| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
The gene expression profiles of 33 renal cell carcinomas (RCCs) and nine normal kidney samples were examined using high-density oligonucleotide microarrays in an attempt to identify biomolecular markers for the diagnosis of tumor subtypes and also for prediction of prognosis. Hierarchical clustering demonstrated that clear-cell RCC, chromophobe RCC, and normal kidney tissue showed distinctive gene expression profiles. The mean expression levels of 149 of 12500 genes were more than three times higher in clear-cell RCC than in chromophobe RCC and normal kidney tissue. Among the genes whose expression was up-regulated in clear-cell RCC, adipose differentiation-related protein (ADFF) was selected for further analysis. Consistent with the results of the microarray, increased levels of ADFP mRNA were found more frequently in clear-cell RCCs than in other non-clear-cell tumor subtypes using real-time quantitative PCR. Immunohistochemistry for ADFP showed strong and unique tumor cell staining
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patterns in the majority of clear-cell RCCs. More importantly, patients bearing tumors with higher AFDP mRNA levels showed significantly better survival in both univariate and multivariate analyses. ADFP is a lipid storage droplet-associated protein and its transcription is considered to be regulated by the von Hippel-Lindau/hypoxia-inducible factor pathway. It is known that clear-cell RCC contains abundant lipids and cholesterols. Thus it is likely that sustained up-regulation of ADFP following VHL inactivation is involved in the morphological appearance of clear-cell RCC. Moreover ADFP expression status may provide useful prognostic information as a biomolecular marker in patients with clear-cell RCC.
Next, we measured VCAM1 expression levels in tumor tissues and evaluated its significance and prognostic utility in renal cell carcinoma. In comparison with normal kidney samples, VCAM1 was significantly up-regulated in clear cell RCC and papillary RCC, while it was down-regulated in chromophobe RCC and oncocytoma. In clear cell RCC, VCAM1 expression levels were apparently high in symptomatic presentation-negative, small tumor size, low-stage, low-grade, microvascular invasion-negative, and VIII, alteration-positive tumors. Univariate analyses demonstrated that VCAM1 high expression is strongly associated with better outcomes in clear cell and papillary RCCs. Further, Cox multivariate analysis models combined with the split-sample method revealed that this association is still significant, especially in cancer-free survival for patients with clear cell RCC after curative surgical resection. VCAM1 expression levels were found to be histologically subtype-specific in renal tumors. Determination of the VCAM1 expression level as a biomarker can provide useful prognostic information for patients with clear cell RCC. Less
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