Cancer Research

Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
0RGLILFDWLRQRIHelicobacter pyloriSHSWLGRJO\FDQHQKDQFHV12'DFWLYDWLRQ
DQGSURPRWHVFDQFHURIWKHVWRPDFK
5XQQLQJWLWOHH. pylori12'JDVWULFFDQFHU
*LRYDQQL6XDUH]-XGLWK5RPHUR*DOOR0%ODQFD3LD]XHOR*H:DQJ5REHUW-
0DLHU/HQQDUW6)RUVEHUJ3DUDVWRR$]DGL0DUWLQ$*RPH]3HOD\R&RUUHD
DQG5LFKDUG03HHN-U
'HSDUWPHQWVRI&DQFHU%LRORJ\DQG0HGLFLQH9DQGHUELOW8QLYHUVLW\1DVKYLOOH71
'HSDUWPHQW RI 0LFURELRORJ\ DQG &RPSOH[ &DUERK\GUDWH 5HVHDUFK &HQWHU
8QLYHUVLW\RI*HRUJLD$WKHQV*$
1DWLRQDO 8QLYHUVLW\ RI &RORPELD 'HSDUWPHQW RI 0HGLFLQH DQG +RVSLWDO (O 7XQDO
8QLWRI*DVWURHQWHURORJ\%RJRWD&RORPELD
&RUUHVSRQGHQFH5LFKDUG3HHN*DUODQG$YHQXH1DVKYLOOH71
3KRQH)D[(PDLOULFKDUGSHHN#YDQGHUELOWHGX
)LQDQFLDO 6XSSRUW 1,+ 5'. 5&$ 3&$ 3
'. 3&$ 8QLYHUVLW\ RI *HRUJLD 5HVHDUFK )RXQGDWLRQ &RPSOH[
&DUERK\GUDWH5HVHDUFK&HQWHU&KHPLFDO6FLHQFHV*HRVFLHQFHVDQG%LRVFLHQFHV
'LYLVLRQ2IILFHRI%DVLF(QHUJ\6FLHQFHV86'2(JUDQW'()*(5
&RQIOLFWVRI,QWHUHVW1RQH
ͳ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
$EVWUDFW
Helicobacter pyloriLVWKHVWURQJHVWNQRZQULVNIDFWRUIRUJDVWULFFDUFLQRJHQHVLV2QH
FDQFHUOLQNHGORFXVLVWKHcagSDWKRJHQLFLW\LVODQGZKLFKWUDQVORFDWHVFRPSRQHQWV
RI SHSWLGRJO\FDQ 3*1 LQWR KRVW FHOOV 12' LV DQ LQWUDFHOOXODU LPPXQH UHFHSWRU
WKDWVHQVHV3*1IURP*UDPQHJDWLYHEDFWHULDDQGUHVSRQGVE\LQGXFLQJDXWRSKDJ\
DQG DFWLYDWLQJ 1)κ% OHDGLQJ WR LQIODPPDWLRQPHGLDWHG EDFWHULDO FOHDUDQFH
KRZHYHU FKURQLF SDWKRJHQV FDQ HYDGH 12'PHGLDWHG FOHDUDQFH E\ DOWHULQJ 3*1
VWUXFWXUH :H SUHYLRXVO\ GHPRQVWUDWHG WKDW WKH H. pylori cag VWUDLQ UDSLGO\
LQGXFHVJDVWULFFDQFHULQ0RQJROLDQJHUELOV8VLQJ'',*(DQGPDVVVSHFWURPHWU\
ZH LGHQWLILHG D QRYHO PXWDWLRQ ZLWKLQ WKH JHQH HQFRGLQJ WKH SHSWLGRJO\FDQ
GHDFHW\ODVH 3JG$ WKHUHIRUH ZH VRXJKW WR GHILQH WKH UROH RI H. pylori 3JG$ LQ
12'GHSHQGHQW DFWLYDWLRQ RI 1)κ% LQIODPPDWLRQ DQG FDQFHU &RFXOWXUH RI H.
pylori VWUDLQ RU LWV pgdA- LVRJHQLF PXWDQW ZLWK $*6 JDVWULF HSLWKHOLDO FHOOV RU
+(.HSLWKHOLDOFHOOVH[SUHVVLQJD1)κ%UHSRUWHUUHYHDOHGWKDWpgdALQDFWLYDWLRQ
VLJQLILFDQWO\GHFUHDVHG12'GHSHQGHQW1)κ%DFWLYDWLRQDQGDXWRSKDJ\,QIHFWLRQ
RI 0RQJROLDQ JHUELOV ZLWK DQ H. pylori pgdA PXWDQW VWUDLQ OHG WR VLJQLILFDQWO\
GHFUHDVHG OHYHOV RI LQIODPPDWLRQ DQG PDOLJQDQW OHVLRQV LQ WKH VWRPDFK KRZHYHU
SUHDFWLYDWLRQ RI 12' SULRU WR EDFWHULDO FKDOOHQJH UHFLSURFDOO\ VXSSUHVVHG
LQIODPPDWLRQ DQG FDQFHU LQ UHVSRQVH WR ZLOGW\SH H. pylori ([SUHVVLRQ RI 12'
GLIIHUV LQ KXPDQ JDVWULF FDQFHU VSHFLPHQV FRPSDUHG WR QRQFDQFHU VDPSOHV
KDUYHVWHG IURP WKH VDPH SDWLHQWV 7KHVH UHVXOWV LQGLFDWH WKDW 3*1 GHDFHW\ODWLRQ
SOD\V DQ LPSRUWDQW UROH LQ PRGXODWLQJ KRVW LQIODPPDWRU\ UHVSRQVHV WR H. pylori,
DOORZLQJWKHEDFWHULDWRSHUVLVWDQGLQGXFHFDUFLQRJHQLFFRQVHTXHQFHVLQWKHJDVWULF
QLFKH
ʹ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
,QWURGXFWLRQ
Helicobacter pyloriLVWKHPRVWFRPPRQEDFWHULDOLQIHFWLRQZRUOGZLGHDQGELRORJLFDO
FRVWV LQFXUUHG E\ FKURQLF JDVWULWLV LQFOXGH DQ LQFUHDVHG ULVN IRU JDVWULF
DGHQRFDUFLQRPD +RZHYHU RQO\ D SHUFHQWDJH RI FRORQL]HG SHUVRQV GHYHORS
QHRSODVLD 2QH VWUDLQVSHFLILF YLUXOHQFH ORFXV WKDW DXJPHQWV FDQFHU ULVN LV WKH cag
SDWKRJHQLFLW\ LVODQG ZKLFK HQFRGHV D W\SH ,9 VHFUHWLRQ V\VWHP 766 WKDW
WUDQVORFDWHV&DJ$LQWRHSLWKHOLDOFHOOV+RZHYHUPRVWSHUVRQVFRORQL]HGZLWK
cagAVWUDLQVGRQRWGHYHORSFDQFHUVXJJHVWLQJWKDWRWKHUH. pyloriFRQVWLWXHQWV
DIIHFWGLVHDVHULVN
,QDGGLWLRQWR&DJ$WKHcag766GHOLYHUVSHSWLGRJO\FDQLQWRKRVWFHOOVZKHUHLWLV
UHFRJQL]HGE\12'DQLQWUDF\WRSODVPLFVHQVRURISHSWLGRJO\FDQFRPSRQHQWV
H. pylori FDQ DOVR GHOLYHU SHSWLGRJO\FDQ LQWR KRVW FHOOV YLD RXWHU PHPEUDQH
YHVLFOHV 0RVW JDVWURLQWHVWLQDO HSLWKHOLDO FHOOV H[SUHVV 12' DQG DFWLYDWLRQ RI
12'E\WKHPXURSHSWLGHγ'JOXWDP\OmesoGLDPLQRSLPHOLFDFLGL('$3OHDGVWR
F\WRNLQH SURGXFWLRQ DV ZHOO DV LQGXFWLRQ RI DXWRSKDJ\ 12' DFWLYDWLRQ LV
WLJKWO\UHJXODWHGE\DQHJDWLYHDXWRFULQHIHHGEDFNV\VWHPLQZKLFK12'UHJXODWHG
HIIHFWRUVFRQFRPLWDQWO\VXSSUHVVWKHGRZQVWUHDPHIIHFWVRI12'DFWLYDWLRQ
&KURQLFSDWKRJHQVFDQHYDGH12'PHGLDWHGFOHDUDQFHE\DOWHULQJ3*1VWUXFWXUH
12' VHQVLQJ RI H. pylori SHSWLGRJO\FDQ LQGXFHV 1)κ% DFWLYDWLRQ DQG H[SUHVVLRQ
RIW\SH,,)1YLD,)15HJXODWRU\)DFWRU0,3DQGβGHIHQVLQDQG
͵
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
H. pyloriFRORQL]HVNod1-/-GHILFLHQWPLFHPRUHGHQVHO\FRPSDUHGWRZLOGW\SHPLFH
,QKXPDQVJHQHWLFYDULDWLRQLQATG16L1ZKLFKHQFRGHVDNH\HIIHFWRURI
12'GHSHQGHQW DXWRSKDJ\ DQG LQIODPPDWLRQ DOWHUV VXVFHSWLELOLW\ WR H. pylori
LQIHFWLRQ 7KH UROH RI DEHUUDQW 12' DFWLYDWLRQ E\ H. pylori LQ JDVWULF
FDUFLQRJHQHVLVKRZHYHUKDVQRW\HWEHHQLQYHVWLJDWHG
:H SUHYLRXVO\ GHPRQVWUDWHG WKDW in vivo DGDSWDWLRQ DXJPHQWV WKH DELOLW\ RI DQ H.
pylori VWUDLQ WR LQGXFH JDVWULF FDQFHU LQ 0RQJROLDQ JHUELOV 8VLQJ PDVV
VSHFWURPHWU\ZHVXEVHTXHQWO\LGHQWLILHGDQRYHOPXWDWLRQZLWKLQWKHJHQHHQFRGLQJ
WKHSHSWLGRJO\FDQGHDFHW\ODVH3JG$+3KRPRORJLQWKLVFDUFLQRJHQLFVWUDLQ
:H QRZ GHILQH WKH UROH RI 3JG$ LQ 12'GHSHQGHQW DFWLYDWLRQ RI 1)κ%
LQIODPPDWLRQDQGLQIODPPDWLRQUHODWHGFDQFHUWKDWGHYHORSVLQUHVSRQVHWRH. pylori
Ͷ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
0HWKRGV
%DFWHULDOVWUDLQV
H. pyloriZLOGW\SHVWUDLQVRULVRJHQLFcagA RUcagEPXWDQWVKDYHEHHQGHVFULEHG
'LVUXSWLRQ RI H. pylori pgdA ZDV DFFRPSOLVKHG YLD LQVHUWLRQ RI D NDQDP\FLQ
FDVVHWWHLQWRpgdADVGHVFULEHG $QH. pyloripgdAFRPSOHPHQWHG VWUDLQ
ZDV JHQHUDWHG E\ LQVHUWLRQ RI WKH pgdA JHQH LQWR WKH hp0203/0204 LQWHUJHQLF
FKURPRVRPDO UHJLRQ )ODQNLQJ VHTXHQFHV WDUJHWLQJ hp0203 DQG hp0204 ZHUH
FORQHGLQWRWKHYHFWRUS%6&$FKORUDPSKHQLFROUHVLVWDQFHFDVVHWWHDQGWKHH.
