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Grisard, Eleonora (2017) BTBD7, a gene identified with a transposon based forward genetic screening, is important for colorectal cancer metastasis. [Ph.D. thesis]

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Abstract (english)

Colorectal cancer (CRC) is the second most lethal cancer because of the metastatic spread of the primary tumor. A current hypothesis is that metastasis relies on epithelial to mesenchymal transition (EMT), which is a biological process in which epithelial cells gradually loose epithelial features to switch to a mesenchymal program. In vitro assays that select EMT cells are fundamental to perform in vitro genetic screens that select cells switched to EMT program. For instance, in vitro anoikis assay consists in growing cells in low adherence conditions (loss of cell-matrix contacts) and has been used to select more aggressive tumor cells; however, some tumor cells survive to loss of cell-matrix contacts by strengthening cell-cell contacts, which is counteracting for cells that undergo to EMT. An assay that was developed in our lab and was named Forced Single Cell Suspension Assay (fSCS) is more stringent compared to in vitro anoikis and selects for cells that undergo EMT. The non-coding part of the genome, despite having a fundamental role in regulating EMT and metastasis (e.g miRNAs) is less studied respect to the protein-coding counterpart. Transposon based screens interrogate the genome more randomly than other screens (e.g retroviral based screens). To perform an in vitro assay that permits the high-throughput screening of EMT genes, we combined fSCS with an in vitro Sleeping Beauty (SB) transposon (TN) based screen in HCT116 CRC cells. We identified a cell clone, TN4_20, that shows the following features: greatest fSCS resistance, mesenchymal morphology, expression of EMT markers (e.g. Slug ↑, Twist ↑, Vimentin ↑, E-cadherin ↓, Has-2 ↑), and the ability to generate more satellite colonies in matrigel evasion assay. Moreover, in a pilot in vivo experiment, TN4_20 intra-caecal injected mice developed distant metastases compared to control. We retrieved the genomic position of TN insertions from TN4_20 genomic DNA, and we focused on the TN insertion located within the 3’ UTR of BTBD7. We chose to study this insertion because BTBD7 is a known EMT and metastasis regulator and because, interestingly, this TN insertion locates within the predicted target site of miR-23b, a known anti-metastatic miRNA. We hypothesized and demonstrated that miR-23b targets BTBD7 gene, and our data suggest that TN insertion impairs miR-23b/BTBD7 interaction. Moreover, we demonstrated that the interaction between miR-23b and BTBD7 is important for fSCS resistance. We found that Btbd7 silencing impairs fSCS survival in HCT116 parental and in TN4_20, and that the overexpression of ectopic eGFP-Btbd7 in HCT116 parental confers fSCS resistance and the ability to generate more satellite colonies in matrigel evasion assay. Moreover, the overexpression of ectopic eGFP-Btbd7 induces the down-regulation of E-cadherin at the mRNA and protein level, and the up-regulation of Vimentin, both markers of EMT. In addition, Btbd7 overexpression up-regulates Zeb-1 transcription factor mRNA and protein levels.
In an extended version of our TN- fSCS based screen, by performing sequential rounds of fSCS in both HCT116 Parental and Piggybac (PB) TN-cells, we obtained pools of fSCS resistant cells, instead of single clones. We observed that cells that survived to each round of fSCS generated more surviving colonies and acquired a greater scattered/mesenchymal morphology. Moreover, surviving colonies after fSCS showed decreased E-cadherin expression, increased Vimentin expression and increased number of cells with EpCAM low (dim), suggesting that multiple rounds of fSCS enriches for EMT/stem-cell traits. In addition, we observed that enriched fSCS resistant cells showed increased resistance to 5-fluoro-uracil (5FU) treatment and increased in vivo metastatic potential. Finally, repeated rounds of fSCS enrich for two families of miRNAs, miR-30 and miR-302 that were already shown to regulate EMT and metastasis and that may potentially regulate fSCS resistance.

Abstract (italian)

