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[(types,)-395.9(including)-397.4(lung)-396.2(squamous)-396.7(carcinoma)-396(where)-394.6(they)-397.4(are)]TJ
0 -1.1174 TD
[(found)-310.7(in)-313.4(a)-307.5(third)-311(of)-313.2(cancer)-310.7(patients)-316.6(\(19\),)-313(and)-309.7(promote)-309.7(NRF2)]TJ
0 -1.1116 TD
[(activation)-245.4(and)-234.9(the)-240.7(growth)-238(of)-238.3(cancer)-241.6(cells)-244(\(92\).)-238.2(Accumulation)]TJ
T*
[(of)-203.8(NRF2)-202(in)-203.9(cancer)-201.3(cells)-209.5(is)-198(often)-202.6(a)-203.8(poor)-200.2(prognosis)-205.5(indicator,)-206.1(as)]TJ
0 -1.1174 TD
[(NRF2)-184.7(protects)-189.7(against)-188.7(oxidative)-185.4(stress)-185.8(and)-188.8(promotes)-183.9(anabolic)]TJ
0 -1.1116 TD
[(metabolism,)-393.8(leading)-396.2(to)-388.2(a)-393.9(favorable)-393.6(environment)-396(for)-394.9(tumor)]TJ
T*
[(growth.)-183.8(Furthermore,)-186(it)-181(has)-188.6(been)-179.5(shown)-184.7(that)-184.4(NRF2)-184.7(serves)-187.1(as)-181.7(a)]TJ
T*
[(protective)-245.3(agent)-249.9(against)-240.5(chemotherapy)-249.6(and)-246.4(radiotherapy)-247.3(\(30,)]TJ
0 -1.1174 TD
[(114,)-352.3(115\).)-353.4(The)-351.2(importance)-355.8(of)-353.5(KEAP1)-353.9(in)-347.9(controlling)-353.6(NRF2)]TJ
0 -1.1116 TD
[(activation)-435.5(is)-428.4(further)-429.4(highlighted)-428.5(by)-428.4(the)-430.8(early)-428.4(postnatal)-432.9(le-)]TJ
T*
[(thality)-303.1(of)-301.7(mice)-301.8(decient)-300.4(in)-301.8(KEAP1,)-299.7(which)-301.4(present)-303.7(with)-299.3(ele-)]TJ
0 -1.1174 TD
[(vated)-480.3(NRF2)-478.4(target)-481.5(gene)-479(expression)-479.6(and)-476.8(NRF2-dependent)]TJ
0 -1.1116 TD
[(hyperkeratosis)-283.7(of)-284.4(the)-281.1(esophagus)-282.6(and)-280.9(forestomach)-287.4(\(134\).)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 62.022 94.9039 Tm
[(NRF2)-338.2(activation)-333.9(by)-332.7(competitive)-335.5(binding)]TJ
/F5 1 Tf
9.843 0 0 9.843 72 78.463 Tm
.0123 Tc
[(Act)5.3(i)-.4(vati)5.3(on)-438.1(of)-438(NRF)5.6(2)-438.1(is)-437.9(no)5.4(t)-443.9(l)5.3(imit)5.3(ed)-438(t)5.3(o)-443.8(p)5.4(o)-.3(s)5.6(ttr)5.5(an)5.4(sl)5.3(ati)5.3(o)-.3(n)5.4(a)-1.5(l)]TJ