pylori pgdA JHQH ZHUH WKHQ FORQHG LQWR hp0203/hp0204 WKDW ZDV SUHYLRXVO\
LQVHUWHGLQS%6&H. pylori pgdA-ZDVQDWXUDOO\WUDQVIRUPHGZLWKS%6&pgdA
DQGFRORQLHVVHOHFWHGIRUFKORUDPSKHQLFRODQGNDQDP\FLQUHVLVWDQFHZHUHWHVWHGE\
3&5DQG:HVWHUQEORWWRFRQILUPUHH[SUHVVLRQRIpgdA 6XSSOHPHQWDU\)LJXUH
&HOOOLQHVDQGFXOWXUH
$*6FHOOV&5/DQG+(.FHOOV&5/ZHUHSXUFKDVHGIURP$7&&
DQGWHVWHGIRUP\FRSODVPDFRQWDPLQDWLRQ$*6FHOOVVWDEO\H[SUHVVLQJDOXFLIHUDVH
EDVHG 1)κ% UHSRUWHU ZHUH JHQHUDWHG E\ WUDQVIHFWLRQ RI WKH SODVPLG
S*/>luc2P1)κ%5(+\JUR@ 3URPHJD DQWLELRWLF VHOHFWLRQ DQG FORQLQJ $*6
FHOOVVWDEO\WUDQVIHFWHGZLWKWKH1)κ%UHSRUWHUZHUHDOVRWUDQVIHFWHGZLWKDPL[RI
VK51$V WDUJHWLQJ NOD1 &RORQLHV ZHUH VHOHFWHG XVLQJ SXURP\FLQ ȝJP/ DQG
WHVWHGIRUNOD1H[SUHVVLRQE\UHDOWLPH573&5DQG:HVWHUQEORW
ͷ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
0DVVVSHFWURPHWU\
$QDO\VLV RI H. pylori SHSWLGRJO\FDQ E\ PDVV VSHFWURPHWU\ ZDV SHUIRUPHG DV
UHSRUWHGH. pyloriZHUHKDUYHVWHGZDVKHGZLWKLFHFROGP0VRGLXPDFHWDWH
S+FHQWULIXJHGUHVXVSHQGHGDQGWKHQDGGHGWRERLOLQJ6'6EXIIHUHGZLWK
P0VRGLXPDFHWDWHS+IRUPLQXWHV6DPSOHVZHUHWKHQFRROHGDQG6'6
LQVROXEOHPDWHULDOZDVFROOHFWHGE\FHQWULIXJDWLRQ7KHSHOOHWZDVUHVXVSHQGHGLQ
PORIP07ULV+&OS+DQGP01D&O7HQȝJPO'1DVHDQGȝJPORI
51DVH 6LJPD ZHUH DGGHG DQG LQFXEDWHG IRU KRXUV )LIW\ ȝJPO SURWHLQDVH .
,QYLWURJHQZDVDGGHGWRWKHUHDFWLRQDQGLQFXEDWHGRYHUQLJKW7KH6'6LQVROXEOH
PDWHULDOZDVUHH[WUDFWHGE\ERLOLQJLQ6'6DQGFROOHFWHGE\FHQWULIXJDWLRQ7KH
SHSWLGRJO\FDQSHOOHWZDVUHVXVSHQGHGLQGLVWLOOHGZDWHUO\RSKLOL]HGDQGVXVSHQGHG
LQ ȝO RI P0 VRGLXP SKRVSKDWH EXIIHU S+ )ROORZLQJ VRQLFDWLRQ
VXVSHQVLRQV ZHUH GLJHVWHG ZLWK ȝJȝO RI PXUDPLGDVH IRU KRXUV DW ƒ&
(Q]\PH LQFXEDWLRQV ZHUH SODFHG LQ D ƒ& EDWK IRU PLQXWHV FRROHG DQG WKHQ
FHQWULIXJHG WR UHPRYH LQVROXEOH PDWHULDO 6XSHUQDWDQWV ZHUH WKHQ ILOWHUHG DQG
FRQFHQWUDWHGIRUPDVVVSHFWURPHWU\DQDO\VLV
3RUWLRQVRIWKHUHDFWLRQPL[WXUHVUHVXOWLQJIURPO\VR]\PHGLJHVWLRQZHUHGHVDOWHGE\
GLDO\VLVPROHFXODUZHLJKWFXWRIIIRUGD\V7KHUHWDLQHGVROXWLRQVFRQWDLQLQJ
PXUDP\O SHSWLGHV ZHUH FRQFHQWUDWHG DQG DQDO\]HG E\ 0$/',72) PDVV
VSHFWURPHWU\ DV GHVFULEHG &KHPLFDO NDFHW\ODWLRQ RI SHSWLGRJO\FDQ ZDV
SHUIRUPHGDVGHVFULEHG
͸
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
&HOOYLDELOLW\
&HOO YLDELOLW\ ZDV PHDVXUHG XVLQJ WKH YLEUDQW 077 FHOO DVVD\ NLW IROORZLQJ WKH
PDQXIDFWXUHU¶V LQVWUXFWLRQV 0ROHFXODU SUREHV &RQWURO DQG 12'RYHUH[SUHVVLQJ
S812K12',QYLYRJHQ+(.FHOOVZHUHSODWHGLQDZHOOSODWHDW[
FHOOVZHOO 7KH IROORZLQJ GD\ PHGLD ZDV UHSODFHG ZLWK ȝ/ RI '0(0
VXSSOHPHQWHGZLWK)%6DQGP0RI077DQGLQFXEDWHGIRUKRXUVDWƒ&
$GKHVLRQDVVD\V
&RFXOWXUHVRI$*6FHOOVDQGH. pylori02,ZHUHKDUYHVWHGDIWHUPLQXWHVRI
LQFXEDWLRQ$*6FHOOVZHUHZDVKHGWRUHPRYHXQERXQGEDFWHULDO\VHGZLWKGLVWLOOHG
ZDWHU VHULDO GLOXWLRQV ZHUH SODWHG RQ 76$EORRG DJDU SODWHV DQG FRORQ\IRUPLQJ
XQLWV&)8ZHUHGHWHUPLQHGDVGHVFULEHG
/XFLIHUDVHDVVD\
$*6FHOOVVWDEO\WUDQVIHFWHGZLWKWKH1)κ%UHSRUWHUZHUHFRFXOWXUHGZLWKH. pylori
DQG O\VHG XVLQJ ȝ/ RI OXFLIHUDVH UHSRUWHU O\VLV EXIIHU 3URPHJD 7ZHQW\
PLFUROLWHUV RI FHOO O\VDWH ZDV WKHQ PL[HG ZLWK ȝ/ RI OXFLIHUDVH DVVD\ VXEVWUDWH
3URPHJDDQGOXFLIHUDVHDFWLYLW\ZDVPHDVXUHG
*HQWDP\FLQSURWHFWLRQDVVD\V
͹
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
&RFXOWXUHV RI $*6 FHOOV DQG H. pylori 02, ZHUH LQFXEDWHG IRU KRXUV
VXSHUQDWDQWVZHUHUHPRYHGDQGFHOOVZHUHLQFXEDWHGIRUDQDGGLWLRQDOKRXUVZLWK
JHQWDP\FLQȝJP/&HOOVZHUHO\VHGZLWKVWHULOHZDWHUDQGVHULDOGLOXWLRQVZHUH
SODWHG
5HDOWLPH573&5
0RQJROLDQ JHUELO SULPHUV DQG SUREHV ZHUH GHVLJQHG EDVHG RQ JHUELO P51$
VHTXHQFHV GHSRVLWHG LQ WKH 1&%, GDWDEDVH 51$ ZDV LVRODWHG XVLQJ 4LDJHQ
51HDV\ NLW DQG J'1$ ZDV UHPRYHG E\ GLJHVWLRQ ZLWK 51$VH IUHH'1$VH ,
3URPHJD F'1$ ZDV V\QWKHVL]HG XVLQJ WKH KLJK FDSDFLW\ F'1$ UHYHUVH
WUDQVFULSWLRQ NLW $SSOLHG %LRV\VWHPV 4XDQWLWDWLYH 3&5 ZDV SHUIRUPHG XVLQJ D
7DTPDQ 8QLYHUVDO 3&5 PDVWHU PL[ RU 6<%5 JUHHQ 8QLYHUVDO 3&5 PDVWHU PL[
$SSOLHG %LRV\VWHPV LQ D 5HDO 7LPH 3&5 V\VWHP $SSOLHG %LRV\VWHPV $OO
VDPSOHVZHUHQRUPDOL]HGWRH[SUHVVLRQRI*$3'+
:HVWHUQEORW
$*6 FHOOV FRFXOWXUHG ZLWK H. pylori ZHUH O\VHG FHQWULIXJHG DQG SURWHLQV ZHUH
VHSDUDWHG XVLQJ 6'6 3$*( PLQL JHOV WUDQVIHUUHG WR 39') PHPEUDQHV DQG
PHPEUDQHV ZHUH EORFNHG ZLWK %6$ )RU GHWHFWLRQ RI /&% PHPEUDQHV ZHUH
LQFXEDWHG IRU KRXU ZLWK UDEELW DQWL/&% GLOXWLRQ 1RYXV %LRORJLFDOV $Q
DQWLUDEELW +53FRQMXJDWHG 6DQWD &UX] %LRWHFKQRORJ\ VHFRQGDU\ DQWLERG\ ZDV
WKHQLQFXEDWHGZLWKPHPEUDQHVDWDGLOXWLRQIRUKRXU
ͺ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
7UDQVPLVVLRQ(OHFWURQ0LFURVFRS\
&RFXOWXUHV RI $*6 FHOOV DQG H. pylori ZHUH IL[HG LQ JOXWHUDOGHK\GH LQ 0
FDFRG\ODWHEXIIHUWUDQVIHUUHGWRƒ&DQGOHIWRYHUQLJKW6DPSOHVZHUHWKHQZDVKHG
LQ 0 FDFRG\ODWH EXIIHU LQFXEDWHG IRU KRXU LQ RVPLXP WHWUDR[LGH DQG
ZDVKHG ZLWK 0 FDFRG\ODWH EXIIHU 6DPSOHV ZHUH GHK\GUDWHG XVLQJ D JUDGHG
HWKDQRO VHULHV DQG LQFXEDWHG IRU PLQXWHV LQ HWKDQRO DQG SURS\OHQH R[LGH
32 IROORZHG E\ H[FKDQJHV RI SXUH 32 6DPSOHV ZHUH LQIXVHG ZLWK (SRQ
UHVLQDQG32LQILOWUDWHGZLWK(SRQUHVLQDQG32H[FKDQJHG
ZLWKQHZ(SRQUHVLQDQG32DQGLQFXEDWHGRYHUQLJKW6DPSOHVZHUH
WKHQVXEMHFWHGWRDUHVLQ32H[FKDQJHDQGH[FKDQJHGLQWRSXUHHSR[\
UHVLQ RYHUQLJKW 7KH UHVLQ ZDV H[FKDQJHG XVLQJ IUHVKO\ PDGH SXUH HSR[\ UHVLQ
LQFXEDWHGIRUKRXUVDQGHPEHGGHGLQHSR[\UHVLQDQGSRO\PHUL]HGDW°&IRU
KRXUV
)LYHKXQGUHG QP WR PLFURQ WKLFN VHFWLRQV ZHUH JHQHUDWHG XVLQJ D /HLFD 8OWUDFXW
PLFURWRPH7KLFNVHFWLRQVZHUHFRQWUDVWVWDLQHGZLWKWROXLGLQHEOXHDQGLPDJHG
ZLWK D 1LNRQ $= PLFURVFRSH 8OWUDWKLQ VHFWLRQV QP ZHUH WKHQ FXW DQG
SODFHG RQWR PHVK FRSSHU JULGV SRVWVHFWLRQ VWDLQHG ZLWK XUDQ\O DFHWDWH
DTXHRXV IRU PLQXWHV DQG WKHQ ZLWK OHDG FLWUDWH IRU PLQXWHV 6DPSOHV ZHUH
LPDJHGRQD3KLOLSV)(,7HFQDL7HOHFWURQPLFURVFRSH
