Puca, Francesca (2014) HMGA1 expression controls the symmetric/asymmetric division ratio of colon cancer stem cells by regulating p53 and NUMB. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: HMGA1 expression controls the symmetric/asymmetric division ratio of colon cancer stem cells by regulating p53 and NUMB.
Autori:
AutoreEmail
Puca, Francescafra.puca@yahoo.it
Data: 31 Marzo 2014
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Oncologia ed endocrinologia molecolare
Ciclo di dottorato: 26
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomasantor@unina.it
Tutor:
nomeemail
Fusco, Alfredo[non definito]
Data: 31 Marzo 2014
Parole chiave: HMGA1, p53, NUMB, stem cells
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Depositato il: 11 Apr 2014 10:22
Ultima modifica: 15 Lug 2015 01:02
URI: http://www.fedoa.unina.it/id/eprint/9960

Abstract

High-mobility group A1 (HMGA1) proteins are architectural chromatinic proteins that are abundantly expressed during embryogenesis and in most cancer tissues, but are expressed at low levels or are absent in normal adult tissues. Several studies have demonstrated that HMGA1 proteins play a causal role in neoplastic cell transformation. HMGA1 has been shown to induce stem cell-like properties in colon cancer cells, suggesting that HMGA1 may be a key regulator in the maintenance of a stem cell-like state. The aim of this study was to investigate the role of these proteins in the control of cancer stem cells (CSCs), which have emerged as a preferred target in cancer therapy, because of their role in tumor recurrence. First, we observed that HMGA1 is overexpressed in colon tumor stem cell (CTSC) lines with respect to normal and colon cancer tissues. We demonstrated that the inhibition of HMGA1 expression in CTSCs increases the percentage of PKH26-positive cells, indicating increased stem cell quiescence. Moreover, HMGA1 silencing induces a drastic reduction in their self-renewal and sphere-forming efficiency (SFE). This effect, together with the finding of an asymmetric NUMB distribution in interfered cells, is indicative of the recovery of an asymmetric division pattern, characteristic of normal stem cells. Indeed, we have been able to demonstrate that HMGA1 negatively regulates p53 and NUMB expression at transcriptional level, thereby accounting for their increased expression at protein level in CTSC-HMGA1-silenced cells. Indeed, p53 has been recently found to regulate the balance between symmetric and asymmetric division; on the other hand, NUMB is known for its role as cell fate determinant in stem cells and effector in the stabilization of p53. The HMGA1 transcriptional regulation of NUMB and p53 likely accounts for the reduced SFE of silenced CTSCs. Preliminary data suggest that targeting HMGA1 makes resistant CTSCs more sensitive to chemotherapeutic agents. Therefore, our data indicate a critical role for HMGA1 in regulating both self-renewal and the balance of symmetric/asymmetric division in colon CSCs and suggest that blocking HMGA1 function may be an effective anti-cancer therapy.

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