HMGA1 silencing reduces stemness and temozolomide resistance in glioblastoma stem cells

ABSTRACT

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.

KEYWORDS:

• HMGA1
• cancer stem cells
• glioblastoma
• MGMT
• temozolomide

Acknowledgments

This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 11477), from Ministero dell’Università e della Ricerca Scientifica e Tecnologica- MIUR (PRIN 2011, Progetto di interesse strategico “Invecchiamento” PNR-CNR 2012-2014 and Progetto PON01-02782 “Nuove Strategie Nanotecnologiche per la messa a punto di farmaci e presidi diagnostici diretti verso cellule cancerose circolanti”), from CNR (Epigenomic Flagship Project “EPIGEN”) and from Regione Campania (Progetto Legge 5). We thank Prof. Ruggero de Maria for providing the BTSC lines. We are grateful to Dott. Marco De Martino for the assistance with digital images and Dott. Nunzio Antonio Cacciola for contributing in the analysis of experiments with TMZ. We are grateful to Prof. Girolama Condorelli for providing some reagents and to Serenella Eppenberger-Castori and Petra Hirschmann for technical assistance in IHC.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Supplementary material

The supplemental data for this article can be accessed here.

Additional information

Funding

This paper has been funded by Associazione Italiana per la Ricerca sul Cancro [IG 11477]; Consiglio Nazionale delle Ricerehe [PNR-CNR 2012-2014]; Ministero dell’Istruzione, dell’Università e della Ricerca [PON01-02782].