detection-alternative-splicing-during-epithelial-mesenchymal

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition

Alternative splicing plays a critical role in the epithelial-mesenchymal transition (EMT), an essential cellular program that occurs in various ...

Northwestern University Feinberg School of Medicine

Hepatitis C virus (HCV) binds to apolipoprotein B (ApoB) and low-density lipoprotein (LDL) before entering into hepatocytes. ApoB promoter polymorphisms influence the levels of ApoB and LDL in blood. We investigated the correlations between ApoB promoter polymorphism and HCV infection.

Association of functional polymorphism of ApoB promoter with hepatitis C virus infection.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer deaths globally. Chronic hepatitis B virus (HBV) infection accounts for over 75% of all HCC cases; however, the molecular pathogenesis of HCC is not well understood. In this study, we found that the expression of the newly identified gene melanoma inhibitory activity 2 (MIA2) was reduced by HBV infection in vitro and in vivo, and that HBV X protein (HBx) plays a major role in this regulation. Recent studies have revealed that MIA2 is a potential tumor suppressor, and that, in most HCCs, MIA2 expression is down-regulated or lost. We found that the knock-down of MIA2 in HepG2 cells activated cell growth and proliferation, suggesting that MIA2 inhibits HCC cell growth and proliferation. In addition, the over-expression of HBx alone induced cell proliferation, whereas MIA2 over-expression impaired the HBx-mediated induction of proliferation. Taken together, our results suggest that HBx activates hepatoma cell growth and proliferation through repression of the potential tumor suppressor MIA2.

The X protein of hepatitis B virus activates hepatoma cell proliferation through repressing melanoma inhibitory activity 2 gene.

Carcinome h&eacute;patocellulaire (CHC) est la quatri&egrave;me cause de d&eacute;c&egrave;s par cancer dans le monde. L&#39;infection chronique h&eacute;patite B (VHB) repr&eacute;sente plus de 75 % de tous les cas de CHC ; Toutefois, la pathogen&egrave;se mol&eacute;culaire de la HCC n&#39;est pas bien comprise. Dans cette &eacute;tude, nous avons constat&eacute; que l&#39;expression de l&#39;activit&eacute; inhibitrice du m&eacute;lanome g&egrave;ne nouvellement identifi&eacute; 2 (MIA2) a &eacute;t&eacute; r&eacute;duite par l&#39;infection par le VHB in vitro et in vivo, et que la prot&eacute;ine X HBV (HBx) joue un r&ocirc;le majeur dans le pr&eacute;sent r&egrave;glement. Des &eacute;tudes r&eacute;centes ont r&eacute;v&eacute;l&eacute; que le MIA2 est un suppresseur de tumeur potentiel, et que, dans la plupart HSSC, MIA2 expression est perdues ou diminu&eacute;es. Nous avons trouv&eacute; que la pr&eacute;cipitation de MIA2 dans les cellules HepG2 activ&eacute; la croissance cellulaire et la prolif&eacute;ration, ce qui sugg&egrave;re que le MIA2 inhibe la prolif&eacute;ration et la croissance des cellules HCC. En outre, la sur-expression de HBx seul induit la prolif&eacute;ration cellulaire, alors que la surexpression de MIA2 avec facult&eacute;s affaiblies de l&#39;induction par HBx de prolif&eacute;ration. Ensemble, nos r&eacute;sultats sugg&egrave;rent que HBx active la croissance de cellules de tumeur h&eacute;patique et prolif&eacute;ration par l&#39;interm&eacute;diaire de r&eacute;pression contre le suppresseur de tumeur potentiel MIA2.

La prot&eacute;ine X du virus de l&#39;h&eacute;patite B active la prolif&eacute;ration cellulaire par le biais de r&eacute;primant le g&egrave;ne de l&#39;activit&eacute; inhibitrice 2 m&eacute;lanome h&eacute;patome.

