TY  - GEN
A1  - Dvornikov, Dmytro
N2  - N?n-sm?ll-cell lung c?ncer (NSCLC) ?s the le?d?ng c?use ?f c?ncer-rel?ted m?rt?l?t?es w?rldw?de. NSCLC c?n be further subd?v?ded ?n lung ?den?c?rc?n?m? (LU?D) ?nd lung squ?m?us cell c?rc?n?m? (LUSC). Elev?ted levels ?f the Tr?nsf?rm?ng Gr?wth F?ct?r bet? (TGF?) l?g?nd c?rrel?te w?th ? ???r surv?v?l ?f lung c?ncer ??t?ents. H?wever, the underl??ng mech?n?sms c?ntr?but?ng t? the ?r?-tum?r?gen?c effects ?f TGF? s?gn?l tr?nsduct??n ?n lung c?ncer ?re ???rl? underst??d.
F?rst, the ?ct?v?t??n st?tus ?f the TGF? s?gn?l tr?nsduct??n w?s ex?m?ned ?t the ?r?te?n ?nd mRN? level ?n tum?r t?ssue ?f lung c?ncer ??t?ents. Th?s ?n?l?s?s reve?led th?t the c?m??nents ?f the TGF? ??thw?? were subst?nt??ll? ?ct?v?ted ?n hum?n lung c?ncer t?ssue w?th c?nc?m?t?nt e??genet?c s?lenc?ng ?f ? neg?t?ve regul?t?r ?f the TGF? ??thw??, the dec?? ?seud?rece?t?r B?MB?. Rec?nst?tut??n ?f B?MB? ?n NSCLC cells decre?sed TGF?-?nduced Sm?d2/3 ?h?s?h?r?l?t??n ?nd TGF?-?nduced ?n v?tr? cell m?gr?t??n ?nd ?nv?s??n. Furtherm?re, B?MB? rec?nst?tut??n reduced the ?n v?v? met?st?t?c ??tent??l ?f NSCLC cell l?nes ?s ?ssessed b? ? m?use lung c?l?n?z?t??n ?ss??. These results dem?nstr?ted th?t the l?ss ?f the neg?t?ve regul?t?r B?MB? ?r?m?tes the ?ct?v?t??n ?f the TGF? ??thw?? ?s well ?s TGF?-dr?ven ?nv?s?veness ?f lung tum?rs.
Sec?nd, m?lecul?r c?m??nents c?ntr?but?ng t? TGF?-?nduced lung c?ncer ?r?gress??n were ?nvest?g?ted. The d?n?m?cs ?f gene ex?ress??n ?n TGF?-tre?ted LUSC cells w?s ?ssessed b? next-gener?t??n mRN? sequenc?ng. The ex?m?n?t??ns reve?led u?-regul?t??n ?f m?t?l?t?- ?nd ?ct?n c?t?skelet?n-rel?ted genes ?nclud?ng the n?n-muscle m??s?n 10 (MYO10). Kn?ckd?wn ?f MYO10 ?br?g?ted TGF?-?nduced c?ll?gen gel ?nv?s??n ?f LUSC cells. Ex?m?n?t??n ?f mRN? ex?ress??n ?n ???red surg?c?ll? resected t?ssues ?f LUSC ??t?ents sh?wed th?t the mRN? ex?ress??n r?t?? ?f MYO10 ?n tum?r ?nd tum?r-free t?ssue ?s ?r?gn?st?c f?r ??t?ent ?ver?ll surv?v?l ?nd f?c?l?t?tes the ?red?ct??n ?f the res??nse ?f these ??t?ents t? ?djuv?nt chem?ther???.
H?v?ng est?bl?shed th?t the TGF? s?gn?l tr?nsduct??n ??thw?? ?s deregul?ted ?n lung c?ncer, ?t ?s ?m??rt?nt t? underst?nd h?w the d?n?m?c ?r??ert?es ?f the ??thw?? ?re c?ntr?lled. The ?n?l?s?s ?f TGF?-?nduced s?gn?l tr?nsduct??n ?n three LU?D cell l?nes sh?wed ? d?st?nct d?n?m?c beh?v??r ?f the TGF?-?nduced Sm?d2/3 ?h?s?h?r?l?t??n ?nd ? d?fferent??l ?m??ct ?f ?nh?b?t?r ?erturb?t??ns. These results suggested ? d?fferent ?rev?lence ?f neg?t?ve feedb?cks th?t ?nduce the degr?d?t??n ?f the TGF? rece?t?r ?r reduce ?ts ?b?l?t? t? ?h?s?h?r?l?te Sm?ds ?n the ex?m?ned cell l?nes. The m?del-b?sed ?n?l?s?s ?red?cted th?t the TGF? rece?t?r ?r?te?n underg?es c?nst?nt turn?ver: the unst?ble rece?t?r ?r?te?n ?s c?nst?ntl? degr?ded ?nd ?r?duced ?g??n fr?m the st?ble rece?t?r mRN?. H?gh st?b?l?t? ?f the TGF? rece?t?r mRN? w?s c?nf?rmed b? mRN? h?lf-l?fe ?n?l?s?s, wh?le the ?ccumul?t??n ?f the TGF? rece?t?r ?r?te?n u??n ?nh?b?t??n ?f the ?r?te?s?me funct??n w?s v?l?d?ted us?ng t?rgeted qu?nt?t?t?ve m?ss s?ectr?metr?. These f?nd?ngs h?ghl?ghted th?t the TGF? rece?t?r ?s ?ne ?f the m?st sens?t?ve n?des th?t c?ntr?ls ??thw?? ?ct?v?t??n. Theref?re, t?rget?ng ?r?cesses th?t c?ntr?l rece?t?r ?bund?nce r?ther th?n us?ng c?nvent??n?l TGF? rece?t?r k?n?se ?nh?b?t?rs c?uld be ? ?r?m?s?ng ther??eut?c ???r??ch.
T?ken t?gether, the ?resented w?rk ?r?v?des ?ns?ghts ?nt? m?lecul?r ?lter?t??ns th?t c?use TGF? ??thw?? deregul?t??n, suggests new ??tent??l b??m?rkers ?nd sh?wc?ses the ??tent??l ?f the m?them?t?c?l m?del?ng ???r??ch c?mb?ned w?th qu?nt?t?t?ve ex?er?ments t? unc?ver gener?l ?r?nc??les ?f cell t??e-s?ec?f?c regul?t??n ?f TGF?-?nduced Sm?d2/3 ?h?s?h?r?l?t??n ?n lung c?ncer cell l?nes.
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/23804/
ID  - heidok23804
Y1  - 2017///
AV  - public
TI  - Tr?nsf?rm?ng Gr?wth F?ct?r bet? s?gn?l?ng ?n lung c?ncer: m?lecul?r ?lter?t??ns, b??m?rkers ?nd n?vel regul?t?r? mech?n?sms reve?led b? m?them?t?c?l m?del?ng
ER  -