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Whyworkingthenightshiftcanposeacancerrisk|MITNews

Inhumanandmototherorganim,a
circadianclockgovernedlight
regulatethetimingofkeapectof
humanphiolog,controllingcellular
activitieuchametaolimand
diviion.
Image:NationalCancerIntitute,Chritine
Daniloff/MIT

Whworkingthenighthiftcanpoeacancerrik
Newtudrevealalinketweencircadianclockdiruptionandtumorgrowth.
AnneTrafton|MITNewOffice
Jul28,2016

RLATD

Ahandfuloflargetudieofcancerrikfactorhavefoundthatworkingthenighthift,a

JackLa

nearl15percentofAmericando,ootthechanceofdevelopingcancer.MITiologit
havenowfoundalinkthatmaexplainthiheightenedrik.

KochIntitute

Inhumanandmototherorganim,acircadianclockgovernedlightregulatethetiming
ofkeapectofhumanphiolog,controllingcellularactivitieuchametaolimand

Departmentofiolog

diviion.Inatudofmice,theMITteamfoundthattwoofthegenethatcontrolcell
circadianrhthmalofunctionatumoruppreor.

choolofcience

Looftheetumoruppreor,eitherthroughgenedeletionordiruptionofthenormal
light/darkccle,allowtumortoecomemoreaggreive.
ARCHIV

Itdoentmatterhowoudirupttheclockothwa,loofiteemtodrive
tumorigenei,aThalePapagiannakopoulo,aformerpotdocatMITKochIntitutefor
IntegrativeCancerReearchandtheleadauthorofthetud,whichappearintheJul28

Fatmodelingof
cancermutation

iueofCellMetaolim.
TlerJack,directoroftheKochIntituteandtheDavidH.KochProfeorofiolog,ithe
papereniorauthor.

Newviewoftumor
evolution

reakingthecircadianclock
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Whyworkingthenightshiftcanposeacancerrisk|MITNews

Inhuman,thecentralcircadianclockilocatedintherainuprachiamaticnucleu(CN),
whichreceiveinformationaoutlightlevelfromtheretina.TheCNcommunicatethi
informationtocellintheodthroughhormoneandotherignalingmolecule.
Withincell,agenecalledmal1ireponileforturningonothergenethatcontrol

Thelinketweencircadianrhthm
andaging

circadianactivitie,includingonecalledPer2.Leveloftheproteinencodedtheegene
normallocillatethroughouttheda,utwhennormallight/darkcclearedirupted,thoe
ocillationdiappear.
Cellneedthelightcue,whichilikeareetuttonfortheclock.Whenouloethatcue,
ouloethenormalrhthminevercellinourod,aPapagiannakopoulo,whoinow
anaitantprofeorofpathologatNewYorkUniveritchoolofMedicine.
Heandhicolleagueetouttoinvetigateapoilelinketweencancerandtheegene,
inmicethataregeneticallengineeredtodevelopatpeoflungcancerknownanon-mall
celllungcancer.
Theeganexpoingthemicetotwodifferentlight/darkchedule.Onegroupofmice
livedwithanormalcheduleof12houroflightfollowed12hourofdarkne,whilethe
othermicewentontoajetlagchedule:vertwotothreeda,thewereexpoedtoan
additionaleighthouroflight.Thimimictheiologicalclockdiruptionthatoccurwhen
humanworknighthiftortravelthroughmultipletimezone.
Underthejetlagcenario,tumorgrewfaterandweremoreaggreivethanthoeinthe
micelivingwithanormallight/darkchedule.
Intheirnextetofexperiment,thereearcherkeptthemiceonanormallight/darkchedule
utknockedoutthegeneformal1andPer2.Inthoemice,tumorgrewfater,jutathe
didunderthejetlagcenario.
Ifoudirupttheegeneinevercelloftheod,thelightcuethatounormallreceive
donotappl,Papagiannakopouloa.Itawaoftakingamolecularhammerandjut
reakingthiclock.
Out-of-controlgrowth
mal1andPer2controlthetimingofproductionofacancer-promotingproteinknownacmc,owhenthoegenearedirupted,c-mcegintoaccumulate,purringanincreaein
cellmetaolimandproliferation.
C-mcturnonthiprogramthatmakecellproducemoremetaolite,morenutrient,
moreuildinglockfornewcell.Iteentialfortheailitofcelltoproliferate,
Papagiannakopouloa.
JoephTakahahi,chairoftheDepartmentofNeurocienceattheUniveritofTexa
outhweternMedicalCenter,athetudofferanimportantlinketweencancerand
circadianclockdfunction.
Thiworkiverclearanddefinitive,aTakahahi,whowanotinvolvedinthereearch.
Thatwhatweneedtoreallhowthatthecircadianclockmahaveimplicationforcancer
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Whyworkingthenightshiftcanposeacancerrisk|MITNews

andtumorprogreion.
TheMITreearcheraloanalzedhumanlungtumorampleandfoundmuchlowerlevelof
mal1andPer2geneexpreion,awellaotherkecircadianclockgene,inthetumor
thaninnormallungtiuefromtheamepatient.Themotaggreivetumorhadeven
lowerlevelofthoegene.
Papagiannakopouloinowinvetigatingwhethercancercellthathavearokenclock,for
examplethroughloofmal1andPer2,haveanweakneethatcouldeexploiteda
potentialdrugtarget.Healoplantotudhowcircadiandiruptionaffectothertpeof
cancer,includingpancreaticcancer.
ThereearchwafundedaNationalCancerIntituteCancerCenterupportCoreGrant,
theLungCancerReearchFoundation,andtheKochIntituteFrontierFund.

Topic:

Reearch

Cancer

iolog

KochIntitute

choolofcience

AoutThiWeite
ThiWeiteimaintainedtheMITNewOffice.

MITNewOfficeuilding11-400
MaachuettIntituteofTechnologCamridge,MA02139-4307

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