Carcinoma epatocellulare (HCC) &egrave; la quarta principale causa di decessi per cancro a livello mondiale. Infezione da epatite cronica B virus (HBV) rappresenta oltre il 75% dei casi di HCC; Tuttavia, la patogenesi molecolare della HCC non &egrave; ben compreso. In questo studio, abbiamo trovato che l&#39;espressione dell&#39;attivit&agrave; inibitoria di melanoma gene recentemente identificata 2 (MIA2) &egrave; stato ridotto di infezione da HBV in vitro e in vivo, e tale proteina X HBV (HBx) svolge un ruolo importante in questo regolamento. Recenti studi hanno rivelato che MIA2 &egrave; un soppressore del tumore di potenziale, e che, nella maggior parte dei HCCs, espressione MIA2 &egrave; down-regolato o perso. Abbiamo trovato che il knock-down di MIA2 nelle cellule HepG2 attiva crescita cellulare e la proliferazione, suggerendo che MIA2 inibisce la proliferazione e la crescita di cellule HCC. Inoltre, la sovraespressione di HBx solo indotta da proliferazione cellulare, mentre MIA2 sovraespressione ha alterato l&#39;induzione della proliferazione HBx-mediata. Presi insieme, i nostri risultati suggeriscono che HBx attiva crescita di cellule di epatoma e proliferazione attraverso la repressione del potenziale soppressore tumorale MIA2.

La proteina X del virus dell&#39;epatite B attiva la proliferazione di cellule di epatoma attraverso reprimendo gene attivit&agrave; inibitoria 2 melanoma.

&#x4E0A;&#x76AE;-&#x95F4;&#x5145;&#x8D28;&#x7EC6;&#x80DE;&#x8F6C; (EMT) &#x76D1;&#x7BA1;&#x4E25;&#x5BC6;&#x7684;&#x8FC7;&#x7A0B;&#xFF0C;&#x662F;&#x53D1;&#x5C55;&#x7684;&#x5173;&#x952E;&#x662F;&#x7ECF;&#x5E38;&#x91CD;&#x65B0;&#x542F;&#x52A8;&#x671F;&#x95F4;&#x764C;&#x75C7;&#x8F6C;&#x79FB;&#x548C;&#x590D;&#x53D1;&#x3002;&#x6211;&#x4EEC;&#x4EE5;&#x524D;&#x62A5;&#x9053; CD44 &#x9F3B;&#x606F;&#x8089;&#x5207;&#x6362;&#x662F;&#x5173;&#x952E;&#x7684; EMT &#x548C;&#x663E;&#x793A; ESRP1 &#x7684;&#x526A;&#x63A5;&#x56E0;&#x5B50;&#x6291;&#x5236;&#x5207;&#x6362;&#x671F;&#x95F4; EMT CD44 &#x5F02;&#x6784;&#x4F53;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x5176;&#x4E2D; ESRP1 &#x89C4;&#x7BA1;&#x671F;&#x95F4; EMT &#x673A;&#x5236;&#x5C1A;&#x672A;&#x5145;&#x5206;&#x4E86;&#x89E3;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x8868;&#x660E;&#xFF0C;&#x8717;&#x725B;&#x7ED1;&#x5B9A;&#x5230; E &#x6846;&#x5728; ESRP1 &#x542F;&#x52A8;&#x5B50;&#xFF0C;&#x5BFC;&#x81F4;&#x9547;&#x538B;&#x7684; ESRP1 &#x57FA;&#x56E0;&#x7684;&#x8F6C;&#x5F55;&#x963B;&#x904F;&#x7269;&#x3002;&#x751F;&#x5316;&#xFF0C;&#x6211;&#x4EEC;&#x5B9A;&#x4E49;&#x7684; ESRP1 &#x8C03;&#x8282; CD44 &#x526A;&#x63A5;&#x7684;&#x673A;&#x5236;&#xFF1A; ESRP1 &#x5C06;&#x7ED1;&#x5B9A;&#x5230;&#x4FA7;&#x7FFC; CD44 &#x53EF;&#x53D8;&#x5916;&#x663E;&#x5B50;&#x5185;&#x542B;&#x5B50;&#x533A;&#x57DF;&#x548C;&#x5BFC;&#x81F4;&#x589E;&#x52A0;&#x53EF;&#x53D8;&#x5916;&#x663E;&#x5B50;&#x5217;&#x5165;&#x3002;&#x6211;&#x4EEC;&#x8FDB;&#x4E00;&#x6B65;&#x663E;&#x793A; ectopically &#x8868;&#x793A; ESRP1 &#x6291;&#x5236;&#x9489;&#x87BA;&#x8BF1;&#x5BFC;&#x7684; EMT&#xFF0C;&#x6697;&#x793A;&#x8BE5;&#x4E0B;&#x8C03;&#x7684; ESRP1 &#x662F;&#x5728; EMT &#x8717;&#x725B;&#x7684;&#x529F;&#x80FD;&#x9700;&#x8981;&#x3002;&#x5728;&#x4E00;&#x8D77;&#xFF0C;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x8868;&#x660E;&#x5982;&#x4F55;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x8717;&#x725B;&#x4ECB;&#x5BFC; EMT &#x901A;&#x8FC7;&#x526A;&#x63A5;&#x56E0;&#x5B50;&#x7684;&#x8C03;&#x8282;&#x3002;

