Variable Expression of PIK3R3 and PTEN in Ewing Sarcoma Impacts Oncogenic Phenotypes

Abstract

Ewing Sarcoma is an aggressive malignancy of bone and soft tissue affecting children and young adults. Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent tumor suppressor, is lost in a subset of Ewing Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of Ewing Sarcoma cells to the microtubule inhibitor vincristine, a relevant chemotherapeutic agent in this cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in Ewing Sarcoma, with potential clinical implications.

Long Noncoding RNA FER1L4 Suppresses Tumorigenesis by Regulating the Expression of PTEN Targeting miR-18a-5p in Osteosarcoma

“…These studies suggest that FER1L4 functions as a ceRNA of miR-18a-5p in OS. Phosphatase and tensin homologue (PTEN), located on chromosome10q23, has been reported to be downregulated in OS tissues and cell lines, and low PTEN expression was associated with poor prognosis [28][29][30]. In addition, overexpression of PTEN significantly inhibits OS cell proliferation, migration, and invasion, and induces cell apoptosis [31,32].…”

MicroRNA-411 inhibits malignant biological behaviours of colorectal cancer cells by directly targeting PIK3R3

“…PIK3R3 is a member of the phosphatidylinositol 3-kinase (PI3K) family and was found to be abnormally upregulated in various types of human cancers, such as glioma (38), ovarian (39), gastric (40), hepatocellular carcinoma (32), lung (41) and breast cancer (42). The oncogenic roles of PIK3R3 on cancer initiation and progression has been described in several types of cancers, such as Ewing sarcoma (43), gastric (40), ovarian (39) and breast cancer (42). In CRC, PIK3R3 was upregulated in clinical specimens and cell lines.…”

Genome-wide association analysis reveals genetic loci and candidate genes for feeding behavior and eating efficiency in Duroc boars

“…The marker ALGA0037698 on SSC6, which is located on fourth intron of the PIK3R3 gene, was associated with DFI ( Table 2 ). Previous studies have shown that the gene PIK3R3 is involved in cancer development, such as gastric cancer[ 42 ], ewing Sarcoma[ 43 ] and metastatic colorectal cancer[ 44 ]. However, no report to date has described a link between DFI and PIK3R3 in any species.…”