Abstract
Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive malignant neoplasm that typically involves the abdominal or pelvic peritoneum in children and young adults. This tumor is characterized by the presence of a specific EWS-WT1 fusion gene, which is the result of recurrent chromosomal translocation, t(11;22)(p13;q12). EWS encodes a putative RNA binding protein of unknown function with an N-terminal domain that mediates potent transcriptional activation when fused to heterologous DNA binding domains. WT1 is a tumor suppressor gene initially identified based on its inactivation in Wilms tumor. The chimeric proteins resulting from these chromosomal translocations usually possess gain-of-function transcriptional activities and define histologically and biologically distinct tumor types. EWS-WT1 has two isoforms of EWS-WT1(-KTS) and EWS-WT1(+KTS). Previous studies have identified several EWS-WT1(-KTS) target genes, most of which are involved in growth factor signaling. In the current study, using an exogenous EWS-WT1(-KTS) induction system along with the selection from candidates for target genes based on the microarray data, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential EWS-WT1(-KTS) target and this induction accompanied with increased phosphorylation form of Akt and MAPK, suggesting a post-transcriptional modulation by EWS-WT1(-KTS). In addition, CTNNB1 was also identified as a potential EWS-WT1(-KTS) target that defines epithelial characteristics of DSRCT. Furthermore, up-regulation of CTNNB1 driven by EWS-WT1(-KTS) was independent of FGFR4 regulation. Expressions of FGFR4 and CTNNB1 in DSRCT clinical samples were confirmed by immunohistochemistry. This study provides regulatory mechanism of FGFR4 in DSRCT and also novel insights into the acquisition of epithelial characteristics in DSRCT.
Highlights
Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive malignant tumor that typically involves the abdominal or pelvic peritoneum in children and young adults [1]
The molecular targets of EWS-WT1(-KTS) chimeric proteins that have been reported include insulin-like growth factor-I receptor (IGF-IR) gene [8,9,10]; the beta-chain of the interleukin-2/15 receptor (IL-2/15Rβ) [11]; platelet-derived growth factor-A (PDGFA) [12]; BAI1-associated protein 3 (BAIAP3), which encodes a protein implicated in regulated exocytosis; a potential regulator of growth-factor release [13]; and T-cell acute lymphoblastic leukemia-associated antigen 1 (TALLA-1)
In addition to ERBB2 (HER2) and fibroblast growth factor receptor 4 (FGFR4) listed in Supplementary Table 1, the expressions of ERBB3 (Her3) and epidermal growth factor Receptor (EGFR) were examined by immunocytochemistry in the JN-DSRCT cell line
Summary
Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive malignant tumor that typically involves the abdominal or pelvic peritoneum in children and young adults [1]. This tumor is characterized histologically by solid nests of small round-cell tumor cells expressing epithelial, muscular, and neural markers, surrounded by a dense reactive stroma. This tumor is characterized by the presence of specific EWS-WT1 fusion genes related to the recurrent chromosomal translocation, t(11;22)(p13;q12) [2,3]. The molecular targets of EWS-WT1(-KTS) chimeric proteins that have been reported include insulin-like growth factor-I receptor (IGF-IR) gene [8,9,10]; the beta-chain of the interleukin-2/15 receptor (IL-2/15Rβ) [11]; platelet-derived growth factor-A (PDGFA) [12]; BAI1-associated protein 3 (BAIAP3), which encodes a protein implicated in regulated exocytosis; a potential regulator of growth-factor release [13]; and T-cell acute lymphoblastic leukemia-associated antigen 1 (TALLA-1)
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