&#x8717;&#x725B;&#x538B;&#x6291;&#x62FC;&#x63A5;&#x7684;&#x7A33;&#x538B;&#x5668; ESRP1&#xFF0C;&#x4FC3;&#x8FDB;&#x4E0A;&#x76AE;-&#x95F4;&#x5145;&#x8D28;&#x7EC6;&#x80DE;&#x8F6C;&#x3002;

Epithelial-mesenchymal transition (EMT), a tightly regulated process that is critical for development, is frequently re-activated during cancer metastasis and recurrence. We previously reported that CD44 isoform switching is critical for EMT and showed that the splicing factor ESRP1 inhibits CD44 isoform switching during EMT. However, the mechanism by which ESRP1 is regulated during EMT has not been fully understood. Here we show that the transcription repressor Snail binds to E-boxes in the ESRP1 promoter, causing repression of the ESRP1 gene. Biochemically, we define the mechanism by which ESRP1 regulates CD44 alternative splicing: ESRP1 binds to the intronic region flanking a CD44 variable exon and causes increased variable exon inclusion. We further show that ectopically expressing ESRP1 inhibits Snail-induced EMT, suggesting that downregulation of ESRP1 is required for Snail's function in EMT. Together, these data reveal how the transcription factor Snail mediates EMT through regulation of a splicing factor.

Snail Represses the Splicing Regulator ESRP1 to Promote Epithelial-Mesenchymal Transition.

Transition &eacute;pith&eacute;liales-m&eacute;senchymateuse (EMT), un processus &eacute;troitement r&eacute;glement&eacute; qui est critique pour le d&eacute;veloppement, est souvent r&eacute;-au cours de la r&eacute;cidive et de m&eacute;tastases canc&eacute;reuses. Pr&eacute;c&eacute;demment, nous avons signal&eacute; que la commutation de l&#39;isoforme CD44 est critique pour EMT et ont montr&eacute; que le facteur d&#39;&eacute;pissage ESRP1 inhibe l&#39;isoforme CD44 commutation au cours de l&#39;EMT. Toutefois, le m&eacute;canisme par lequel la ESRP1 est r&eacute;glement&eacute; au cours de l&#39;EMT n&#39;a pas &eacute;t&eacute; pleinement compris. Ici, nous montrons que le r&eacute;presseur de transcription Qu&#39;escargot se lie aux E-bo&icirc;tes dans le promoteur ESRP1, causant la r&eacute;pression du g&egrave;ne ESRP1. Biochimiquement, nous d&eacute;finissons le m&eacute;canisme par lequel les ESRP1 r&eacute;gule CD44 &eacute;pissage alternatif : ESRP1 se lie &agrave; la r&eacute;gion intronic flanquant un exon variable CD44 et entra&icirc;ne l&#39;inclusion accrue exon variable. De plus, nous montrons que fa&ccedil;on ectopique exprimant ESRP1 inhibe EMT induite par l&#39;escargot, ce qui sugg&egrave;re que la diminution de ESRP1 est requis pour la fonction d&#39;escargot en EMT. Ensemble, ces donn&eacute;es r&eacute;v&egrave;lent comment le facteur de transcription escargot m&eacute;die EMT dans le r&egrave;glement d&#39;un facteur d&#39;&eacute;pissage.