-1.0137 -1.1116 TD
.013 Tc
[(m)4.9(odi)6(c)5(at)6(ion)6.1(s)-419.9(of)-420(K)5.3(E)-.8(A)5.3(P).5(1)-420.1(o).4(r)-420(c)5(an)6.1(ce)5(r)-420(m)-.8(u)6.1(t).3(a)5(tio)6.1(ns)6.3(.)-422.4(N)-.5(R)5.1(F).6(2)-420.1(c)5(an)]TJ
T*
.0121 Tc
[(be)-295.4(tr)5.3(an)5.2(slo)5.2(c)-1.7(ated)-300(t)5.1(o)-300(t)5.1(h)-.5(e)-301.2(n)5.2(ucleus)-294.1(due)-295.4(to)-294.3(co)5.2(mp)5.2(et)5.1(it)5.1(ive)-295.4(N)-1.4(RF2)-294.3(o)-.5(r)]TJ
25.504 36.8045 TD
[(KEAP1)-409.4(b)5.3(in)5.3(di)5.2(ng)-409.4(by)-409.4(o)5.3(t)-.5(h)5.3(e)-1.6(r)-409.3(p)5.3(rot)5.2(ei)5.2(ns)5.5(.)-411.7(O)-1.3(n)5.3(e)-410.5(su)5.3(ch)-409.3(competi)5.2(tiv)5.3(e)]TJ
0 -1.1116 TD
[(bin)5.2(d)-.5(er)-340.3(is)-340.1(cyclin)5.2(-d)5.2(ep)5.2(en)5.2(den)5.2(t)-340.5(ki)5.1(nase)-341.5(i)5.1(nhi)5.1(bi)5.1(to)5.2(r)-340.3(1)-.5(,)-336.9(o)-.5(r)-340.3(p)-.5(2)5.2(1)-.5(.)-336.9(T)-1.7(h)5.2(e)]TJ
T*
[(KRR)-226.2(d)-.5(o)5.2(m)-1.7(ain)-225.1(o)-.5(f)-225.1(p21)-225.1(bi)5.1(nd)5.2(s)-230.7(t)-.6(h)5.2(e)-232.1(DLG)-226(m)-1.7(o)5.2(tif)-225.1(of)-225.1(NRF2,)-227.5(t)5.1(hereb)5.2(y)]TJ
0 -1.1174 TD
.0117 Tc
[(prevent)4.7(ing)-398.3(K)4(EAP1)-398.3(fro)4.8(m)-399.6(t)-1(arge)]TJ
12.8038 0 TD
[(ti)4.7(ng)-398.3(NRF2)-398.3(fo)4.8(r)-404.1(p)4.8(ro)4.8(teaso)4.8(m)-2.1(al)]TJ
-12.8038 -1.1116 TD
.0122 Tc
[(deg)5.3(r)-.4(adati)5.2(o)-.4(n)-196.2(\()-.4(2)5.3(2\).)-192.8(As)-196.1(a)-203.2(p)5.3(ri)5.2(mary)-196.2(targ)5.3(et)-196.4(fo)5.3(r)-202(p)5.3(53)-196.2(acti)5.2(vi)5.2(ty)5.3(,)-198.6(p)-.4(2)5.3(1)-202(i)5.2(s)]TJ
T*
.0131 Tc
[(cri)6.1(t).4(i)6.1(c)-.7(a)5.1(l)-327.9(fo)6.2(r)-327.8(m)5(ed)6.2(iat)6.1(i).4(n)6.2(g)-327.8(th)6.2(e)-329(c)5.1(el)6.1(lu)6.2(lar)-322(r).5(e)5.1(s).7(po)6.2(ns)6.4(es)-327.6(t)6.1(o)-327.8(p5)6.2(3)-327.8(a)5.1(ct)6.1(iva)5.1(-)]TJ
0 -1.1174 TD
.0117 Tc
[(tio)4.8(n.)-268.2(p5)4.8(3)-271.6(p)-.9(lays)-271.4(i)4.7(m)-2.1(p)4.8(o)-.9(r)4.9(t)-1(ant)-271.8(f)-.9(u)4.8(n)-.9(cti)4.7(ons)-271.4(i)4.7(n)-271.6(th)4.8(e)-272.8(c)-2.1(ell)4.7(u)-.9(lar)-271.6(r)-.9(esp)4.8(ons)5(e)]TJ
