A Radial Glia Gene Marker, Fatty Acid Binding Protein 7 (FABP7), Is Involved in Proliferation and Invasion of Glioblastoma Cells

Abstract

Glioblastoma multiforme (GBM) is among the most deadly cancers. A number of studies suggest that a fraction of tumor cells with stem cell features (Glioma Stem-like Cells, GSC) might be responsible for GBM recurrence and aggressiveness. GSC similarly to normal neural stem cells, can form neurospheres (NS) in vitro, and seem to mirror the genetic features of the original tumor better than glioma cells growing adherently in the presence of serum. Using cDNA microarray analysis we identified a number of relevant genes for glioma biology that are differentially expressed in adherent cells and neurospheres derived from the same tumor. Fatty acid-binding protein 7 (FABP7) was identified as one of the most highly expressed genes in NS compared to their adherent counterpart. We found that down-regulation of FABP7 expression in NS by small interfering RNAs significantly reduced cell proliferation and migration. We also evaluated the potential involvement of FABP7 in response to radiotherapy, as this treatment may cause increased tumor infiltration. Migration of irradiated NS was associated to increased expression of FABP7. In agreement with this, in vivo reduced tumorigenicity of GBM cells with down-regulated expression of FABP7 was associated to decreased expression of the migration marker doublecortin. Notably, we observed that PPAR antagonists affect FABP7 expression and decrease the migration capability of NS after irradiation. As a whole, the data emphasize the role of FABP7 expression in GBM migration and provide translational hints on the timing of treatment with anti-FABP7 agents like PPAR antagonists during GBM evolution.

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

“…[20][21][22] GAP43, S100B, FABP7, and the SOX10 transcription factors are all involved in neuronal development and were previously reported to be positively expressed in nerve-derived tumors such as schwannomas. [23][24][25][26][27] Our reidentification of such known biomarkers adds to our confidence in our study's novel differential expression results.…”

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

“…This led to the selection of only three studies published by Lee et al in 2006 [15], Schulte et al in 2011 [16] and De Rosa et al in 2012 [17].…”

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

“…Manipulating FABP7 levels by either expressing it in the FABP7-negative malignant glioma cell line U87 or depleting it from the FABP7-positive cell line U251 had a striking effect on malignant glioma growth properties, with FABP7 expression correlating with reduced proliferation and increased cell migration [13,[17][18]. Similar results were observed upon depleting FABP7 in glioblastoma neurospheres [57]. When combined with immunostaining data showing the presence of FABP7 at sites of tumor infiltration in grade IV astrocytomas, these data suggest a role for FABP7 in tumor infiltration and recurrence [17].…”

“…Borderline (p=0.084) negative association of survival with cytoplasmic FABP7 has also been reported [16]. Furthermore, FABP7 is highly expressed in glioblastoma neurospheres [57,66], with evidence of radiation-induced upregulation of FABP7 [57]. Manipulating FABP7 levels by either expressing it in the FABP7-negative malignant glioma cell line U87 or depleting it from the FABP7-positive cell line U251 had a striking effect on malignant glioma growth properties, with FABP7 expression correlating with reduced proliferation and increased cell migration [13,[17][18].…”

“…When mixed cultures of rodent glial cells and neurons were incubated with an anti-FABP7 antibody, inhibition of glial fiber formation and neuronal migration was observed, indicating a role for B-FABP in the establishment of the radial glial fiber system [55]. FABP7 has garnered attention because of its association with decreased survival in glioblastoma patients [13,[15][16]57]. Another FABP, FABP4, has recently been shown to be preferentially expressed in grade IV astrocytomas compared to low grade astrocytomas and normal brain tissue [58].…”