Escargot r&eacute;prime l&#39;&eacute;pissage ESRP1 r&eacute;gulateur pour favoriser la Transition &eacute;pith&eacute;liale-m&eacute;senchymateuse.

Epitheliale-Mesenchymale Transition (EMT), streng geregelte Prozess wird sich entscheidend f&uuml;r Entwicklung, ist w&auml;hrend der Krebsmetastase und Wiederholung h&auml;ufig reaktiviert. Wir zuvor berichtet, dass CD44 Isoform Wechsel f&uuml;r EMT kritisch ist und zeigte, dass der Splei&szlig;en Faktor ESRP1 CD44 Isoform Umschalten zwischen w&auml;hrend EMT hemmt. Jedoch hat der Mechanismus, durch den ESRP1 w&auml;hrend der EMT reguliert wird, nicht vollst&auml;ndig verstanden. Hier zeigen wir, dass die Transkription-Hemmer, die Schnecke an E-Boxen in der ESRP1-Projekttr&auml;ger, die Unterdr&uuml;ckung des ESRP1-Gens verursacht bindet. Biochemisch, definieren wir den Mechanismus, durch den ESRP1 CD44 alternatives Splei&szlig;en regelt: ESRP1 bindet an der verband intronic Region Flankenangriff eine Variable CD44-Exon und verursacht erh&ouml;hte Variable Exon-Aufnahme. Weiter zeigen wir, dass ectopically Ausdruck ESRP1 Schnecke-induzierte EMT hemmt, was darauf hindeutet, dass Heraufregulation des ESRP1 ist erforderlich f&uuml;r Schneckentempo Funktion in EMT. Zusammen zeigen diese Daten, wie der Transkriptionsfaktor Schnecke EMT durch Verordnung Splei&szlig;en Faktor vermittelt.

Schnecke unterdr&uuml;ckt das Splei&szlig;en Regulator ESRP1 epitheliale-Mesenchymale Transition zu f&ouml;rdern.

Transizione epiteliale-mesenchimale (EMT), un processo strettamente regolamentato che &egrave; fondamentale per lo sviluppo, &egrave; frequentemente riattivato durante la recidiva e le metastasi del cancro. Precedentemente abbiamo segnalato che CD44 isoforma di commutazione &egrave; critica per EMT e ha mostrato che il fattore di splicing ESRP1 inibisce la isoforma CD44 commutazione durante EMT. Tuttavia, il meccanismo con cui ESRP1 &egrave; regolato durante EMT non &egrave; stato pienamente compreso. Qui vi mostriamo che il repressore della trascrizione che lumaca si lega a E-boxes in ESRP1 promotore, causando la repressione del gene ESRP1. Biochimicamente, definiamo il meccanismo mediante il quale ESRP1 regola CD44 splicing alternativo: ESRP1 si lega alla regione intronic che fiancheggiano un esone variabile CD44 e provoca esone variabile maggiore inclusione. Mostriamo ulteriormente che esprimendo ectopically ESRP1 inibisce la lumaca-indotta EMT, suggerendo che la downregulation di ESRP1 &egrave; richiesto per la funzione di lumaca in EMT. Insieme, questi dati rivelano come il fattore di trascrizione lumaca da intermediario EMT attraverso il regolamento di un fattore di splicing.

Lumaca reprime la giunzione ESRP1 regolatore per promuovere la transizione epiteliale-Mesenchymal.