0 -1.1116 TD
.0121 Tc
[(to)-288.5(geno)5.2(to)5.2(xi)5.1(c)-289.7(s)-.3(tr)5.3(es)5.4(s;)-288.6(h)5.2(o)-.5(wever,)]TJ
12.3603 0 TD
.0132 Tc
[(it)-287.5(i)6.2(s)-287.2(be)5.2(co)6.3(mi)6.2(ng)-287.4(m)5.1(o).6(r)6.4(e)-288.6(ap)6.3(pre)5.2(ci)6.2(-)]TJ
-12.3603 -1.1116 TD
.0103 Tc
[(a)-3.5(t)-2.4(ed)-342.1(tha)-3.5(t)-342.3(p53)-342.1(a)2.3(lso)-342.1(p)3.4(lays)-341.9(a)-343.3(c)2.3(ritica)-3.5(l)-342.3(r)3.5(ole)-337.5(i)-2.4(n)-342.1(r)-2.3(egulating)-342.1(m)-3.5(eta-)]TJ
0 -1.1174 TD
.0118 Tc
[(bol)4.8(ic)-272.7(homeo)4.9(st)4.8(as)5.1(is)-277.1(\(1)4.9(2\))5(.)-279.6(I)5(nd)4.9(eed,)-273.8(DNA)-278.2(d)-.8(amagi)4.8(n)-.8(g)-277.3(a)3.8(gent)4.8(s)-277.1(c)-2(an)]TJ
0 -1.1116 TD
.0122 Tc
[(pro)5.3(mo)5.3(te)-566(NRF)5.5(2)-564.9(st)5.2(ab)5.3(il)5.2(izati)5.2(o)-.4(n)-564.9(a)4.2(nd)-559.1(trans)5.5(c)-1.6(ri)5.2(pt)5.2(io)5.3(nal)-565(a)-1.6(cti)5.2(v)-.4(it)5.2(y)]TJ
T*
.0127 Tc
[(thr)5.9(o).1(u)5.8(g).1(h)-345.5(p53)5.8(-i)5.7(nd)5.8(uced)-345.5(p21)-345.5(ex)5.8(pr)5.9(ess)6(i)0(o)5.8(n)-351.3(\()5.9(21\))5.9(.)-347.8(T)-1.1(h)5.8(e)-352.4(r)5.9(o).1(l)5.7(e)-352.4(of)-345.5(th)5.8(e)]TJ
T*
.0121 Tc
[(p21)5.2(-NRF)5.4(2)-207.9(a)-1.7(x)5.2(i)-.6(s)-207.7(i)5.1(n)-207.9(t)-.6(h)5.2(e)-209(co)5.2(nt)5.1(rol)-202.2(of)-207.8(met)5.1(a)-1.7(b)5.2(o)-.5(li)5.1(sm)-209.1(b)5.2(y)-207.9(p)5.2(5)-.5(3)-207.9(r)-.5(emain)5.2(s)]TJ
0 -1.1174 TD
.0124 Tc
[(to)-276.7(be)-277.8(expl)5.4(or)5.6(ed)5.5(.)]TJ
1.0137 -1.1116 TD
0 Tc
[(Another)-585.8(competitive)-593.3(KEAP1)-584.3(binder)-589.6(is)-583.9(the)-586.3(autophagy)]TJ
-1.0137 -1.1116 TD
[(adapt)-8(or)-353.5(sequestosome)-357.3(1)-352.4(\(p62\))-356.8(\(59\).)-353.4(Autophagy)-357.7(is)-353.5(the)-355.9(cata-)]TJ
0 -1.1174 TD
[(bolic)-306.4(process)-309.1(that)-305.3(cells)-307.4(undergo)-308.3(to)-301.8(break)-307.3(down)-304.8(proteins)-309.5(and)]TJ
0 -1.1116 TD
[(intracellul)-10.5(ar)-285.5(organelles)-291(to)-284.6(maintain)-289.2(cellular)-289.1(homeostasis,)-289.5(re-)]TJ