&RQIRFDOPLFURVFRS\
ͻ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
$*6FHOOV ZHUHSODWHG[ FHOOVZHOOLQZHOOVOLGHV1XQFIRUKRXUVDQG
FRFXOWXUHG ZLWK H. pylori IRU KRXUV /LYH VWDLQLQJ ZLWK ,PDJH,7 O\VRVRPDO DQG
QXFOHDU ODEHOLQJ NLW /LIH WHFKQRORJLHV ZDV SHUIRUPHG SHU WKH PDQXIDFWXUHU¶V
LQVWUXFWLRQV$*6FHOOVH[SUHVVLQJWKHIXVLRQSURWHLQ*)3/&ZHUHFRFXOWXUHGZLWK
H. pyloriIL[HGZLWKF\WRIL[F\WRSHUP%HFWRQ'LFNLQVRQDQGPRXQWHG,PDJHVZHUH
DFTXLUHGXVLQJD/600(7$LQYHUWHGFRQIRFDOPLFURVFRSH=HLVV
5RGHQWLQIHFWLRQV
$OO SURFHGXUHV ZHUH DSSURYHG E\ WKH $QLPDO &DUH &RPPLWWHH RI 9DQGHUELOW
8QLYHUVLW\ *HUELOVZHUHWUHDWHGZLWKRUZLWKRXW&L('$3,QYLYRJHQDWGRVHVRI
RUȝJDQLPDOLQP/RI3%6IRUGD\VYLDJDYDJHGD\WR$QLPDOV
ZHUH FKDOOHQJHG ZLWK [ H. pylori ZLOGW\SH RU pgdA- PXWDQW VWUDLQV DW WLPHSRLQWVGD\VDQGDVSUHYLRXVO\GHVFULEHG6HUXPVDPSOHVDQGJDVWULF
WLVVXH ZHUH KDUYHVWHG DQG D VLQJOH SDWKRORJLVW VFRUHG LQGLFHV RI LQIODPPDWLRQ DQG
FDQFHU DV GHVFULEHG )RU TXDQWLWDWLYH FXOWXUH VHULDO GLOXWLRQV RI KRPRJHQL]HG
WLVVXHZHUHSODWHGRQVHOHFWLYHDQWLELRWLF76$EORRGDJDUSODWHVDVGHVFULEHG
(/,6$
H. pylori ZLOGW\SH VWUDLQ [ FHOOV ZDV O\VHG LQ ȝ/ RI ,3 /\VLVZDVK
EXIIHU 7KHUPR (/,6$ SODWHV ZHUH FRDWHG ZLWK ȝ/ RI O\VDWH GLOXWHG LQ
FRDWLQJEXIIHU06RGLXPFDUERQDWHS+DWƒ&RYHUQLJKW:HOOVZHUHWKHQ
EORFNHG ZLWK ȝ/ RI %6$ IRU KRXU DQG ȝ/ RI VHUXP GLOXWHG LQ 3%6%6$
ZDVLQFXEDWHGIRUKRXUVIROORZHGE\DKRXULQFXEDWLRQZLWK3URWHLQ*
ͳͲ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
FRQMXJDWHG ZLWK +53 ȝJP/ 7HWUDPHWK\OEHQ]LGLQH 70% ZDV XVHG DV D
VXEVWUDWHDQGWKHFRORULPHWULFGHQVLW\DWZDYHOHQJWKQPZDVPHDVXUHG
,PPXQRKLVWRFKHPLVWU\DQGUHDOWLPH573&5RQWLVVXH
7KH ,QVWLWXWLRQDO 5HYLHZ %RDUG RI WKH ³+RVSLWDO (O 7XQDO´ LQ %RJRWD &RORPELD
DSSURYHG WKLV SURWRFRO %LRSV\ VDPSOHV IURP SDWLHQWV ZLWK PRGHUDWHO\
GLIIHUHQWLDWHG LQWHVWLQDOW\SH JDVWULF DGHQRFDUFLQRPD REWDLQHG YLD HQGRVFRS\ IURP
IRFL RI FDQFHU RU XQDIIHFWHG UHJLRQV ZHUH XVHG IRU LPPXQRKLVWRFKHPLVWU\ Q PDOH PHDQDJH \HDUV IHPDOH PHDQDJH \HDUV RU UHDOWLPH 573&5
Q PDOHPHDQDJH\HDUVIHPDOHPHDQDJH\HDUV6DPSOHVZHUH
VWDLQHG ZLWK D PRQRFORQDO DQWL12' DQWLERG\ 5' %LRVFLHQFHV RU DQ
LVRW\SH FRQWURO DQWLERG\ $ VLQJOH SDWKRORJLVW 0%3 VFRUHG 12' VWDLQLQJ E\
DVVHVVLQJ WKH SHUFHQWDJH RI 12' HSLWKHOLDO FHOOV DQG JUDGLQJ WKH LQWHQVLW\ RI
12'VWDLQLQJLQHSLWKHOLDOFHOOVVHPLTXDQWLWDWLYHO\)RU573&5JDVWULFWLVVXHZDV
KRPRJHQL]HG DQG 51$ H[WUDFWHG 4LDJHQ DFFRUGLQJ WR WKH PDQXIDFWXUHU¶V
LQVWUXFWLRQV 5HYHUVHWUDQVFULSWDVH 3&5 DQG TXDQWLWDWLYH 3&5 ZHUH SHUIRUPHG
DFFRUGLQJ WR WKH PDQXIDFWXUHU¶V LQVWUXFWLRQV WR GHWHUPLQH UHODWLYH GLIIHUHQFHV LQ
H[SUHVVLRQ OHYHOV RI NOD1 +VBP), CDX2 +VBP, SOX2
+VBV DQG TRAF3 +VBP QRUPDOL]HG WR OHYHOV RI GAPDH
( $SSOLHG%LRV\VWHPV
6WDWLVWLFDODQDO\VLV
ͳͳ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
7KH0DQQ:KLWQH\WHVWZDVXVHGWRFRPSDUHWZRJURXSVDQGRQHZD\$QRYDZLWK
D 1HZPDQ.HXOV SRVWWHVW ZDV XVHG WR FRPSDUH WKUHH RU PRUH JURXSV 'DWD ZHUH
SORWWHGDQGDQDO\]HGXVLQJ3ULVP9E*UDSK3DGVRIWZDUH,QF
ͳʹ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
5HVXOWV
Inactivation of H. pylori pgdA affects peptidoglycan acetylation and attenuates
NOD1-dependent NF-κB activation induced by H. pylori in vitro
2XU SUHYLRXV SXEOLFDWLRQ UHSRUWHG WKDW OHYHOV RI 3JG$ LQLWLDOO\ DSSHDUHG WR EH
GLIIHUHQWLQWKHGHULYDWLYHH. pyloriVWUDLQFRPSDUHGWRLWVSURJHQLWRUVWUDLQ%
+RZHYHUGHWDLOHGLQVSHFWLRQRIWKH'',*(JHOVUHYHDOHGWKDWDSSDUHQWGLIIHUHQFHV
LQSURWHLQOHYHOVUHVXOWHGIURPWKHSUHVHQFHRIGLIIHUHQWFKDUJHGLVRIRUPVUDWKHUWKDQ
DQ DEXQGDQFH FKDQJH LQ 3JG$ EHWZHHQ WKH WZR VWUDLQV 7KLV GLIIHUHQFH ZDV
FRQILUPHG E\ JHQRPLF VHTXHQFLQJ RI pgdA LQ VWUDLQV % DQG ZKLFK
GHPRQVWUDWHG D VLQJOH SRLQW PXWDWLRQ WKDW FRQYHUWHG D F\VWHLQH DW DPLQR DFLG
SRVLWLRQLQVWUDLQ%WRDQDUJLQLQHLQVWUDLQ:HWKHUHIRUHTXDQWLILHG
OHYHOV RI H[SUHVVLRQ RI 3JG$ LQ ZLOGW\SH VWUDLQV % DQG DQ LVRJHQLF pgdAPXWDQWDQGDpgdAFRPSOHPHQWHGVWUDLQ7KHUHZHUHQRGLIIHUHQFHVLQ
H[SUHVVLRQ RI 3JG$ EHWZHHQ WKHH. pylori ZLOGW\SH VWUDLQ WKH % ZLOGW\SH
VWUDLQ RU WKH pgdA FRPSOHPHQWHG PXWDQW DQG DV H[SHFWHG QR 3JG$
H[SUHVVLRQZDVSUHVHQWLQWKHpgdALVRJHQLFPXWDQW6XSSOHPHQWDO)LJXUH$
:H QH[W VRXJKW WR GHWHUPLQH ZKHWKHU 3JG$ IXQFWLRQV DV D SHSWLGRJO\FDQ
GHDFHW\ODVH LQ RXU SURWRW\SH VWUDLQ RI LQWHUHVW 7KHUHIRUH ZH DQDO\]HG WKH
PXURSHSWLGH FRPSRVLWLRQ RI SHSWLGRJO\FDQ SXULILHG IURP ZLOGW\SH H. pylori VWUDLQ
WKH LVRJHQLF pgdA PXWDQW DQG WKH pgdA FRPSOHPHQWHG VWUDLQ
'XULQJSUHSDUDWLRQRIWKHPXURSHSWLGHVDQLPSRUWDQWLQLWLDOREVHUYDWLRQZDVWKDWWKH
SHSWLGRJO\FDQVDPSOHVUHVSRQGHGYHU\GLIIHUHQWO\WRPXUDPLGDVHWUHDWPHQW:KLOH
SHSWLGRJO\FDQ IURP WKH pgdA PXWDQW ZDV FRPSOHWHO\ GLJHVWHG E\ O\VR]\PH
ͳ͵
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
SHSWLGRJO\FDQ IURP WKH :7 DQG WKH pgdA FRPSOHPHQWHG VWUDLQV ZHUH KLJKO\
UHVLVWDQW WR O\VR]\PH WUHDWPHQW ZLWK PRUH WKDQ KDOI RI WKH SHSWLGRJO\FDQ IURP WKH
ODWWHU WZR VWUDLQV UHPDLQLQJ LQVROXEOH GDWD QRW VKRZQ 7KLV UHVXOW VXJJHVWHG WKDW
WKH FRPSOHPHQWHG pgdA VWUDLQ ZDV VLPLODU WR WKH :7 VWUDLQ LQ WHUPV RI LWV 3*
VWUXFWXUH
$IWHU XVLQJ PRUH LQWHQVH FRQGLWLRQV IRU GLJHVWLRQ WKH GLJHVWHG 3* VDPSOHV
PXURSHSWLGH IUDJPHQWV ZHUH VXEMHFWHG WR 0$/',72) DQDO\VLV $ GLVWLQFW VHW RI
PXURSHSWLGHV 03 ZLWK PDVV XQLW DFHW\O JURXS GLIIHUHQFHV 03 DQG
03ZHUHLGHQWLILHGWKDWUHDGLO\GLVWLQJXLVKHGWKH:7VWUDLQIURPWKHpgdA
PXWDQW VWUDLQ )LJXUH $ 7KH SURSRVHG VWUXFWXUH IRU 03 LV *OF1$F0XU1$F
*OF1$F0XU1$FZKLFKKDUERUVDOLQNHGVLGHFKDLQRIDPLQRDFLGV$OD*OX'DS$OD
$OD:KHQRQHRIWKH*OF1$FPRLHWLHVLVGHDFHW\ODWHG*OF1+03EHFRPHV
036XSSOHPHQWDO)LJXUH%:LOGW\SHVWUDLQFRQWDLQHGUHODWLYHO\HTXDO
DPRXQWVRI03DQG03UDWLRGH$FHW\ODWHG$FHW\ODWHG KRZHYHUWKH