&#x4E0A;&#x76AE;&#x9593;&#x8449;&#x8EE2;&#x63DB; &#xFF08;EMT&#xFF09;&#x3001;&#x958B;&#x767A;&#x306E;&#x975E;&#x5E38;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3059;&#x5805;&#x304F;&#x8ABF;&#x6574;&#x3055;&#x308C;&#x305F;&#x30D7;&#x30ED;&#x30BB;&#x30B9;&#x306F;&#x3001;&#x304C;&#x3093;&#x306E;&#x8EE2;&#x79FB;&#x304A;&#x3088;&#x3073;&#x518D;&#x767A;&#x6642;&#x306B;&#x983B;&#x7E41;&#x306B;&#x518D;&#x6D3B;&#x6027;&#x5316;&#x3067;&#x3059;&#x3002;&#x4EE5;&#x524D;&#x3001;CD44 &#x30A2;&#x30A4;&#x30BD; &#x30D5;&#x30A9;&#x30FC;&#x30E0;&#x306E;&#x5207;&#x308A;&#x66FF;&#x3048;&#x306E;&#x305F;&#x3081;&#x306E; EMT &#x91CD;&#x8981;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x5831;&#x544A;&#x3057;&#x3001;&#x30B9;&#x30D7;&#x30E9;&#x30A4;&#x30B7;&#x30F3;&#x30B0;&#x56E0;&#x5B50; ESRP1 CD44 &#x30A2;&#x30A4;&#x30BD; &#x30D5;&#x30A9;&#x30FC;&#x30E0;&#x306E; EMT &#x4E2D;&#x306B;&#x5207;&#x308A;&#x66FF;&#x3048;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x305F;&#x3060;&#x3057;&#x3001;EMT &#x4E2D;&#x3067; ESRP1 &#x304C;&#x5236;&#x7D04;&#x3055;&#x308C;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x5B8C;&#x5168;&#x306B;&#x7406;&#x89E3;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x3053;&#x3053;&#x3067;&#x79C1;&#x9054;&#x306F;&#x30AB;&#x30BF;&#x30C4;&#x30E0;&#x30EA; E-&#x30DC;&#x30C3;&#x30AF;&#x30B9;&#x306B;&#x30D0;&#x30A4;&#x30F3;&#x30C9;&#x3059;&#x308B; ESRP1 &#x907A;&#x4F1D;&#x5B50;&#x306E;&#x6291;&#x5727;&#x306E;&#x539F;&#x56E0; ESRP1 &#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x306E;&#x8EE2;&#x5199;&#x30EA;&#x30D7;&#x30EC;&#x30C3;&#x30B5;&#x30FC;&#x306F;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x751F;&#x5316;&#x5B66;&#x7684;&#x3001;&#x6211;&#x3005; &#x306F;&#x3001;ESRP1 &#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B; CD44 &#x9078;&#x629E;&#x7684;&#x30B9;&#x30D7;&#x30E9;&#x30A4;&#x30B7;&#x30F3;&#x30B0;&#x6A5F;&#x69CB;&#x3092;&#x5B9A;&#x7FA9;&#x3057;&#x307E;&#x3059;: ESRP1 CD44 &#x5909;&#x6570;&#x30A8;&#x30AF;&#x30BD;&#x30F3;&#x306B;&#x4E26;&#x3076;&#x30A4;&#x30F3;&#x30C8;&#x30ED;&#x30F3;&#x306E;&#x9818;&#x57DF;&#x306B;&#x30D0;&#x30A4;&#x30F3;&#x30C9;&#x3057;&#x3066;&#x5897;&#x52A0;&#x5909;&#x6570;&#x30A8;&#x30AF;&#x30BD;&#x30F3;&#x5305;&#x542B;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3057;&#x307E;&#x3059;&#x3002;&#x3055;&#x3089;&#x306B;&#x57F9;&#x990A; ESRP1 &#x3092;&#x8868;&#x73FE;&#x3059;&#x308B;&#x30AB;&#x30BF;&#x30C4;&#x30E0;&#x30EA;&#x8A98;&#x8D77; EMT &#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3059;&#x305D;&#x306E; ESRP1 &#x306E;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3092;&#x793A;&#x5506; EMT &#x3067;&#x30AB;&#x30BF;&#x30C4;&#x30E0;&#x30EA;&#x306E;&#x6A5F;&#x80FD;&#x304C;&#x5FC5;&#x8981;&#x3067;&#x3059;&#x3002;&#x4E00;&#x7DD2;&#x306B;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3069;&#x306E;&#x3088;&#x3046;&#x306B;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x30AB;&#x30BF;&#x30C4;&#x30E0;&#x30EA; EMT &#x30B9;&#x30D7;&#x30E9;&#x30A4;&#x30B7;&#x30F3;&#x30B0;&#x56E0;&#x5B50;&#x306E;&#x8ABF;&#x7BC0;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x4EF2;&#x4ECB;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x307E;&#x3059;&#x3002;