T*
[(move)-243(buildup)-244.1(of)-238.3(toxic)-243.1(substances,)-247.9(and)-240.6(sustain)-244.9(metabolism)-240.6(in)]TJ
0 -1.1174 TD
[(extreme)-248.7(instances.)-247.1(While)-245.3(in)-244.2(normal)-239.5(tissues)-250.5(autophagy)-242.8(serves)]TJ
0 -1.1116 TD
[(to)-399.7(promote)-401.9(overall)-407.7(survival,)-399.3(autophagy)-404(can)-397.3(be)-400.8(both)-402(tumor)]TJ
T*
[(promoting)-472.2(and)-465.2(tumor)-473.4(suppressive)-469(\(106,)-468.6(140,)-467.5(142\).)-468.6(It)-463.1(has)]TJ
T*
[(previously)-375.1(been)-375.3(demonstrated)-375.1(that)-374.5(hypoxic)-371.9(tumor)-369.7(environ-)]TJ
0 -1.1174 TD
[(ments)-203.7(have)-208.3(higher)-203.7(basal)-203.6(autophagy)-202.4(levels)-204.8(than)-201.5(normal)-204.9(tissues)]TJ
0 -1.1116 TD
[(\(49\),)-341.8(thereby)-344.2(promoting)-339.7(tumor)-340.9(cell)-341.1(survival,)-341.7(tumor)-340.9(growth,)]TJ
T*
[(and)-505.6(metastasis.)-502.8(In)-503.3(a)-497.6(mouse)-503(model)-497.6(of)-503.3(K-Ras-driven)-506.9(lung)]TJ
0 -1.1174 TD
[(cancer,)-268.1(autophagy)-260(deciency)-268(caused)-263.3(by)-261.4(the)-258(deletion)-265(of)-261.4(Atg7)]TJ
0 -1.1116 TD
[(gene)-312(resulted)-316.4(in)-307.6(induction)-311(of)-307.4(p53,)-312(cell)-312.2(cycle)-314.4(arrest,)-311.7(and)-309.7(cell)]TJ
T*
[(death)-468.7(\(36\).)-468.5(While)-464.2(the)-471.1(ability)-464.4(of)-462.9(autophagy)-473.2(to)-463.1(fuel)-466.4(tumor)]TJ
0 -1.1174 TD
[(growth)-399.2(has)-390.2(been)-398.4(well)-392.6(established,)-399.2(recent)-396.1(data)-398.5(suggest)-394.5(that)]TJ
0 -1.1116 TD
[(diminished)-434.1(autophagy)-427.1(may)-426.2(also)-431.7(promote)-430.7(tumorigenesis)-426.8(in)]TJ
T*
[(certain)-293.6(contexts.)-291.1(p62)-291.3(selectively)-293.6(ags)-287.4(targets)-292.3(for)-291.2(autophagic)]TJ
0 -1.1174 TD
[(degradation)-349.9(but)-337.5(accumulates)-347.5(in)-342.2(situations)-340.6(of)-342(autophagy)-340.7(de-)]TJ
0 -1.1116 TD
[(ciency.)-285.3(The)-282.1(Keap1)-279.4(interacting)-286.8(region)-278.6(of)-284.4(p62)-274(competitiv)-9.3(ely)]TJ
