHJXODWHG +ȕ'V RQ chemotactic   migration   of   lymphatic   endothelial   cells   ZDV WKHQ DVVHVVHG XVLQJ D %R\GHQ FKDPEHU DVVD\ $V VKRZQLQ)LJXUH&DVLJQL¿FDQWLQFUHDVHGPLJUDWLRQRI LPPRUWDOL]HGK7(57/(&O\PSKDWLFHQGRWKHOLDOFHOOV ZDVREVHUYHGLQWKHSUHVHQFHRIERWK9(*)&SRVLWLYH FRQWURODQG+ȕ'FRPSDUHGWRQHJDWLYHFRQWURO 0RUHRYHUWKHFKHPRWDFWLFDFWLYLW\RI+ȕ'VRQO\PSKDWLF HQGRWKHOLDOFHOOVZDVVLPLODUZKHQZHXVHG—JPORU KLJKHUFRQFHQWUDWLRQV)LJXUH&6LPLODUUHVXOWVZHUH REWDLQHG ZLWK QRUPDO FHOOV +09(& 6XSSOHPHQWDO )LJXUH+ȕ'GHSHQGHQWHQKDQFHGPLJUDWLRQZDVWRWDOO\ DEURJDWHG E\ DGGLWLRQ RI D &&5EORFNLQJ DQWLERG\ )LJXUH ' 5HJDUGLQJ FHOO JURZWK DQG YLDELOLW\ QR GLIIHUHQFH ZDV REVHUYHG ZKHQ O\PSKDWLF HQGRWKHOLDO FHOOV ZHUH WUHDWHG ZLWK +ȕ'V   RU  )LJXUH () 7KHO\PSKDQJLRJHQLFDFWLYLW\RI+ȕ'Vin  vivoZDVWKHQ LQYHVWLJDWHG XVLQJ WKH &$0 DVVD\ 1XPHURXV YDVFXODU 7DEOH  9DULDEOH DQDO\VLV IRUǻ1S H[SUHVVLRQ LQ

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structures,  lined  by  alpha  SMA-­negative  endothelial  cells,   ZHUHGHWHFWDEOHRQ&$0VHFWLRQV,PPXQRKLVWRFKHPLFDO VWDLQLQJ IRU WKH O\PSKDWLF ELRPDUNHU 3UR[ FRQ¿UPHG WKHO\PSKDWLFQDWXUHRIWKHVHYHVVHOV)LJXUH*,PDJH DQDO\VLV ZDV XVHG WR TXDQWLI\ &$0 O\PSKDQJLRJHQLF response   from   optical   microscopy   observation   (Prox-­ VWDLQLQJ:HGHPRQVWUDWHGWKDWERWKVHUXPSRVLWLYH FRQWURODQG+ȕ'VLQGXFHDVLJQL¿FDQWLQFUHDVHLQUHODWLYH O\PSKDWLFYDVFXODUDUHDFRPSDUHGWR3%6)LJXUH+ 7KLVLQFUHDVHGO\PSKDWLFYHVVHODUHDZDVUHOLHGRQDKLJKHU YHVVHOQXPEHU)LJXUH,6LPLODUWRDQJLRJHQHVLV+ȕ' RYHUH[SUHVVLQJWXPRUVSHFLPHQVZHUHDVVRFLDWHGZLWKD higher   tumor   lymphangiogenesis   compared   to   cancers   GLVSOD\LQJ D ZHDNO\ SRVLWLYH +ȕ' LPPXQRUHDFWLYLW\ 6XSSOHPHQWDO)LJXUH&ROOHFWLYHO\RXUUHVXOWVVXSSRUW WKHLPSOLFDWLRQRI+ȕ'VLQO\PSKDQJLRJHQHVLV

DISCUSSION

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SDWLHQWVXUYLYDO>@+RZHYHUWKHPROHFXODUDQGFHOOXODU basis   of   blood   and   lymphatic   abnormalities   associated   ZLWKFDQFHUVUHPDLQVXQFOHDUDQGWKHVXEMHFWRIQXPHURXV LQYHVWLJDWLRQV

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