PARD3 Protein Overexpression Is Associated with Poor Survival of Patients with Clear-Cell Renal-Cell Carcinoma
Frederic Dugay, Xavier LeGoff, Franck Chesnel, Gregory Verhoest, Florence Jouan, Catherine Henry, Cecile Vigneau, Nathalie Rioux-Leclercq, Yannick Arlot-Bonnemains, Marc-Antoine Belaud-Rotureau. Faculty of Medicine, Rennes, France; CHU Pontchaillou, Rennes, France
Background: Establishment of epithelial apicobasal polarity is crucial for proper kidney development and function. Among the kidney cancers, clear-cell renal-cell carcinomas (ccRCC) are characterised by loss of cell-cell junctions, loss of cell apicobasal polarity and increase in cell proliferation. We performed a comparative study between two original cell-lines generated from surgery specimens of 2 ccRCC with different clinical progression and have found a differential PARD3 gene amplification. The link between PARD3 gene overexpression and survival was then demonstrated on a serie of 96 ccRCC specimens.
Design: The R-180 and R-305 cell lines were generated from surgery specimens of 2 patients with a ccRCC. The histological characteristics of these 2 tumors were similar but the survival of the patients was different: 1 year (R-180) and 7 years (R-305). Cytogenetic analyses by karyotype (conventional R-banding and multi FISH), CGH-array and FISH were performed to determine chromosomal and gene imbalances. Immunohistochemistry was performed to assess protein overexpression.
Results: The R-180 and R-305 cells were respectively diploid and hypotetraploid. Both R-180 and R-305 cells showed a heterozygous loss of VHL (3p25) and p16 (9p21) gene as well as a loss of one chromosome 14. Only the R-180 cell-line harbored already known poor prognostic anomalies such as the loss of a chromosome 4 and the loss of the short arm of a chromosome 9. Moreover, CGH-array analysis showed a high level amplification of the PARD3 gene (10p11.21) in these cells. This amplification was correlated to the overexpression of the PARD3 protein. Thus, PARD3 protein overexpression was assayed by immunohistochemistry in a series of 96 ccRCC specimens (6 years follow-up). The results confirmed that PARD3 overexpression on the membrane and in the cytoplasm of the tumor cells is significantly associated with a shorter progression free survival (28 vs 57, p<5.10-7) and a shorter overall survival (36 vs 64, p<2.10-8). PARD3 gene amplification was not always associated with high protein expression suggesting regulations of PARD3 overexpression as the result of post-transcriptional and / or post-translational control.
Conclusions: PARD3 protein overexpression is associated with poor survival of patients with clear cell renal cell carcinoma. The analysis of the function of the oncogenic role of this protein in ccRCC is under progress.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 186, Tuesday Afternoon