Novel report of expression and function of CD97 in malignant gliomas: correlation with Wilms tumor 1 expression and glioma cell invasiveness

Abstract

Object. The Wilms tumor 1 (WT1) protein-a developmentally regulated transcription factor-is aberrantly expressed in gliomas and promotes their malignant phenotype. However, little is known about the molecular allies that help it mediate its oncogenic functions in glioma cells.Methods. The authors used short interfering RNA (siRNA) to suppress WT1 expression in glioblastoma (GBM) cells and evaluated the effect of this on GBM cell invasiveness. Gene expression analysis was then used to identify the candidate genes that were altered as a result of WT1 silencing. One candidate target, CD97, was then selected for further investigation into its role by suppressing its expression using siRNA silencing, followed by proliferation and invasion assays.Results. WT1 levels were reliably and reproducibly suppressed by siRNA application. This resulted in a significant decrease in cellular invasiveness. Microarray analyses identified the gene products that were consistently downregulated (27) and upregulated (11) with WT1 silencing. Of these, CD97 expression was consistently suppressed across the 3 different GBM cell lines studied and was found on further investigation to significantly impact GBM cell invasiveness.Conclusions. Although CD97 expression in gliomas has not been described previously, we conclude that the possible upregulation of CD97 mediated by WT1 promotes cellular invasiveness-one of the most characteristic and challenging aspects of glial tumor cells. Further studies are needed to clarify the nature of this regulation and its impact, as CD97 could represent a novel target for antiglioma therapies. (http://thejns.org/doi/abs/10.3171/2011.11.JNS111455) Key Words • Wilms tumor 1 • glioblastoma • invasiveness • target genes • oncology 843Abbreviations used in this paper: ATP = adenosine triphosphate; EGF = epidermal growth factor; GBM = glioblastoma; PDGF = platelet-derived growth factor; qRT-PCR = quantitative reverse transcriptase polymerase chain reaction; SDS = sodium dodecyl sulfate; siRNA = short interfering RNA; VCU = Virginia Commonwealth University; WT1 = Wilms tumor 1.

Phage display discovery of novel molecular targets in glioblastoma-initiating cells

“…No clear link between the expression of VAV3 or CD97 and the tumor hierarchy has been previously described but reports have suggested that both may mediate invasion in glioma, 34,40,41 yet the mechanisms remain unclear. CD97 binds and amplifies the activity of the LPA receptor 54 as well as the decay-accelerating factor (CD55), 55 a regulator of complement activity.…”

“…40,41 To confirm that CD97 was expressed in xenograft glioblastoma tissue and preferentially expressed within the GICs, we performed immunofluorescent staining on a xenografted tumor specimen. CD97 co-stained with the GIC marker, Sox2, in glioblastoma specimens (Figure 6d).…”

CD97 is a multifunctional leukocyte receptor with distinct roles in human cancers

“…The role of CD97 isoforms in invasion is an active area of investigation. Studies have shown CD97 to confer an invasive cell phenotype in both glioblastoma (32,71) and colorectal carcinoma (28), although its expression does not appear to affect tumor cell proliferation in these tumors. Our group recently reported on the role of CD97 in glioblastoma (71).…”

“…expressed in a number of malignancies including those of the breast (24), thyroid (25), stomach (26,27), esophagus (26), colon (28), pancreas (26,29) and brain (30)(31)(32). Moreover, these receptors have been shown to confer an invasive cell phenotype (23,(32)(33)(34)(35) despite no known effects on tumor growth.…”

“…Moreover, these receptors have been shown to confer an invasive cell phenotype (23,(32)(33)(34)(35) despite no known effects on tumor growth. More recently, CD97 became the first member of the EGF-TM7 family to be directly implicated in cell signaling.…”