HMGA1 silencing reduces stemness and temozolomide resistance in glioblastoma stem cells

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posted on 2016-09-08, 17:35 authored by Marianna Colamaio, Nadia Tosti, Francesca Puca, Alessia Mari, Rosaria Gattordo, Yalçın Kuzay, Antonella Federico, Anna Pepe, Daniela Sarnataro, Elvira Ragozzino, Maddalena Raia, Hidenari Hirata, Marica Gemei, Koshi Mimori, Luigi del Vecchio, Sabrina Battista, Alfredo Fusco

Objective: Glioblastoma multiforme (GBM) develops from a small subpopulation of stem-like cells, which are endowed with the ability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages. These cells are resistant to conventional chemo- and radiotherapy and are hence also responsible for tumor recurrence.

HMGA1 overexpression has been shown to correlate with proliferation, invasion, and angiogenesis of GBMs and to affect self-renewal of cancer stem cells from colon cancer. The role of HMGA1 in GBM tumor stem cells is not completely understood.

Research design and methods: We have investigated the role of HMGA1 in brain tumor stem cell (BTSC) self-renewal, stemness and resistance to temozolomide by shRNA- mediated HMGA1 silencing.

Results: We first report that HMGA1 is overexpressed in a subset of BTSC lines from human GBMs. Then, we show that HMGA1 knockdown reduces self-renewal, sphere forming efficiency and stemness, and sensitizes BTSCs to temozolomide. Interestingly, HMGA1 silencing also leads to reduced tumor initiation ability in vivo.

Conclusions: These results demonstrate a pivotal role of HMGA1 in cancer stem cell gliomagenesis and endorse HMGA1 as a suitable target for CSC-specific GBM therapy.