&#x30AB;&#x30BF;&#x30C4;&#x30E0;&#x30EA;&#x306F;&#x3001;&#x4E0A;&#x76AE;&#x9593;&#x8449;&#x8EE2;&#x63DB;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x30B9;&#x30D7;&#x30E9;&#x30A4;&#x30B7;&#x30F3;&#x30B0;&#x306E;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF;&#x306E; ESRP1 &#x3092;&#x6291;&#x5236;&#x3057;&#x307E;&#x3059;&#x3002;

Epithelial &#xC5FD; &#xC804;&#xD658; (&#xC751;&#xAE09;) &#xAC1C;&#xBC1C;&#xC744; &#xC704;&#xD55C; &#xC911;&#xC694; &#xAE34;&#xBC00; &#xD558; &#xAC8C; &#xADDC;&#xC81C; &#xD504;&#xB85C;&#xC138;&#xC2A4;&#xB294; &#xC554; &#xC804;&#xC774; &#xBC0F; &#xC7AC;&#xBC1C; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xC790;&#xC8FC; &#xB2E4;&#xC2DC;. &#xC6B0;&#xB9AC;&#xAC00; &#xC774;&#xC804;&#xC5D0; &#xBCF4;&#xACE0; CD44 isoform &#xC2A4;&#xC704;&#xCE6D;&#xC774; &#xAD6C;&#xAE09; &#xB300;&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xC694; &#xD558; &#xACE0; &#xC811;&#xD569; &#xACC4;&#xC218; ESRP1 CD44 isoform &#xAD6C;&#xAE09; &#xB300; &#xC911; &#xC804;&#xD658; &#xC5B5;&#xC81C; &#xBCF4;&#xC5EC;&#xC8FC;&#xC5C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, ESRP1 &#xC751;&#xAE09; &#xC911; &#xADDC;&#xC81C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; &#xC644;&#xBCBD; &#xD558; &#xAC8C; &#xC774;&#xD574; &#xB418;&#xC9C0; &#xC788;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xB294; &#xB2EC;&#xD33D;&#xC774; ESRP1 &#xC720;&#xC804;&#xC790;&#xC758; &#xC5B5;&#xC81C;&#xB97C; &#xC77C;&#xC73C;&#xD0A4;&#xB294; ESRP1 &#xBAA8;&#xD130;&#xC5D0; &#xC804;&#xC790; &#xC0C1;&#xC790;&#xB97C; &#xBC14;&#xC778;&#xB529;&#xD569;&#xB2C8;&#xB2E4; &#xC804;&#xC0AC; &#xC9C4;&#xC555;&#xC744; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; ESRP1 CD44 &#xB300;&#xCCB4; &#xC811;&#xD569;&#xC744; &#xC870;&#xC808; &#xD558;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC815;&#xC758; &#xD558;&#xB294; &#xD654;&#xD559;&#xC801;,: ESRP1 &#xCE21;&#xBA74; CD44 &#xBCC0;&#xC218; exon intronic &#xC9C0;&#xC5ED;&#xC5D0; &#xBC14;&#xC778;&#xB529;&#xD558;&#xACE0; &#xC99D;&#xAC00; &#xBCC0;&#xC218; exon &#xD3EC;&#xD568; &#xD558;&#xBA74;. &#xC6B0;&#xB9AC;&#xB294; &#xB354;&#xB294; &#xAD6C;&#xAE09; &#xB300; &#xB2EC;&#xD33D;&#xC774; &#xC720;&#xBC1C; &#xC5B5;&#xC81C; ectopically ESRP1 &#xD45C;&#xD604; &#xBCF4;&#xC5EC; &#xC81C;&#xC548; &#xD558;&#xB294; esrp1&#xC758; downregulation &#xADF8;&#xB294; &#xAD6C;&#xAE09; &#xB300;&#xC5D0; &#xB2EC;&#xD33D;&#xC774; &#xAE30;&#xB2A5;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC694; &#xD569;&#xB2C8;&#xB2E4;. &#xD568;&#xAED8;, &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130; &#xACF5;&#xAC1C; &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778; &#xB2EC;&#xD33D;&#xC774; &#xC811;&#xD569; &#xC694;&#xC18C;&#xC758; &#xB808; &#xADE4; &#xB808;&#xC774; &#xC158;&#xC744; &#xD1B5;&#xD574; &#xC751;&#xAE09;&#xC744; &#xC911;&#xC7AC; &#xD558;&#xB294; &#xBC29;&#xBC95;.