ET
q
336.928 0 0 281.82 64.006 450.198 cm
/Im1 Do
Q
BT
/F7 1 Tf
9.845 0 0 9.845 411.3636 722.551 Tm
[(FI)20.1(G.)-777.2(1.)-977.6(Me)17.7(ch)14.3(an)21.2(is)21(m)-785.1(o)0(f)-779.4(N)0(R)19.4(F)0(2)]TJ
0 -1.0135 TD
[(tr)19.9(an)21.2(sc)20.1(ri)13.9(pt)21.2(io)20.9(na)21.2(l)-582.8(a)0(c)19.9(t)0(i)20.9(v)0(a)21.1(t)0(i)15.1(o)0(n)21.2(.)]TJ
/F5 1 Tf
11.7935 0 TD
[(Mu)20.2(lt)20.7(i-)]TJ
-11.7935 -1.0077 TD
[(pl)20.9(e)-485.9(s)0(i)21(g)0(n)15.3(a)0(l)19.7(s)-484.5(me)18.7(di)20.9(at)19.7(e)-485.9(N)0(R)19.2(F)0(2)-479.8(n)0(u)21.1(c)0(l)19.7(e)0(a)18.7(r)]TJ
0 -1.0135 TD
[(ac)18.7(cu)19.9(mu)19.9(la)19.7(ti)20.7(on)15.3(.)-659.9(I)0(n)-658.5(t)0(h)20.9(e)-664.4(ba)14.1(sa)20.1(l)-663.4(s)0(t)21(a)0(t)13.9(e)0(,)]TJ
T*
[(KE)19.1(AP)20.4(1)-496.2(b)0(i)20.9(n)0(d)15.3(s)-496.1(NR)19.2(F2)-485.5(an)19.9(d)-502(l)0(e)19.7(a)0(d)19.9(s)-496.1(to)]TJ
T*
[(CU)19.2(L3)19.9(-m)19.9(ed)19.9(ia)19.7(te)13.9(d)-306.2(N)0(R)19.2(F)0(2)-301.3(d)0(e)19.9(g)0(r)21(a)0(d)19.9(a)0(t)19.7(i)0(o)15.1(n)0(.)]TJ
0 -1.0078 TD
[(Fo)21.2(ll)20.7(ow)20.2(in)15.1(g)-1003(o)0(x)21.1(i)0(d)20.9(a)0(t)19.7(i)0(v)15.1(e)-1004.2(st)21(re)19.9(ss)-997.9(an)19.9(d)]TJ
0 -1.0135 TD
[(fu)21(ma)18.7(ra)19.9(te)19.7(-m)19.9(ed)14.1(ia)19.7(te)19.7(d)-225.6(m)0(o)19.9(d)0(i)20.9()0(c)20.1(a)0(t)19.7(i)0(o)20.9(n)0(,)-217.4(t)0(h)20.9(e)]TJ
T*
[(cy)19.9(st)21(ei)19.7(ne)-648.1(re)19.9(si)21(du)21.1(es)-642.2(on)-646.9(KE)19.1(AP)20.4(1)-651.7(a)0(r)19.9(e)]TJ
T*
[(al)19.7(te)19.7(re)19.9(d,)-309.6(le)19.7(ad)19.9(in)20.9(g)-317.7(t)0(o)-307.4(a)-313.1(co)19.9(nf)15.3(or)21(ma)18.7(ti)20.7(on)21.1(al)]TJ
0 -1.0077 TD
[(ch)19.9(an)19.9(ge)-348.7(an)19.9(d)-358(K)0(E)19.1(A)0(P)20.4(1)-358(sa)14.3(tu)20.9(ra)19.9(ti)20.7(on)21.1(.)-360.4(p)0(2)21.1(1)]TJ
0 -1.0135 TD
[(bi)20.9(nd)21.1(s)-283(t)0(o)-272.8(t)0(h)20.9(e)-284.3(DL)19.1(G)-284(a)0(n)19.9(d)-283.2(EG)19.1(TE)-275(mo)19.9(ti)20.7(fs)]TJ
T*
[(in)-1234.5(NR)19.2(F2)21.2(,)-1247.2(t)0(h)20.9(e)0(r)19.9(e)0(b)19.9(y)-1244.8(pr)15.3(ev)19.9(en)19.9(ti)20.7(ng)]TJ
