Abstract
We have previously described that the NFκB pathway is upregulated during differentiation of glioblastoma stem-like cells (GSCs) which keeps differentiating GSCs in a proliferative astrocytic precursor state. However, extracellular signals and cellular mediators of this pathway are not clear yet. Here, we show that TLR4 is a key factor to promote NFκB activation in differentiating GSCs. TLR4 is upregulated during differentiation of GSCs and promotes transcriptional activation of NFκB as determined by luciferase-reporter assays and expression of NFκB target genes. Downregulation of TLR4 by shRNAs or blockade with anti-TLR4 specific antibodies drastically inhibited NFκB activity which promoted further differentiation and reduced proliferation of GSCs. We found that hyaluronic acid (HA), a main component of brain extracellular matrix, triggers the TLR4-NFκB pathway in differentiating GSCs. Moreover, HA is synthesized and released by GSCs undergoing differentiation and leads to transcriptional activation of NFκB, which is inhibited following downregulation of TLR4 or blockade of HA synthesis. Thus, we have demonstrated that during the process of differentiation, GSCs upregulate TLR4 and release the TLR4 ligand HA, which activates the TLR4-NFκB signaling pathway. This strategy may efficiently be used by differentiating GSCs to maintain their proliferative potential and consequently their tumorigenic capacity.
Highlights
Glioblastoma is a highly aggressive tumor with poor survival rates and treatment remains a challenge
We have previously demonstrated that canonical NFκB signaling, that is poorly activated in glioblastoma stem-like cells (GSCs), is upregulated during differentiation of GSCs which allows cells to proliferate and avoid terminal differentiation and senescence[12]
We showed that TLR4 was the only Toll-like receptor (TLR) member consistently upregulated in all differentiating GSC cultures established from surgical specimens of GBM patients
Summary
Glioblastoma is a highly aggressive tumor with poor survival rates and treatment remains a challenge. There are many signaling pathways that promote oncogenic transformation or maintain the aggressiveness of tumor cells Some of these pathways induce activation of NFκB, a transcription factor involved in many cellular processes including cell survival, proliferation and migration[5]. Proinflammatory signals like cytokines and pathogen-associated molecular patterns (PAMP) trigger an intracellular mechanism that leads to the activation of NFκB9. Several of these signaling pathways are initiated by activating cell surface receptors, including tumor necrosis factor receptor and Toll-like receptor (TLR) superfamilies. We show that TLR4 is upregulated during differentiation of GSCs, which triggers the NFκB transcriptional pathway, avoiding terminal differentiation and maintaining proliferation This cell behaviour is reversed following downregulation or inactivation of TLR4. We show that TLR4 is activated by hyaluronic acid (HA) that is synthesized and secreted by differentiating GSCs
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