&#xB2EC;&#xD33D;&#xC774; &#xB204;&#xB974;&#xB294; &#xC911;&#xAC04; &#xC5FD; &#xC0C1;&#xD53C; &#xC804;&#xD658; &#xD64D;&#xBCF4; &#xC811;&#xD569; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130; ESRP1.

Transici&oacute;n epitelio-mes&eacute;nquima (EMT), un proceso regulado firmemente que es fundamental para el desarrollo, se reactiva con frecuencia durante la recidiva y met&aacute;stasis del c&aacute;ncer. Previamente inform&oacute; que la conmutaci&oacute;n de isoformas de CD44 es cr&iacute;tica para la EMT y demostr&oacute; que el factor de empalme ESRP1 inhibe la isoforma CD44 conmutaci&oacute;n durante la EMT. Sin embargo, el mecanismo por el cual se regula la ESRP1 durante la EMT no ha sido totalmente entendido. Aqu&iacute; demostramos que el represor de la transcripci&oacute;n que caracol se une a E-cajas en el promotor de ESRP1, causando la represi&oacute;n del gen ESRP1. Bioqu&iacute;micamente, definimos el mecanismo por el cual ESRP1 regula CD44 splicing alternativo: ESRP1 se une a la regi&oacute;n intronic que flanquea un ex&oacute;n variable de CD44 y causa ex&oacute;n variable mayor inclusi&oacute;n. Mostramos m&aacute;s que expresar ect&oacute;picamente ESRP1 inhibe la EMT inducida por caracol, sugiriendo que downregulation de ESRP1 es necesario para la funci&oacute;n de caracol en la EMT. Juntos, estos datos revelan c&oacute;mo el factor de transcripci&oacute;n caracol media EMT a trav&eacute;s de un factor de empalme.

Caracol reprime el empalme ESRP1 regulador para promover la transici&oacute;n epitelial-mesenquimal.

Papilloma intraductal del seno pu&ograve; assomigliare a carcinoma duttale invasivo (IDC). Lo scopo di questo studio era quello di caratterizzare caratteristiche MRI di papillomi intraductal solitario e identificare le caratteristiche che differenziano i papillomi intraductal da piccolo IDC.

Papillomi intraductal solitario del seno: caratteristiche di MRI e differenziazione dal piccolo carcinoma duttale invasivo.

Intraductal papilloma of the breast can resemble invasive ductal carcinoma (IDC). The purpose of this study was to characterize MRI features of solitary intraductal papillomas and identify features that differentiate intraductal papillomas from small IDCs.

Solitary intraductal papillomas of the breast: MRI features and differentiation from small invasive ductal carcinomas.

Papillome intracanalaire du sein peut s&#39;apparenter &agrave; carcinome canalaire infiltrant (IDC). Le but de cette &eacute;tude &eacute;tait de caract&eacute;riser les caract&eacute;ristiques de MRI des papillomes intracanalaire solitaire et identifier les caract&eacute;ristiques qui diff&eacute;rencient les papillomes intracanalaire de petits pays en d&eacute;veloppement insulaires.

Papillomes solitaires intracanalaire du sein : caract&eacute;ristiques de MRI et diff&eacute;renciation de petits carcinomes canalaires invasifs.

Imaging manifestation of mammary fibromatosis.

Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFβ signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFβ-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.

Yilin Xu

Division of Hematology/Oncology,
Department of Medicine,
Robert H. Lurie Comprehensive Cancer Center,
Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center

Northwestern University Feinberg School of Medicine

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition

Yilin Xu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Division of Hematology/Oncology,Department of Medicine,Robert H. Lurie Comprehensive Cancer Center,Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center

Northwestern University Feinberg School of Medicine

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition

Division of Hematology/Oncology,
Department of Medicine,
Robert H. Lurie Comprehensive Cancer Center,
Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center