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BMI-1 promotes Ewing sarcoma tumorigenicity independent of CDKN2a-repression

ABSTRACT: Over-expression of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we investigate the role of BMI-1 as a functional oncogene in the Ewing’s Sarcoma Family of Tumors (ESFT), a highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by the majority of primary ESFT and ESFT cell lines. However, in contrast to previous reports in other human cancer cell types, knockdown of BMI-1 in ESFT cell lines has no effect on cell survival. Instead, gain and loss of function studies in vitro and in vivo demonstrate that BMI-1 promotes the anchorage independent growth and tumorigenicity of ESFT. Importantly, we also find that modulation of BMI-1 alters the tumorigenicity of both p16-wild type and p16-null cell lines and that BMI-1-mediated effects on growth promotion are independent of CDKN2a repression. Gene expression profiling of ESFT cells following BMI-1 modulation reveals novel downstream effectors of BMI-1 function including key developmental, cell:cell and cell:matrix adhesion pathways. These data support a central role for BMI-1 in the pathogenesis of ESFT and reveal that p16-independent functions of BMI-1 are largely responsible for its oncogenic function in this tumor family. Keywords: Modification of BMI-1 expression in ESFT cell lines

ORGANISM(S): Homo sapiens

PROVIDER: GSE12064 | GEO | 2008/07/18

SECONDARY ACCESSION(S): PRJNA113399

REPOSITORIES: GEO

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Project description:Bmi-1 and Mel-18 are close structural homologues that belong to the polycomb group (PcG) of transcriptional regulators of homeotic gene expression in development. They are believed to stably maintain repression of gene expression by altering the state of chromatin at specific promoters. A number of clinical and experimental observations have also implicated Bmi-1 in tumorigenesis and stem cell maintenance. Bmi-1 overexpression or amplification has been observed in a number of human malignancies, particularly in B-cell lymphomas, medulloblastomas and breast cancer. We report here that shRNA-mediated knock-down of either Bmi-1 or Mel-18 in human medulloblastoma DAOY cells results in the inhibition of proliferation, loss of clonogenic survival and anchorage-independent growth, and suppression of xenograft tumor formation in nude mice. Furthermore, overexpression of both Bmi-1 and Mel-18 significantly increased clonogenic survival of Rat1 fibroblasts. In contrast, stable downregulation of Bmi-1 or Mel-18 alone did not affect the growth of SK-OV-3 or U2OS cancer cell lines or normal human WI38 fibroblasts. Gene expression analysis of shRNA-expressing DAOY cells has demonstrated a significant overlap in the Bmi-1- and Mel-18-regulated genes and revealed novel gene targets under their control. Taken together, these results suggest that Bmi-1 and Mel-18 might have overlapping functions in human tumorigenesis. Experiment Overall Design: DAOY cells were transduced with the indicated lentiviral shRNA and stable cell lines were generated by selection in puromycin (1 Âµg/ml). 2 x 105 cells of each stable cell line were plated onto 60 mm dishes in triplicates and harvested 4 days later. Triplicate total RNA samples from shRNA-expressing and mock-transduced DAOY cells were isolated using affinity resin (Qiagen RNeasy Mini Kit, Qiagen AG). RNA Integrity and purity were assessed with the RNA 6000 Nano LabChip system on Bioanalyzer 2100 (Agilent Technologies). Gene array analysis was conducted at the Genomics Factory at Novartis PHARMA AG, Basel, Switzerland using Gene Chip Human Genome 133 2.0 Plus Expression Array (Affymetrix Inc.).

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BMI-1 promotes Ewing sarcoma tumorigenicity independent of CDKN2a-repression

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