H[WHQW RI GHDFHW\ODWLRQ ZDV JUHDWO\ GLPLQLVKHG LQ WKHpgdA- PXWDQW VWUDLQ UDWLR GH
$FHW\ODWHG$FHW\ODWHG )LJXUH$,QWKHpgdAFRPSOHPHQWHGVWUDLQWKHUDWLR
RI
LQWHQVLWLHV
RI
WKHVH
WZR
03V
UHDSSURDFKHG
HTXDOLW\
UDWLR
GH
$FHW\ODWHG$FHW\ODWHG VXJJHVWLQJ WKDW GHDFHW\ODWLRQ DFWLYLW\ ZDV QHDUO\
UHVWRUHG 7R GHPRQVWUDWH WKLV PRUH GHILQLWLYHO\ FKHPLFDO NDFHW\ODWLRQ RI WKH
PXURSHSWLGHV ZDV SHUIRUPHG %RWK 03V DQG EHFDPH RU DFHW\O JURXSV DIWHU FKHPLFDO NDFHW\ODWLRQ GDWD QRW VKRZQ 7KHVH GDWD DUH
FRQFRUGDQW ZLWK UHVXOWV IURP WKH O\VR]\PH VHQVLWLYLW\ VWXGLHV LQGLFDWLQJ WKDW 3JG$
IXQFWLRQVDVDSHSWLGRJO\FDQGHDFHW\ODVHLQH. pyloriVWUDLQ
ͳͶ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
7R GHWHUPLQH ZKHWKHU HQGRJHQRXV 12' ZDV IXQFWLRQDOO\ UHVSRQVLYH WR
FDUFLQRJHQLFH. pylori cagVWUDLQ$*6FHOOVZHUHVWDEO\WUDQVIHFWHGZLWKD1)
κ%UHSRUWHU7UHDWPHQWRIWUDQVIHFWHGFHOOVZLWKWKH12'VHOHFWLYHDJRQLVW&L(
'$3 VLJQLILFDQWO\ LQFUHDVHG OXFLIHUDVH DFWLYLW\ )LJXUH % 7UDQVIHFWHG $*6 FHOOV
ZHUHWKHQLQIHFWHGZLWKZLOGW\SH:7VWUDLQZKLFKDOVRVLJQLILFDQWO\LQFUHDVHG
OXFLIHUDVHDFWLYLW\FRPSDUHGWRXQLQIHFWHGFHOOV)LJXUH%,VRJHQLFLQDFWLYDWLRQRI
pgdA VLJQLILFDQWO\ DWWHQXDWHG 1)κ% DFWLYDWLRQ FRPSDUHG WR WKH ZLOGW\SH VWUDLQ
KRZHYHU DFWLYDWLRQ ZDV QHDUO\ FRPSOHWHO\ UHVWRUHG ZKHQ $*6 FHOOV ZHUH LQIHFWHG
ZLWKWKHH. pylori pgdAFRPSOHPHQWHGPXWDQW)LJXUH%
:HWKHQWHVWHGDcagEPXWDQWZKLFKODFNVDIXQFWLRQDOcag766WRGHILQHWKHUROH
RI WKH 766 LQ 12'GHSHQGHQW 1)κ% DFWLYDWLRQ /RVV RI cagE VLJQLILFDQWO\
UHGXFHGWKHDELOLW\RIH. pyloriWRDFWLYDWH1)κ%)LJXUH%7KHcagLVODQGGHOLYHUV
QRW RQO\ 3*1 EXW DOVR &DJ$ LQWR KRVW FHOOV DQG &DJ$ FDQ DFWLYDWH 1)κ% )LJXUH%'HOHWLRQRIcagA LQVWUDLQSDUWLDOO\EXWQRWFRPSOHWHO\UHGXFHG1)
κ% DFWLYDWLRQ )LJXUH % 7KHVH UHVXOWV VXJJHVW WKDW D FRPSRQHQW RI 1)κ%
DFWLYDWLRQ WKDW GHYHORSV LQ UHVSRQVH WR H. pylori PD\ EH PHGLDWHG E\ D GLIIHUHQW
HIIHFWRUWUDQVORFDWHGE\WKHcagW\SH,9VHFUHWLRQV\VWHPVXFKDV3*1
7RHVWDEOLVKVSHFLILFLW\$*6FHOOVZHUHVWDEO\FRWUDQVIHFWHGZLWKD1)κ%UHSRUWHU
DQGHLWKHUDWUXQFDWHGIRUPRI12'ZKLFKODFNVWKH&$5'GRPDLQDQGH[HUWVD
GRPLQDQW QHJDWLYH HIIHFW '1 12' )LJXUH & RU VK51$ WDUJHWLQJ NOD1 RU
ͳͷ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
NOD2)LJXUH'12'DFWLYDWLRQLQUHVSRQVHWRWUHDWPHQWZLWK&L('$3RUH.
pylori, EXW QRW WKH 12'LQGHSHQGHQW 1)κ% DFWLYDWRU 30$ ZDV VLJQLILFDQWO\
DWWHQXDWHG LQ FHOOV WUDQVIHFWHG ZLWK '1 12' RU NOD1VSHFLILF EXW QRW NOD2
VSHFLILFVK51$LQGLFDWLQJWKDWDFWLYDWLRQRI12'E\H. pyloriLVVSHFLILF)LJXUH&
' NOD1VSHFLILF VK51$ VXSSUHVVHG HQGRJHQRXV NOD1 E\ DSSUR[LPDWHO\ 6XSSOHPHQWDO)LJXUH7KXV12'LVIXQFWLRQDOO\DFWLYHLQJDVWULFHSLWKHOLDOFHOOV
LQIHFWHG ZLWK D FDUFLQRJHQLF H. pylori cag+ VWUDLQ DQG WKLV LV GHSHQGHQW RQ
SHSWLGRJO\FDQGHDFHW\ODVHDQGDIXQFWLRQDOcag766
Inactivation of pgdA attenuates H. pylori-induced autophagy
+DYLQJ GHPRQVWUDWHG WKDW H. pylori FDQ DFWLYDWH 12' ZH QH[W H[DPLQHG WKH
HIIHFWVRI3JG$RQDXWRSKDJ\:HILUVWFRPSDUHGELQGLQJRIZLOGW\SHVWUDLQ
RUDpgdA-PXWDQWWR$*6FHOOVQRGLIIHUHQFHVLQDGKHUHQFHZHUHIRXQG
EHWZHHQ WKH VWUDLQV )LJXUH $ +RZHYHU WKHUH ZHUH VWULNLQJ GLIIHUHQFHV LQ
LQWUDFHOOXODU VXUYLYDO DV WKH QXPEHU RI YLDEOH pgdA- PXWDQWV UHFRYHUHG ZDV
VLJQLILFDQWO\ UHGXFHG FRPSDUHG ZLWK WKH ZLOGW\SH VWUDLQ )LJXUH % 7UDQVPLVVLRQ
HOHFWURQ PLFURVFRS\ DQG /\VRWUDFNHU VWDLQLQJ UHYHDOHG WKDW WKH QXPEHU RI
O\VRVRPHVZDVVLJQLILFDQWO\LQFUHDVHGLQFHOOVLQIHFWHGZLWKWKHLVRJHQLFpgdA-
PXWDQWFRPSDUHGWRWKHZLOGW\SHVWUDLQ)LJXUH&'
7KH IRUPDWLRQ RI O\VRVRPHV FDQ UHSUHVHQW RQH VWHS LQ WKH DXWRSKDJ\ SDWKZD\ ,Q
DGGLWLRQWRDXWRSKDJ\KRZHYHUO\VRVRPHVDOVRUHSUHVHQWDFHOOXODUFRQVWLWXHQWWKDW
FDQGHJUDGHHQGRF\WLFVXEVWUDWHV7RGHWHUPLQHWKLVPRUHGHILQLWLYHO\ZHQH[W
ͳ͸
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
GHILQHG WKH UROH RI 3JG$ RQ DXWRSKDJ\ E\ TXDQWLI\LQJ D sine qua non DXWRSKDJLF
UHVSRQVH FRQYHUVLRQ RI /&, WR /&,, &RQIRFDO PLFURVFRS\ XVLQJ $*6 FHOOV
WUDQVIHFWHGZLWKD*)3/&IXVLRQSURWHLQWRDVFHUWDLQWKHSUHVHQFHRILQWUDFHOOXODU
YHVLFOHV FRQWDLQLQJ /& GHPRQVWUDWHGWKDW ORVV RI pgdA DWWHQXDWHG WKH LQFUHDVH LQ
OHYHOV RI /& LQGXFHG E\ ZLOGW\SH VWUDLQ )LJXUH ( 7KHVH UHVXOWV ZHUH
VXEVHTXHQWO\ FRQILUPHG DV OHYHOV RI /&,, ZHUH VLJQLILFDQWO\ UHGXFHG LQ FHOOV
LQIHFWHG ZLWK WKH pgdA PXWDQW FRPSDUHG WR FHOOV LQIHFWHG ZLWK ZLOGW\SH H. pylori
)LJXUH ) 7KHVH IXQFWLRQDO VWXGLHV VXSSRUW RXU HDUOLHU UHVXOWV IRFXVHG RQ 12'
DFWLYDWLRQ DQG LQGLFDWH WKDW 3JG$ GHDFHW\ODVH SOD\V D UROH LQ UHJXODWLQJ 12'
GHSHQGHQWFHOOXODUUHVSRQVHVLQFOXGLQJDXWRSKDJ\)XUWKHUWKHVHGDWDVXJJHVWWKDW
LQFUHDVHGIRUPDWLRQRIO\VRVRPHVLQGXFHGE\WKHpgdAPXWDQWUHIOHFWVDQLQFUHDVH
LQHQGRF\WRWLFWUDIILFNLQJWRO\VRVRPHVWKDWLVLQGHSHQGHQWRIDXWRSKDJ\
Colonization of wild-type H. pylori or pgdA- mutants in a rodent model of gastric
cancer
:H QH[W VRXJKW WR GHWHUPLQH ZKHWKHU ORVV RI PLFURELDO FRQVWLWXHQWV UHTXLUHG IRU
12' DFWLYDWLRQ DOWHUHG SDWKRORJLFDO UHVSRQVHV LQ D URGHQW PRGHO RI H. pylori
LQGXFHG JDVWULF FDUFLQRJHQHVLV 7KHUH ZDV D VLJQLILFDQW GLIIHUHQFH LQ FRORQL]DWLRQ
HIILFLHQF\ EHWZHHQ 0RQJROLDQ JHUELOV LQIHFWHG ZLWK WKH ZLOGW\SH VWUDLQ DQG
WKH LVRJHQLF pgdA PXWDQW DW DQG ZHHNV FRPELQHG )LJXUH $
&RORQL]DWLRQGHQVLW\OHYHOVZHUHDOVRVLJQLILFDQWO\GHFUHDVHGLQJHUELOVVXFFHVVIXOO\
LQIHFWHGZLWKWKHpgdA-PXWDQWYHUVXVWKHZLOGW\SHVWUDLQ)LJXUH%&/HYHOVRI
DQWLH. pyloriDQWLERGLHVZHUHVLJQLILFDQWO\ORZHUDPRQJJHUELOVLQIHFWHGZLWKWKH
pgdA PXWDQW YHUVXVWKH ZLOGW\SH VWUDLQ ZHHNV SRVWFKDOOHQJH )LJXUH ' :H
ͳ͹
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
QH[WFRPSDUHGEDFWHULDOFRORQL]DWLRQGHQVLW\DQGOHYHOVRIDQWLH. pyloriDQWLERGLHV
)RU JHUELOV LQIHFWHG ZLWK ZLOGW\SH VWUDLQ WKHUH ZDV D VLJQLILFDQW LQYHUVH
