Puca, Francesca
(2014)
HMGA1 expression controls the symmetric/asymmetric division ratio of colon cancer stem cells by regulating p53 and NUMB.
[Tesi di dottorato]
Tipologia del documento: |
Tesi di dottorato
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Lingua: |
English |
Titolo: |
HMGA1 expression controls the symmetric/asymmetric division ratio of colon cancer stem cells by regulating p53 and NUMB. |
Autori: |
Autore | Email |
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Puca, Francesca | fra.puca@yahoo.it |
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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: |
nome | email |
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Santoro, Massimo | masantor@unina.it |
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Tutor: |
nome | email |
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Fusco, Alfredo | [non definito] |
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Data: |
31 Marzo 2014 |
Parole chiave: |
HMGA1, p53, NUMB, stem cells |
Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/04 - Patologia generale |
[error in script]
[error in script]
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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