0 -1.0077 TD
[(KE)19.1(AP)20.4(1)-738.1(a)0(s)20.1(s)0(o)15.5(c)0(i)19.7(a)0(t)19.7(i)0(o)20.9(n)0(.)-729.9(P)0(T)20.1(M)0(A)-729.2(p)0(o)21(s)0(-)]TJ
0 -1.0135 TD
[(se)20.1(ss)21.4(es)-423.4(a)-434.1(D)0(L)19.1(G)-428(mo)19.9(ti)20.7(f)-432.9(a)0(n)19.9(d)-432.9(co)19.9(mp)19.9(et)19.7(es)]TJ
T*
[(fo)21(r)-582.6(K)0(E)19.1(A)0(P)20.4(1)-576.9(bi)20.9(nd)15.3(in)20.9(g,)-568.7(th)20.9(er)19.9(eb)19.9(y)-582.6(p)0(r)21.1(e)0(-)]TJ
T*
[(ve)19.9(nt)20.9(in)20.9(g)-340.7(N)0(R)19.2(F)0(2)-324.3(u)0(b)15.3(i)0(q)20.9(u)0(i)20.9(t)0(i)20.7(n)0(a)19.9(t)0(i)14.9(o)0(n)21(.)-337.4(Si)21(mi)19.7(-)]TJ
0 -1.0077 TD
[(la)19.7(rl)20.9(y,)-499.6(PA)20.4(LB)18.9(2)-513.5(p)0(o)21.1(s)0(s)21.4(e)0(s)20.1(s)0(e)14.3(s)-507.6(an)-498.4(ET)18.7(GE)]TJ
0 -1.0135 TD
[(mo)19.9(ti)20.7(f.)-499.6(Co)20.1(ns)21.2(eq)19.9(ue)14.1(nt)20.9(ly)20.9(,)-510.1(K)0(E)19.1(A)0(P)20.4(1)-507.8(ca)18.7(n-)]TJ
T*
[(no)21.1(t)-536.7(p)0(r)21.1(o)0(m)19.9(o)0(t)20.9(e)-537.7(NR)19.2(F2)-525.8(ub)21(iq)15.1(ui)20.9(ti)20.7(na)19.9(ti)20.7(on)15.3(,)]TJ
T*
[(le)19.7(ad)19.9(in)20.9(g)-404.1(t)0(o)-393.7(K)0(E)19.1(A)0(P)20.4(1)-404.1(sa)20.1(tu)20.9(ra)19.9(ti)20.7(on)15.3(.)-400.7(S)0(u)21.2(b)0(-)]TJ
0 -1.0077 TD
[(se)20.1(qu)21(en)19.9(tl)14.9(y,)-240.5(ne)19.9(wl)20.1(y)-254.4(t)0(r)20.9(a)0(n)14.1(s)0(l)21.1(a)0(t)19.7(e)0(d)-245(N)0(R)19.2(F)0(2)-243.7(i)0(s)]TJ
0 -1.0135 TD
[(un)21.1(bo)21(un)21.1(d)-789.9(b)0(y)-779.4(K)0(E)19.1(A)0(P)20.4(1)-789.9(an)19.9(d)-789.9(t)0(r)20.9(a)0(n)19.9(s)0(-)]TJ
T*
[(lo)20.9(ca)18.7(te)19.7(s)-605.5(t)0(o)-595.3(t)0(h)20.9(e)-601.1(nu)21.1(cl)14(eu)19.9(s,)-591.6(bi)20.9(nd)21.1(s)-605.5(t)0(h)20.9(e)]TJ
0 -1.0077 TD
[(AR)19.2(E)-388(t)0(o)20.9(g)0(e)19.9(t)0(h)20.9(e)0(r)-377.5(w)0(i)20.1(t)0(h)-382.2(s)0(m)20.1(a)0(l)19.7(l)-387(Ma)19.1(f)-386.8(p)0(r)21(o)0(-)]TJ
0 -1.0135 TD
[(te)19.7(in)20.9(s,)-643.4(an)14.1(d)-651.7(a)0(c)18.7(t)0(i)20.7(v)0(a)19.9(t)0(e)13.9(s)-651.5(ta)19.7(rg)15.3(et)-642.5(ge)19.9(ne)19.9(s.)]TJ
T*
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