UHODWLRQVKLSEHWZHHQFRORQL]DWLRQGHQVLW\DQGDQWLERG\OHYHOVFRUUHODWLRQFRHIILFLHQW
U S GDWDQRWVKRZQ,QFRQWUDVWWKHUHZDVDVLJQLILFDQWFRQFRUGDQW
UHODWLRQVKLSEHWZHHQDQWLERG\OHYHOVDQGFRORQL]DWLRQGHQVLW\LQJHUELOVLQIHFWHGZLWK
WKHpgdAPXWDQWFRUUHODWLRQFRHIILFLHQWU S GDWDQRWVKRZQ
*HUELOV LQIHFWHG ZLWK ZLOGW\SH H. pylori GHYHORSHG VLJQLILFDQWO\ KLJKHU LQIODPPDWRU\
VFRUHV FRPSDUHG WR JHUELOV VXFFHVVIXOO\ LQIHFWHG ZLWK WKH pgdA PXWDQW VWUDLQ
)LJXUH % :H WKHQ FRPSDUHG EDFWHULDO FRORQL]DWLRQ GHQVLW\ DQG VHYHULW\ RI
LQIODPPDWLRQ LQ JHUELOV LQIHFWHG ZLWK WKH ZLOGW\SH VWUDLQ YHUVXV WKH pgdA PXWDQW
VWUDLQ,QJHUELOVLQIHFWHGZLWKHLWKHU:7VWUDLQRUWKHpgdAPXWDQWWKHUHZDV
DQLQYHUVHUHODWLRQVKLSEHWZHHQFRORQL]DWLRQGHQVLW\DQGOHYHOVRILQIODPPDWLRQGDWD
QRWVKRZQ+RZHYHULQJHUELOVLQIHFWHGZLWK:7H. pyloriQ RUWKHpgdAPXWDQW
Q DQG ZKLFK KDG VLPLODU OHYHOV RI FRORQL]DWLRQ GHQVLW\ UDQJH [ WR [
&)8JUDP VWRPDFK WLVVXH LQIODPPDWLRQ VFRUHV ZHUH YHU\ GLIIHUHQW $OO ILYH RI WKH
pgdAPXWDQWLQIHFWHGJHUELOVKDGLQIODPPDWLRQVFRUHVRILQFRQWUDVWRIWKH
:7LQIHFWHG JHUELOV KDG LQIODPPDWLRQ VFRUHV UDQJLQJ EHWZHHQ &RQVLVWHQW ZLWK
LQFUHDVHG VHYHULW\ RI LQIODPPDWLRQ JDVWULF DGHQRFDUFLQRPD ZDV REVHUYHG PRUH
IUHTXHQWO\LQZLOGW\SHLQIHFWHGJHUELOVFRPSDUHGWRJHUELOVLQIHFWHGZLWK
WKHpgdAPXWDQWVWUDLQ)LJXUH&&ROOHFWLYHO\WKHVHGDWDLQGLFDWHWKDW
3JG$SOD\VDFULWLFDOUROHLQH. pyloriLQGXFHGJDVWULFFDUFLQRJHQHVLV
ͳͺ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Pre-activation of NOD1 suppresses H. pylori-induced signaling and injury in vivo and
in vitro
7KHHIIHFWVRI12'DFWLYDWLRQDUHWLJKWO\UHJXODWHGDQG12'LQGXFHGFRQVWLWXHQWV
FDQLQKLELWWKHVXEVHTXHQWFRQVHTXHQFHVRI12'DFWLYDWLRQ:HVRXJKWWR
GHWHUPLQHZKHWKHUDFWLYDWLRQRI12'SULRUWRH. pyloriLQIHFWLRQFRXOGPRGLI\LQMXU\
ZLWKLQWKHJDVWULFQLFKH*HUELOVZHUHWUHDWHGZLWKWKH12'VSHFLILFDJRQLVW&L(
'$3 IRU VL[ GD\V YLD JDYDJH 7R GHWHUPLQH WKH HIILFDF\ RI DJRQLVW WUHDWPHQW IRU
12'PHGLDWHG 1)κ% DFWLYDWLRQ WKH 1)κ% WDUJHW .& Cxcl1 ZDV TXDQWLILHG LQ
JDVWULF WLVVXH E\ UHDOWLPH 573&5 IROORZLQJ D GD\ WUHDWPHQW /HYHOV RI .& LQ
JHUELOV WUHDWHG ZLWK WKH 12' DJRQLVW LQFUHDVHG LQ D GRVHGHSHQGHQW IDVKLRQ
FRPSDUHGWRYHKLFOHFRQWURO)LJXUH$7KHVHUHVXOWVLQGLFDWHWKDW&L('$3FDQ
VXFFHVVIXOO\DFWLYDWH12'GHSHQGHQWVLJQDOLQJLQWKH VWRPDFK
:H WKHQ H[DPLQHG WKH HIIHFWV RI 12' DFWLYDWLRQ SULRU WR H. pylori LQIHFWLRQ
)ROORZLQJGD\VRI&L('$3WUHDWPHQWJHUELOVZHUHFKDOOHQJHGZLWKRUZLWKRXW
VWUDLQDQGHYDOXDWHGZHHNVSRVWFKDOOHQJH3UHDFWLYDWLRQRI12'OHGWRD
VLJQLILFDQWUHGXFWLRQLQOHYHOVRIFRORQL]DWLRQLQIODPPDWLRQDQGWKHGHYHORSPHQWRI
FDQFHU )LJXUH % & ' :H DOVR QRUPDOL]HG IRU FRORQL]DWLRQ GHQVLW\ LQ WKHVH
H[SHULPHQWVDQGIRXQGWKDWGHQVLWLHVZHUHQRWVLJQLILFDQWO\GLIIHUHQWDPRQJLQIHFWHG
JHUELOV GHYHORSLQJ FDQFHU WKDW ZHUH SUHWUHDWHG ZLWK &L('$3 YHUVXV YHKLFOH
FRQWURO&L('$3WUHDWHGQ PHDQGHQVLW\[&)8JYHKLFOHWUHDWHGQ PHDQ GHQVLW\ [ &)8J S $OWKRXJK WKHVH QXPEHUV DUH VPDOO WKH\
VXJJHVW WKDW WKH VHYHULW\ RI GLVHDVH LV PRUH GHSHQGHQW RQ 12' DFWLYDWLRQ WKDQ
FRORQL]DWLRQGHQVLW\per se
ͳͻ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
:H QH[W VRXJKW WR LQYHVWLJDWH WKHVH in vivo REVHUYDWLRQV LQ JUHDWHU GHSWK XVLQJ
PDQLSXODWDEOH in vitro V\VWHPV +(. FHOOV FDUU\LQJ D 1)κ% DONDOLQH
SKRVSKDWDVHOLQNHGUHSRUWHUDQGFRWUDQVIHFWHGZLWKDKXPDQ12'RYHUH[SUHVVLRQ
YHFWRU12'RUDFRQWUROFRQVWUXFW&RQWUROZHUHSXUFKDVHGDQGFRFXOWXUHGZLWK
H. pyloriVWUDLQIRUKRXUVDQG1)κ%DFWLYLW\ZDVTXDQWLILHG/HYHOVRI1)κ%
DFWLYDWLRQ ZHUH VLJQLILFDQWO\ UHGXFHG LQ H. pyloriLQIHFWHG 12' RYHUH[SUHVVLQJ
FHOOVFRPSDUHGWRLQIHFWHGFRQWUROFHOOV)LJXUH$7RH[WHQGWKHVHUHVXOWV1XOORU
12' RYHUH[SUHVVLQJ FHOOV ZHUH LQIHFWHG ZLWK DQRWKHU H. pylori cag VWUDLQ -
6LPLODUWRUHVXOWVREWDLQHGZLWKVWUDLQRYHUH[SUHVVLRQRI12'DWWHQXDWHG1)
κ%DFWLYDWLRQLQGXFHGE\VWUDLQ-ILQGLQJVFRQVLVWHQWZLWKRXUin vivoGDWD)LJXUH
:HDOVRH[DPLQHGFHOOYLDELOLW\LQ12'RYHUH[SUHVVLQJFHOOVWKDWZHUHHLWKHUFR
FXOWXUHG ZLWK H. pylori RU WUHDWHG ZLWK &L('$3 RU 30$ 7KHUH ZHUH QR
GLIIHUHQFHVLQYLDELOLW\EHWZHHQDQ\RIWKHJURXSVLQGLFDWLQJWKDWWKHFRPELQDWLRQRI
12'RYHUH[SUHVVLRQDQGH. pyloriLQIHFWLRQGRHVQRWLQGXFHLQFUHDVHGOHYHOVRIFHOO
GHDWK6XSSOHPHQWDO)LJXUH
:H WKHQ HPSOR\HG D FRPSOHPHQWDU\ VWUDWHJ\ WR H[DPLQH WKH HIIHFWV RI 12'
DFWLYDWLRQ RQ H. pyloriLQGXFHG FHOOXODU UHVSRQVHV E\ LQKLELWLQJ 12' DFWLYDWLRQ in
vitro IRU H[WHQGHG SHULRGV RI WLPH EHIRUH H[SRVXUH WR H. pylori )RU WKHVH VWXGLHV
$*6 FHOOV ZHUH WUHDWHG ZLWK HLWKHU NOD1WDUJHWLQJ VK51$ RU 0/ D VSHFLILF
LQKLELWRURI12'DFWLYDWLRQKRXUVSULRUWRLQIHFWLRQ([WHQGHGLQKLELWLRQRI12'
EHIRUH LQIHFWLRQ UHFLSURFDOO\ LQFUHDVHG 1)κ% DFWLYDWLRQ LQ UHVSRQVH WR H. pylori
ʹͲ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
LQGLFDWLQJWKDWPDQLSXODWLRQRI12'FDQDIIHFWFHOOXODUUHVSRQVHVWRWKLVSDWKRJHQ
)LJXUH%&
2XUUHVXOWVDERYHLQGLFDWHWKDWSUHDFWLYDWLRQRI12'VXSSUHVVHGH. pyloriLQGXFHG
VLJQDOLQJ UDLVLQJ WKH SRVVLELOLW\ RI D 12'GHSHQGHQW QHJDWLYH IHHGEDFN ORRS 7R
H[SORUH WKHVH REVHUYDWLRQV LQ JUHDWHU GHSWK ZH IRFXVHG RQ D VSHFLILF GRZQVWUHDP
WDUJHW RI 12' 75$) ZKLFK FDQ DOVR EH UHJXODWHG E\ $3 &RFXOWXUH RI
$*6FHOOVZLWKZLOGW\SHVWUDLQLQFUHDVHGH[SUHVVLRQRITRAF3LQ$*6FHOOVEXW
WKLVZDVDWWHQXDWHGE\LQKLELWLRQRI$3IXUWKHULQKLELWLRQRI$3RUTRAF3OHGWR
DUHFLSURFDOLQFUHDVHLQ1)κ%DFWLYLW\ZLWKLQWKHFRQWH[WRIH. pyloriLQIHFWLRQ)LJXUH
') TRAF3VSHFLILF VK51$ VXSSUHVVHG HQGRJHQRXV TRAF3 E\ DSSUR[LPDWHO\
6XSSOHPHQWDO)LJXUH7KXV$3DQG75$)DUHFRPSRQHQWVRIDQHJDWLYH
IHHGEDFNORRSDFWLYDWHGE\H. pyloriWKDWFDQXOWLPDWHO\VXSSUHVV1)κ%VLJQDOLQJ
NOD1 expression in human gastric tissue
:HQH[WH[WHQGHGRXUVWXGLHVDQGH[DPLQHG12'LQJDVWULFWLVVXHKDUYHVWHGIURP
GLIIHUHQWJDVWULFVLWHVXVLQJDSRSXODWLRQRIH. pyloriLQIHFWHGSDWLHQWVIURP&RORPELD