Il tumore del colon-retto è il secondo tumore più letale a causa della diffusione metastatica della lesione primaria. Un’ipotesi attuale è che la metastasi sia basata sulla transizione epitelio-mesenchimale (in inglese EMT, epithelial to mesenchymal transition), un processo biologico in cui le cellule epiteliali perdono gradualmente i loro caratteri epiteliali per convertirsi a un programma di tipo mesenchimale. I saggi in vitro che selezionano cellule EMT sono fondamentali per poter fare screening genetici che selezionano cellule che si sono convertite al programma EMT. Ad esempio, il saggio in vitro di anoikis si basa sulla crescita delle cellule in condizioni di mancanza di attacco alla matrice ed è stato usato per selezionare cellule con fenotipo più aggressivo; tuttavia alcuni tipi di cellule tumorali sono capaci di resistere a queste condizioni di crescita rafforzando i contatti cellula-cellula, un comportamento in netto contrasto con il fenotipo EMT. Un saggio in vitro sviluppato nel nostro laboratorio, denominato forced Single Cell Suspension assay (fSCS) si è rivelato più stringente rispetto al saggio in vitro di anoikis e seleziona cellule andate incontro alla EMT. La parte non codificante del genoma, nonostante abbia un ruolo fondamentale nella regolazione della EMT e nella metastasi (come avviene ad esempio per i miRNA), risulta molto meno studiata rispetto alla controparte codificante. I saggi genetici in vitro basati sull’uso di trasposoni interrogano il genoma in modo più randomico rispetto ad altri tipi di saggi (ad esempio quelli basati sull’uso di retrovirus). Per avvalerci di un saggio in vitro che consenta uno screening molto efficiente dei geni che regolano la EMT, abbiamo combinato il saggio di fSCS con uno screening genetico in vitro basato sull’uso del trasposone Sleeping Beauty in cellule di cancro colo-rettale HCT116. Abbiamo identificato un clone cellulare, TN4_20, che mostra le seguenti caratteristiche: maggior resistenza al saggio di fSCS, morfologia mesenchimale, espressione di marcatori della EMT (ad esempio Slug ↑, Twist ↑, Vimentin ↑, E-cadherin ↓, Has-2 ↑), e abilità di generare un maggior numero di colonie satelliti nel saggio di evasione in matrigel. Inoltre, in un esperimento pilota condotto in vivo, le cellule TN4_20, iniettate in topi mediante iniezione intra-cecale, formano metastasi a distanza. Dopo essere risaliti alle posizioni genomiche delle inserzioni del trasposone nel DNA genomico delle TN4_20, ci siamo focalizzati sull’inserzione localizzata nella 3’UTR (3’ regione non tradotta) del gene BTBD7. Abbiamo scelto di studiare questa inserzione perché BTBD7 è un noto regolatore di EMT e metastasi e perché questa inserzione del trasposone è localizzata nel sito bersaglio predetto del miR-23b, un miRNA con note funzioni anti-metastatiche. Abbiamo ipotizzato e dimostrato che il miR-23b bersaglia il gene BTBD7 e i nostri dati suggeriscono che l’inserzione del trasposone nella 3’UTR di BTBD7 interferisce con questa interazione. Inoltre, abbiamo dimostrato che l’interazione tra il miR-23b e BTBD7 è importante per la resistenza all’ fSCS. I nostri risultati inoltre dimostrano che il silenziamento di BTBD7 interferisce con la resistenza all’ fSCS sia in cellule HCT116 parentali che TN4_20, e che la over-espressione di un costrutto ectopico eGFP-Btbd7 in cellule HCT116 parentali conferisce resistenza all’ fSCS e l’abilità di generare un maggior numero di colonie satelliti nel saggio di evasione in matrigel. Inoltre, l’over-espressione di eGFP-Btbd7 induce una riduzione dei livelli di trascritto e di proteina di E-caderina, e un aumento dei livelli di Vimentina, entrambi marcatori di EMT. In più, la over-espressione di eGFP-Btbd7 aumenta i livelli di trascritto e di proteina del fattore di trascrizione Zeb-1.
In una versione estesa del nostro saggio, attraverso l’esecuzione di round multipli di fSCS sia in cellule HCT116 parentali che in cellule HCT116 trasposte con il trasposone Piggybac (PB), abbiamo ottenuto gruppi, e non singoli cloni, di cellule resistenti all’ fSCS. Abbiamo osservato che cellule che sopravvivono a ogni round di fSCS generano un maggior numero di colonie sopravviventi, le quali acquisiscono una morfologia più mesenchimale. Inoltre, le colonie di cellule sopravvissute all’ fSCS mostrano ridotti livelli di espressione di E-caderina, aumentati livelli di espressione di Vimentina, e un aumentato numero di cellule con ridotta espressione di EpCAM, suggerendo che round multipli di fSCS determinano un arricchimento di cellule con tratti di EMT e staminalità. Inoltre, abbiamo osservato che cellule resistenti all’fSCS mostrano una maggiore resistenza al trattamento con 5-fluororacile (5-FU) e un aumentato potenziale metastatico in vivo. Infine, round ripetuti di fSCS arricchiscono due famiglie di miRNA, cioè miR-30 e miR-302, che sono già stati descritte avere un ruolo nella EMT e nella metastasi, e che potrebbero quindi regolare anche la resistenza all’ fSCS.

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EPrint type:Ph.D. thesis
Tutor:Bernardi, Paolo
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:31 January 2017
Anno di Pubblicazione:31 January 2017
Key Words:epithelial-to-mesenchymal transition, metastasis, transposon transizione epitelio-mesenchimale, metastasi, trasposone
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:10315
Depositato il:03 Nov 2017 11:21
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