MDM2-p53 Pathway Status in Clinical Samples of Well-Differentiated and Dedifferentiated Liposarcoma.
Arisa Kumagai, Toru Motoi, Akihiko Yoshida, Tetsuo Imamura, Toshio Fukusato. Teikyo University School of Medicine, Tokyo, Japan; University of Tokyo, Japan; Teikyo University Hospital, Tokyo, Japan
Background: Well-differentiated liposarcoma (WLPS) and dedifferentiated liposarcoma (DLPS) are genetically characterized by MDM2 gene amplification. Although overexpressed MDM2 is generally believed to suppress p53 function, the status of MDM2-p53 pathway in clinical tumor samples has not been investigated.In this study, tumor cell type-specific status of MDM2-p53 pathway was examined by immunohistochemistry, chromogenic in situ hybridization (CISH), and by measuring microRNAs (miR)-34a, a known target of p53.
Design: Formalin-fixed paraffin-embedded tissue samples of 6 WLPSs and 5 DLPSs containing pairs of dedifferentiated (DD) and well differentiated components (DW) were studied. Tumor cells were morphologically subclassified into 3 groups; adipocyte-like cells and non-adipocyte-like cells in DW and WLPS, and dedifferentiated cells in DD. CISH was performed using dual-color-labeled probes for MDM2 and CEN12. The number of amplified signals (MDM2/CEN12 > 2.0) was counted in 60 nuclei. The number of immunopositive cells was counted in 100 nuclei for MDM2 and p53. The expression of miR-34a was measured by quantitative real-time RT-PCR. Four normal adipose tissues and 5 lipomas were used as controls.
Results: In DLPSs, MDM2 gene amplification, MDM2 and p53 immunoexpression occurred in 33.8%, 8.0%, and 1.7% of adipocyte-like cells; in 54.2%, 30.3%, and 8.6% of non-adipocyte-like cells; and in 75.2%, 41.0%, and 22.5% of dedifferentiated cells. In WLPSs, they occurred in 45.5%, 11.5%, and 5.1% of adipocyte-like cells; and 65.9%; 29.2%, and 8.4% of non-adipocyte-like cells. Adipocyte-like cells showed significantly less positivity for MDM2 amplification and MDM2 expression compared with the other 2 cell types. Dedifferentiated cells were significantly more positive for p53 than the other 2 cell types. miR-34a expression was significantly higher in liposarcomas than controls (p < 0.05), whereas it was comparable among different components of liposarcoma.
Conclusions: The status of MDM2 amplification may reflect the intratumoral heterogeneity. MDM2 amplification and overexpression inversely correlated with adipocytic differentiation. Uncoordinated immunoexpression of MDM2 and p53 indicates dysregulated MDM2-p53 pathway. Constant overexpression of miR-34a regardless of liposarcoma subtypes further suggests that p53 activity is up-regulated rather than suppressed. In conclusion, p53 may not be controlled by MDM2 in liposarcoma contrary to popular belief.
Category: Bone & Soft Tissue
Monday, February 28, 2011 1:00 PM
Poster Session II # 21, Monday Afternoon