ZLWKLQWHVWLQDOW\SHJDVWULFDGHQRFDUFLQRPD(DFKSDWLHQWVHUYHGDVWKHLURZQFRQWURO
DQG VDPSOHV ZHUH LVRODWHG IURP WXPRUDO WLVVXH DQG XQDIIHFWHG UHJLRQV RI WKH
VWRPDFK
ʹͳ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
7KHYDVWPDMRULW\RI12'VWDLQLQJZDVUHVWULFWHGWRJDVWULFHSLWKHOLDOFHOOVDQGWKHUH
ZDV QR VWDLQLQJ XVLQJ DQ LVRW\SH FRQWURO DQWLERG\ )LJXUH $ (SLWKHOLDO VWDLQLQJ
LQWHQVLW\DQGWKHQXPEHURIJDVWULFHSLWKHOLDOFHOOVH[SUHVVLQJGHWHFWDEOH12'ZHUH
VLJQLILFDQWO\ KLJKHU LQ QRQFDQFHU FRPSDUHG WR FDQFHU VDPSOHV )LJXUH $ %
7KHVHUHVXOWVZHUHVXEVHTXHQWO\FRQILUPHGLQDQLQGHSHQGHQWVHWRIVDPSOHVXVLQJ
UHDOWLPH573&5)LJXUH&
&';LVDWUDQVGLIIHUHQWLDWLRQIDFWRUWKDWFDQLQIOXHQFHWKHGHYHORSPHQWRILQWHVWLQDO
W\SHJDVWULFDGHQRFDUFLQRPD3UHYLRXVVWXGLHVKDYHGHPRQVWUDWHGWKDW1)κ%
DFWLYDWLRQOHDGVWRLQFUHDVHGSURGXFWLRQRI&';YLDVXSSUHVVLRQRI62;
2XU in vitro UHVXOWV LQ )LJXUH LQGLFDWH WKDW VXSSUHVVLQJ OHYHOV RI 12' IRU
SURORQJHGSHULRGVRIWLPHOHDGVWRLQFUHDVHG1)κ%H[SUHVVLRQZLWKLQWKHFRQWH[WRI
H. pylori LQIHFWLRQ 7KHUHIRUH ZH QH[W TXDQWLILHG OHYHOV RI CDX2 DQG SOX2
H[SUHVVLRQLQLQWHVWLQDOW\SHJDVWULFFDQFHUDQGQRQPDOLJQDQWJDVWULFWLVVXH/HYHOV
RI CDX2 H[SUHVVLRQ ZHUH VLJQLILFDQWO\ LQFUHDVHG EXW OHYHOV RI SOX2 ZHUH
VLJQLILFDQWO\GHFUHDVHGLQPDOLJQDQWFRPSDUHGWRQRQPDOLJQDQWWLVVXH)LJXUH&
)XUWKHU WKH 12' GRZQVWUHDP WDUJHW TRAF3 ZDV DOVR UHGXFHG LQ FDQFHU YHUVXV
QRQFDQFHUWLVVXHVLPLODUWROHYHOVRINOD1)LJXUH&GAPDHZDVXVHGDVWKH
FRQWUROJHQHWRQRUPDOL]HUHVXOWVIRUWDUJHWJHQHVDQGH[SUHVVLRQOHYHOVIRUDOOJHQHV
WHVWHG ZHUH ZLWKLQ WKH OLPLWV RI GHWHFWLRQ 7KXV GXULQJ WKH ODWH VWDJHV RI JDVWULF
FDUFLQRJHQHVLV 12' H[SUHVVLRQ LV UHGXFHG LQ LQWHVWLQDOW\SH JDVWULF
DGHQRFDUFLQRPDV FRPSDUHG WR XQLQYROYHG JDVWULF WLVVXH ZKLFK LV DFFRPSDQLHG E\
DQLQFUHDVHLQCDX2H[SUHVVLRQ
ʹʹ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
'LVFXVVLRQ
H. pyloricagVWUDLQVGHOLYHUFRPSRQHQWVRISHSWLGRJO\FDQLQWRHSLWKHOLDOFHOOVYLDWKH
cagVHFUHWLRQV\VWHPOHDGLQJWR12'GHSHQGHQWVLJQDOLQJDQGRXUODERUDWRU\
KDVVKRZQWKDWH. pyloriSHSWLGRJO\FDQFDQOHDGWRGHFUHDVHGDSRSWRVLVLQFUHDVHG
SUROLIHUDWLRQ DQG LQFUHDVHG FHOO PLJUDWLRQ +RZHYHU WKH UHODWLRQVKLS EHWZHHQ
12'DFWLYDWLRQDQGH. pyloriLQGXFHGJDVWULFFDUFLQRJHQHVLVUHPDLQVXQFOHDU2XU
FXUUHQW UHVXOWV KDYH QRZ GHPRQVWUDWHG WKDW 12' KDV DQ LPSRUWDQW UROH LQ JDVWULF
FDUFLQRJHQHVLV DQG IXUWKHU WKDW H. pyloriLQGXFHG LQMXU\ FDQ EH VLJQLILFDQWO\
GHFUHDVHG E\ SUHDFWLYDWLRQ RI WKLV UHFHSWRU ZKLFK PD\ RYHU ORQJ SHULRGV RI
LQIHFWLRQ OHDG WR UHGXFWLRQV LQ WKH OHYHOV RI 12' H[SUHVVLRQ DQG LWV WDUJHW JHQHV
)LJXUH'
2XU in vivo VWXGLHV GHPRQVWUDWH WKDW ORVV RI 3JG$ VLJQLILFDQWO\ DWWHQXDWHG WKH
GHYHORSPHQWRILQIODPPDWLRQDQGFDQFHULQ0RQJROLDQJHUELOVLQIHFWHGZLWKH. pylori
LPSOLFDWLQJ WKLV PLFURELDO FRQVWLWXHQW LQ WKH FDVFDGH WR FDUFLQRJHQHVLV 7KHVH GDWD
PLUURU UHVXOWV GHULYHG IURP D PRXVH PRGHO RI H. pylori LQIHFWLRQ LQ ZKLFK ORVV RI
3JG$ OHG WR D VLJQLILFDQW FRORQL]DWLRQ GHIHFW :H DOVR IRXQG LQ D &RORPELDQ
SRSXODWLRQ RI SDWLHQWV ZLWK LQWHVWLQDOW\SH JDVWULF FDQFHU WKDW OHYHOV RI 12' ZHUH
VLJQLILFDQWO\ ORZHU LQ FDQFHU YHUVXV QRQFDQFHU VSHFLPHQV DQG WKLV ZDV
DFFRPSDQLHG E\ DQ LQFUHDVH LQ H[SUHVVLRQ RI WKH LQWHVWLQDOVSHFLILF WUDQVFULSWLRQ
IDFWRUCDX27KLVLVRILQWHUHVWDV$OOLVRQDQGFROOHDJXHVIRXQGGLIIHULQJUHVXOWV
6SHFLILFDOO\ WKHLU UHVXOWV IURP SDWLHQWV UHVLGLQJ LQ $XVWUDOLD LQGLFDWHG WKDW P51$
H[SUHVVLRQOHYHOVRINOD1ZHUHLQFUHDVHGLQFDQFHUYHUVXVQRQWXPRUVDPSOHV
ʹ͵
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
$QRWKHUGLIIHUHQFHLQUHODWLRQWRWKHin vitroH[SHULPHQWVLVWKDWSUHYLRXVVWXGLHVKDYH
VKRZQ WKDW GHDFHW\ODWLRQ RI H. pylori SHSWLGRJO\FDQ FDQ OHDG WR GHFUHDVHG 12'
DFWLYDWLRQ 2XU FXUUHQW UHVXOWV LQGLFDWH WKDW LVRJHQLF LQDFWLYDWLRQ RI H. pylori
pgdALQVWUDLQDWWHQXDWHG1)κ%DFWLYDWLRQFRPSDUHGWROHYHOVLQGXFHGE\WKH
ZLOGW\SHVWUDLQIXUWKHUDQDO\VLVKRZHYHUGHPRQVWUDWHGWKDWSUHDFWLYDWLRQRI12'
DFWXDOO\ VXSSUHVVHG H. pyloriLQGXFHG VLJQDOLQJ :H VSHFXODWH WKDW LQ DGGLWLRQ WR
WLPLQJ RI 12' DFWLYDWLRQ GLIIHUHQFHV LQ WKH KLVWRORJLF W\SHV RI JDVWULF
DGHQRFDUFLQRPD VWXGLHG LQ FRQMXQFWLRQ ZLWK GLIIHUHQW H. pylori VWUDLQ DQG KXPDQ
DQFHVWU\DQGSRVVLEO\in vitroJURZWKFRQGLWLRQVPD\DFFRXQWIRUWKHVHILQGLQJVDQG
IXUWKHU ZRUN LV QHHG WR XQGHUVWDQG WKHVH GLIIHUHQFHV LQ JUHDWHU GHSWK &ROOHFWLYHO\
WKHVHUHVXOWVVXJJHVWWKDWPDQLSXODWLRQRI12'PD\UHSUHVHQWDQRYHOVWUDWHJ\WR
SUHYHQWRUWUHDWSDWKRORJLFRXWFRPHVLQGXFHGE\H. pyloriLQIHFWLRQ
ʹͶ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
$FNQRZOHGJPHQWV
:H WKDQN 'UV /DXUD *UHHQILHOG DQG 1LFROD -RQHV IRU WKH *)3/& IXVLRQ SURWHLQ
DQG'UV-DQLFH:LOOLDPVDQG0DU\'DZHVIRUWKHLUH[SHUWLVHLQLPDJLQJ
ʹͷ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
5HIHUHQFHV
3RON'%3HHN50-UHelicobacter pyloriJDVWULFFDQFHUDQGEH\RQG1DWXUH
5HY&DQFHU
3HHN 50 -U %ODVHU 0- Helicobacter pylori DQG JDVWURLQWHVWLQDO WUDFW
DGHQRFDUFLQRPDV1DWXUH5HY&DQFHU
3OXPPHU0)UDQFHVFKL69LJQDW-)RUPDQ'GH0DUWHO&*OREDOEXUGHQRI
JDVWULF FDQFHU DWWULEXWDEOH WR S\ORUL ,QWHUQDWLRQDO -RXUQDO RI &DQFHU (SXE
0D\
&KHQ < %ODVHU 0- ,QYHUVH DVVRFLDWLRQV RI Helicobacter pylori ZLWK DVWKPD
DQGDOOHUJ\$UFK,QWHUQ0HG
&UDEWUHH-(:\DWW-,6REDOD*00LOOHU*7RPSNLQV'63ULPURVH-1HWDO
6\VWHPLF DQG PXFRVDO KXPRUDO UHVSRQVHV WR Helicobacter pylori LQ JDVWULF
FDQFHU*XW
%ODVHU0-3HUH]3HUH]*,.OHDQWKRXV+&RYHU7/3HHN50&K\RX3+HW
DO ,QIHFWLRQ ZLWK Helicobacter pylori VWUDLQV SRVVHVVLQJ cagA LV DVVRFLDWHG
ZLWKDQLQFUHDVHGULVNRIGHYHORSLQJDGHQRFDUFLQRPDRIWKHVWRPDFK&DQFHU
5HV
%DFNHUW6=LVND(%ULQNPDQQ9=LPQ\$UQGW8)DXFRQQLHU$-XQJEOXW35
HWDO7UDQVORFDWLRQRIWKH Helicobacter pylori&DJ$SURWHLQLQJDVWULFHSLWKHOLDO
FHOOVE\DW\SH,9VHFUHWLRQDSSDUDWXV&HOO0LFURELRO
7DPPHU , %UDQGW 6 +DUWLJ 5 .RQLJ : %DFNHUW 6 $FWLYDWLRQ RI $EO E\
Helicobacter pyloriDQRYHONLQDVHIRU&DJ$DQGFUXFLDOPHGLDWRURIKRVWFHOO
VFDWWHULQJ*DVWURHQWHURORJ\
0XHOOHU'7HJWPH\HU1%UDQGW6<DPDRND<'H3RLUH(6JRXUDV'HWDO
F6UFDQGF$EONLQDVHVFRQWUROKLHUDUFKLFSKRVSKRU\ODWLRQDQGIXQFWLRQRIWKH
&DJ$HIIHFWRUSURWHLQLQ:HVWHUQDQG(DVW$VLDQHelicobacter pyloriVWUDLQV-
&OLQ,QYHVW
+LJDVKL+7VXWVXPL50XWR66XJL\DPD7$]XPD7$VDND0HWDO6+3
W\URVLQHSKRVSKDWDVHDVDQLQWUDFHOOXODUWDUJHWRIHelicobacter pylori&DJ$
SURWHLQ6FLHQFH
+LJDVKL + 1DND\D $ 7VXWVXPL 5 <RNR\DPD . )XMLL < ,VKLNDZD 6 HW DO
Helicobacter pylori &DJ$ LQGXFHV 5DVLQGHSHQGHQW PRUSKRJHQHWLF UHVSRQVH
WKURXJK6+3UHFUXLWPHQWDQGDFWLYDWLRQ-%LRO&KHP
)UDQFR$7,VUDHO'$:DVKLQJWRQ0..ULVKQD8)R[-*5RJHUV$%HWDO
$FWLYDWLRQ RI ‰FDWHQLQ E\ FDUFLQRJHQLF Helicobacter pylori 3URF 1DWO $FDG
6FL86$
0XUDWD.DPL\D1.XUDVKLPD<7HLVKLNDWD<<DPDKDVKL<6DLWR<+LJDVKL
+ HW DO Helicobacter pylori &DJ$ LQWHUDFWV ZLWK (FDGKHULQ DQG GHUHJXODWHV
WKH EHWDFDWHQLQ VLJQDO WKDW SURPRWHV LQWHVWLQDO WUDQVGLIIHUHQWLDWLRQ LQ JDVWULF
HSLWKHOLDOFHOOV2QFRJHQH
9LDOD - &KDSXW & %RQHFD ,* &DUGRQD $ *LUDUGLQ 6( 0RUDQ $3 HW DO
1RG UHVSRQGV WR SHSWLGRJO\FDQ GHOLYHUHG E\ WKH Helicobacter pylori cag
SDWKRJHQLFLW\LVODQG1DW,PPXQRO
%RXJKDQ 3. $UJHQW5+ %RG\0DODSHO 0 3DUN -+(ZLQJV .( %RZLH $*
HW DO 1XFOHRWLGHELQGLQJ ROLJRPHUL]DWLRQ GRPDLQ DQG HSLGHUPDO JURZWK
IDFWRUUHFHSWRUFULWLFDOUHJXODWRUVRIEHWDGHIHQVLQVGXULQJHelicobacter pylori
LQIHFWLRQ-%LRO&KHP
ʹ͸
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
)HUUHUR5/,QQDWHLPPXQHUHFRJQLWLRQRIWKHH[WUDFHOOXODUPXFRVDOSDWKRJHQ
Helicobacter pylori0RO,PPXQRO
(EHUO * %RQHFD ,* %DFWHULD DQG 0$03LQGXFHG PRUSKRJHQHVLV RI WKH
LPPXQHV\VWHP&XUU2SLQ,PPXQRO
6WUREHU : 0XUUD\ 3- .LWDQL $ :DWDQDEH 7 6LJQDOOLQJ SDWKZD\V DQG
PROHFXODULQWHUDFWLRQVRI12'DQG12'1DW5HY,PPXQRO
.DSDUDNLV07XUQEXOO/&DUQHLUR/)LUWK6&ROHPDQ+$3DUNLQJWRQ+&HW
DO %DFWHULDO PHPEUDQH YHVLFOHV GHOLYHU SHSWLGRJO\FDQ WR 12' LQ HSLWKHOLDO
FHOOV&HOO0LFURELRO
3KLOSRWW '- 6RUEDUD 07 5REHUWVRQ 6- &URLWRUX . *LUDUGLQ 6( 12'
SURWHLQV UHJXODWRUV RI LQIODPPDWLRQ LQ KHDOWK DQG GLVHDVH 1DWXUH 5HY
,PPXQRORJ\
6RUEDUD07(OOLVRQ/.5DPMHHW07UDYDVVRV/+-RQHV1/*LUDUGLQ6(HW
DO 7KH SURWHLQ $7*/ VXSSUHVVHV LQIODPPDWRU\ F\WRNLQHV LQGXFHG E\ WKH
LQWUDFHOOXODU VHQVRUV 1RG DQG 1RG LQ DQ DXWRSKDJ\LQGHSHQGHQW PDQQHU
,PPXQLW\
:DWDQDEH7$VDQR1)LFKWQHU)HLJO6*RUHOLFN3/7VXML<0DWVXPRWR<
HWDO12'FRQWULEXWHVWRPRXVHKRVWGHIHQVHDJDLQVWHelicobacter pyloriYLD
LQGXFWLRQRIW\SH,,)1DQGDFWLYDWLRQRIWKH,6*)VLJQDOLQJSDWKZD\-&OLQ
,QYHVW
+H -4 2JDQHV\DQ * 6DKD 6. =DUQHJDU % &KHQJ * 75$) DQG LWV
ELRORJLFDOIXQFWLRQ$GY([S0HG%LRO
=DUQHJDU%<DPD]DNL6+H-4&KHQJ*&RQWURORIFDQRQLFDO1)NDSSD%
DFWLYDWLRQ WKURXJK WKH 1,.,.. FRPSOH[ SDWKZD\ 3URF 1DWO $FDG 6FL 8 6 $
5DMX'+XVVH\6$QJ07HUHEL]QLN056LERQ\0*DOLQGR0DWD(HWDO
9DFXRODWLQJF\WRWR[LQDQGYDULDQWVLQ$WJ/WKDWGLVUXSWDXWRSKDJ\SURPRWH
Helicobacter pyloriLQIHFWLRQLQKXPDQV*DVWURHQWHURORJ\
)UDQFR$7)ULHGPDQ'%1DJ\7$5RPHUR*DOOR-.ULVKQD8.HQGDOO$HW
DO 'HOLQHDWLRQ RI D FDUFLQRJHQLF Helicobacter pylori SURWHRPH 0RO &HOO
3URWHRPLFV
:DQJ * 2OF]DN $ )RUVEHUJ /6 0DLHU 5- 2[LGDWLYH VWUHVVLQGXFHG
SHSWLGRJO\FDQ GHDFHW\ODVH LQ Helicobacter pylori - %LRO &KHP
%UDQGW 6 .ZRN 7 +DUWLJ 5 .RQLJ : %DFNHUW 6 1)N% DFWLYDWLRQ DQG
SRWHQWLDWLRQ RI SURLQIODPPDWRU\ UHVSRQVHV E\ WKH Helicobacter pylori &DJ$
SURWHLQ3URF1DWO$FDG6FL86$
,UYLQJ $7 0LPXUR + .XIHU 7$ /R & :KHHOHU 5 7XUQHU /- HW DO 7KH
LPPXQHUHFHSWRU12'DQGNLQDVH5,3LQWHUDFWZLWKEDFWHULDOSHSWLGRJO\FDQ
RQ HDUO\ HQGRVRPHV WR SURPRWH DXWRSKDJ\ DQG LQIODPPDWRU\ VLJQDOLQJ &HOO
+RVWDQG0LFUREH
/DPE &$ 'RROH\ +& 7RR]H 6$ (QGRF\WRVLV DQG DXWRSKDJ\ 6KDUHG
PDFKLQHU\IRUGHJUDGDWLRQ%LRHVVD\V
&DPLOR9%DUURV56RXVD60DJDOKDHV$0/RSHV70DULR6DQWRV$HWDO
Helicobacter pylori DQG WKH %03 SDWKZD\ UHJXODWH &'; DQG 62;
H[SUHVVLRQLQJDVWULFFHOOV&DUFLQRJHQHVLV
=KDQJ < /LX - <DR 6 /L ) ;LQ / /DL 0 HW DO 1XFOHDU IDFWRU NDSSD %
VLJQDOLQJ LQLWLDWHV HDUO\ GLIIHUHQWLDWLRQ RI QHXUDO VWHP FHOOV 6WHP &HOOV
ʹ͹
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
'HEUX\QH35:LWHN0*RQJ/%LUEH5&KHUYRQHYD,-LQ7HWDO%LOHDFLGV
LQGXFH HFWRSLF H[SUHVVLRQ RI LQWHVWLQDO JXDQ\O\O F\FODVH & WKURXJK QXFOHDU
IDFWRUNDSSD% DQG &G[ LQ KXPDQ HVRSKDJHDO FHOOV *DVWURHQWHURORJ\
$VRQXPD 6 ,PDWDQL $ $VDQR 1 2LNDZD 7 .RQLVKL + ,LMLPD . HW DO
Helicobacter pyloriLQGXFHVJDVWULFPXFRVDOLQWHVWLQDOPHWDSODVLDWKURXJKWKH
LQKLELWLRQRILQWHUOHXNLQPHGLDWHG+0*ER[SURWHLQ6R[H[SUHVVLRQ$PHU-
3K\VLRO*,DQG/LYHU3K\VLRORJ\*
1DJ\ 7$ )UH\ 05 <DQ ) ,VUDHO '$ 3RON '% 3HHN 50 -U Helicobacter
pylori UHJXODWHV FHOOXODU PLJUDWLRQ DQG DSRSWRVLV E\ DFWLYDWLRQ RI
SKRVSKDWLG\OLQRVLWRONLQDVHVLJQDOLQJ-,QIHFW'LV
:DQJ * 0DLHU 6( /R /) 0DLHU * 'RVL 6 0DLHU 5- 3HSWLGRJO\FDQ
GHDFHW\ODWLRQ LQ Helicobacter pylori FRQWULEXWHV WR EDFWHULDO VXUYLYDO E\
PLWLJDWLQJKRVWLPPXQHUHVSRQVHV,QIHFW,PPXQ
$OOLVRQ&&)HUUDQG-0F/HRG/+DVVDQ0.DSDUDNLV/LDVNRV0*UXEPDQ
$HWDO1XFOHRWLGHROLJRPHUL]DWLRQGRPDLQHQKDQFHV,)1JDPPDVLJQDOLQJ
LQJDVWULFHSLWKHOLDOFHOOVGXULQJHelicobacter pyloriLQIHFWLRQDQGH[DFHUEDWHV
GLVHDVHVHYHULW\-,PPXQRO
%RQHFD,*'XVVXUJHW2&DEDQHV'1DKRUL0$6RXVD6/HFXLW0HWDO$
FULWLFDO UROH IRU SHSWLGRJO\FDQ NDFHW\ODWLRQ LQ Listeria HYDVLRQ IURP WKH KRVW
LQQDWHLPPXQHV\VWHP3URF1DW$FDG6FL86$
ʹͺ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
)LJXUH/HJHQGV
)LJXUH,QDFWLYDWLRQRIpgdADIIHFWVSHSWLGRJO\FDQDFHW\ODWLRQDQGDWWHQXDWHV
12'GHSHQGHQW 1)κ% DFWLYDWLRQLQGXFHG E\ H. pyloriin vitro 3HSWLGRJO\FDQ
IURP:7VWUDLQDpgdA-PXWDQWRUDFRPSOHPHQWHGpgdA (pgdA/c)VWUDLQZDV
DQDO\]HG E\ PDVV VSHFWURPHWU\ DQG UDWLRV EHWZHHQ P] GHDFHW\ODWHG DQG
P] DFHW\ODWHG ZHUH FDOFXODWHG $ $*6 FHOOV WUDQVIHFWHG ZLWK D 1)κ%
OXFLIHUDVH UHSRUWHU % FRWUDQVIHFWHG ZLWK D GRPLQDQW QHJDWLYH 12' '1 12'
&RUWUDQVIHFWHGZLWKVK51$WDUJHWLQJNOD1RUNOD2 'ZHUHFRFXOWXUHGZLWK
:7 VWUDLQ D pgdA- PXWDQW, D pgdA FRPSOHPHQWHG PXWDQW pgdA/c, D cagAPXWDQWRUDcagE-PXWDQWIRUKRXUV&L('$3DQG30$ZHUHXVHGDV12'
GHSHQGHQW
DQG
12'LQGHSHQGHQW
DFWLYDWRUV
RI
1)κ%
UHVSHFWLYHO\
S”S”S” S” YHUVXV XQLQIHFWHG FRQWURO 'DWD
UHSUHVHQWPHDQ“6(0IURPDWOHDVWH[SHULPHQWV
)LJXUH,QDFWLYDWLRQRI pgdAVHQVLWL]HVH. pyloriWRLQWUDFHOOXODUGHJUDGDWLRQ
EXWQRWDXWRSKDJ\$&RFXOWXUHVRIH. pyloriDQG$*6FHOOVZHUHO\VHGDQGSODWHG
WR TXDQWLI\ DGKHUHQW EDFWHULD 'DWD UHSUHVHQW PHDQ“6(0 IURP DW OHDVW H[SHULPHQWV161RQVLJQLILFDQW%*HQWDP\FLQSURWHFWLRQDVVD\VZHUHSHUIRUPHG
WR TXDQWLI\ YLDEOH LQWUDFHOOXODU H. pylori S” 'DWD UHSUHVHQW PHDQ“6(0
IURPDWOHDVWH[SHULPHQWV&7UDQVPLVVLRQHOHFWURQPLFURVFRS\RI:7VWUDLQ
RU D pgdA- PXWDQW FRFXOWXUHG ZLWK $*6 FHOOV IRU KRXUV $UURZV EDFWHULD
DUURZKHDGVSKDJRO\VRVRPDOYHVLFOHV'&RQIRFDOLPDJHVRI$*6FHOOVFRFXOWXUHG
ZLWK :7 VWUDLQ RU D pgdA- PXWDQW IRU KRXUV &HOOV ZHUH VWDLQHG ZLWK
/\VR7UDFNHU '1' UHG DQG QXFOHDU VWDLQ +RHFKVW ZKLWH ( &RQIRFDO
ʹͻ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
LPDJHVRI$*6FHOOVH[SUHVVLQJD*)3/&IXVLRQSURWHLQJUHHQFRFXOWXUHGZLWK
:7 VWUDLQ RU LWV pgdA- PXWDQW IRU KRXUV &HOOV ZHUH IL[HG DQG PRXQWHG LQ
PHGLD FRQWDLQLQJ '$3, %OXH ) :HVWHUQ EORW RI $*6 FHOOV FRFXOWXUHG ZLWK :7
VWUDLQ RU LWV pgdA- PXWDQW XVLQJ DQWL/& DQG DQWLDFWLQ DQWLERGLHV DQG
VXEVHTXHQWGHQVLWRPHWU\DQDO\VLVIURPWKUHHUHSOLFDWHVS”
)LJXUH/RVVRIH. pylori pgdAGHFUHDVHVFRORQL]DWLRQLQ0RQJROLDQJHUELOV
$&RORQL]DWLRQHIILFLHQF\RIH. pyloriVWUDLQVLQJHUELOV7ZRDQGWZHOYHZHHNSRVW
FKDOOHQJH UHVXOWV DUH FRPELQHG S” % 6LOYHUVWDLQ LPDJHV IURP JHUELOV
LQIHFWHGZLWK:7RUpgdA- PXWDQW VWUDLQVZHHNVSRVWFKDOOHQJH&&RORQL]DWLRQ
GHQVLW\ RI :7 RU pgdA- VWUDLQV ZHHNV SRVWFKDOOHQJH S” ' H. pylori
VSHFLILF DQWLERGLHV ZHUH TXDQWLILHG E\ (/,6$ LQ VHUD KDUYHVWHG IURP JHUELOV
FKDOOHQJHGZLWK:7RUpgdA-PXWDQWVWUDLQVIRUZHHNVS”
)LJXUH ,QDFWLYDWLRQ RI 3JG$ DOWHUV H. pyloriLQGXFHG LQIODPPDWLRQ DQG
GLVHDVHRXWFRPHLQ0RQJROLDQJHUELOV$+(VWDLQHGJDVWULFWLVVXHIURPJHUELOV
FKDOOHQJHGZLWK:7VWUDLQRUDpgdA-PXWDQWVWUDLQIRUZHHNV8,XQLQIHFWHG
%RWWRPOHIWVHYHUHJDVWULWLVDUURZERWWRPULJKWLQYDVLYHDGHQRFDUFLQRPDDUURZ
% ,QIODPPDWRU\ VFRUHV LQ JHUELOV LQIHFWHG ZLWK H. pylori ZHHNV SRVWLQIHFWLRQ
S”GDWDUHSUHVHQWPHDQ“6(0&'LVHDVHRXWFRPHLQJHUELOVFKDOOHQJHG
ZLWK:7RULWVpgdA- PXWDQWZHHNVSRVWFKDOOHQJH
͵Ͳ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
)LJXUH 3UHDFWLYDWLRQ RI 12' LQ 0RQJROLDQ JHUELOV SULRU WR H. pylori
LQIHFWLRQ DWWHQXDWHVGLVHDVH. $*HUELOVZHUHWUHDWHGZLWKGLIIHUHQWGRVHVRI&
L('$3 IRU GD\V ([SUHVVLRQ RI .& Cxcl1 DW GD\ VHYHQ ZDV PHDVXUHG E\ 57
3&5 DV DQ LQGLFDWRU RI 12' DFWLYDWLRQ 'DWD UHSUHVHQW PHDQ“6(0 &RORQL]DWLRQ
GHQVLW\ % LQIODPPDWLRQ & DQG LQFLGHQFH RI DGHQRFDUFLQRPD ' LQ JHUELOV
WUHDWHG ZLWK &L('$3 ȝJDQLPDOGD\ IRU GD\V EHIRUH DQG GD\V DIWHU
FKDOOHQJH ZLWK :7 VWUDLQ $QLPDOV ZHUH VDFULILFHG ZHHNV SRVWFKDOOHQJH
S”S”
)LJXUH 2YHUH[SUHVVLRQ RU LQKLELWLRQ RI 12' SULRU WR H. pylori LQIHFWLRQ
DOWHUV 1)κ% DFWLYDWLRQ +(. FHOOV FDUU\LQJ D 1)κ% DONDOLQH SKRVSKDWDVH
OLQNHG UHSRUWHU DQG FRWUDQVIHFWHG ZLWK D KXPDQ 12'RYHUH[SUHVVLRQ YHFWRU
S812K12' RU D FRQWURO FRQVWUXFW &RQWURO ZHUH SXUFKDVHG DQG FRFXOWXUHG
ZLWK VWUDLQV RU - IRU KRXUV 6XSHUQDWDQWV ZHUH KDUYHVWHG DQG DONDOLQH
SKRVSKDWDVH DFWLYLW\ ZDV TXDQWLILHG $ $*6 FHOOV ZHUH VWDEO\ WUDQVIHFWHG ZLWK D
1)κ%/XFLIHUDVHOLQNHGUHSRUWHUDQGHLWKHUQRQWDUJHWLQJVK51$RUVK51$VSHFLILF
IRUNOD1 %RUTRAF3)RUSUHWUHDWHGIRUGD\VZLWK0/DVSHFLILFLQKLELWRU
RI 12' DFWLYDWLRQ & RU 65 D VSHFLILF LQKLELWRU RI $3 ' /XFLIHUDVH
DFWLYLW\ ZDV PHDVXUHG DIWHU KRXUV RI FRFXOWXUH ZLWK H. pylori TRAF3 P51$
H[SUHVVLRQ ZDV PHDVXUHG E\ UHDOWLPH 573&5 LQ $*6 FHOOV SUHWUHDWHG ZLWK
65IRUGD\VDQGWKHQFKDOOHQJHGZLWK:7VWUDLQIRUKRXUV('DWD
UHSUHVHQW
PHDQ“6(0
IURP
DW
OHDVW
H[SHULPHQWV
S”S”S”S”FRPSDUHGZLWKXQLQIHFWHGFHOOV
͵ͳ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
)LJXUH ([SUHVVLRQ RI 12' LV GLPLQLVKHG LQ KXPDQ PDOLJQDQW WLVVXH $
,PPXQRKLVWRFKHPLVWU\IRU12'LQWXPRUDOUHGDQGQRQWXPRUDO HSLWKHOLDPLGGOH
SDQHO FRPSDUHG ZLWK LVRW\SH FRQWURO ERWWRP SDQHO % 12' VWDLQLQJ LQWHQVLW\ LQ
HSLWKHOLDOFHOOVWRSSDQHODQGSHUFHQWDJHRI12'SRVLWLYHHSLWKHOLDOFHOOVERWWRP
SDQHO'DWDUHSUHVHQWPHDQ“6(0S” &4XDQWLWDWLYH573&5H[SUHVVLRQ
IRUNOD1DQGUHODWHGJHQHV LQJDVWULFELRSVLHVIURPWXPRUDODQGQRQWXPRUDOWLVVXH
S”S”S” 5HVXOWV H[SUHVVHG DV UDWLR RI WDUJHW JHQH*$3'+
P51$ LQ FDQFHU RU QRQFDQFHU VDPSOHV UHODWLYH WR WKH PHDQ UDWLR LQ QRQWXPRU
WLVVXH 'DWD UHSUHVHQW PHDQ“6(0 IURP UHSOLFDWHVVDPSOH ' :RUNLQJ PRGHO RI
12' DFWLYDWLRQ DQG GRZQVWUHDP FRQVHTXHQFHV ZLWKLQ WKH FRQWH[W RI H. pylori
LQIHFWLRQ
͵ʹ
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 2, 2015; DOI: 10.1158/0008-5472.CAN-14-2291
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Modification of Helicobacter pylori peptidoglycan enhances
NOD1 activation and promotes cancer of the stomach
Giovanni Suarez, Judith Romero-Gallo, Maria B. Piazuelo, et al.
Cancer Res Published OnlineFirst March 2, 2015.
Updated version
Supplementary
Material
Author
Manuscript
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
doi:10.1158/0008-5472.CAN-14-2291
Access the most recent supplemental material at:
http://cancerres.aacrjournals.org/content/suppl/2015/02/28/0008-5472.CAN-14-2291.DC1
Author manuscripts have been peer reviewed and accepted for publication but have not yet been
edited.
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 2015 American Association for Cancer Research.