miR-210 (Hypoxia-Responsive) a Marker of Poor Prognosis in Clear Cell Renal Cell Carcinoma.
Vladimir A Valera Romero, Beatriz A Walter Rodriguez, Mark Sobel, WM Linehan, Maria J Merino. National Cancer Institute, NIH, Bethesda
Background: Clear cell renal cell carcinomas are characterized by the inactivation or loss of the VHL protein. Such inactivation is usually followed by accumulation of hypoxia inducible factors (HIFs), mostly HIF1-A with a resulting pseudo-hypoxic state. Small non-coding RNAs (micro-RNAs) have been shown to be altered in response to hypoxia. Particularly, the hypoxia-responsive miR-210 has been described to be regulated in hypoxic tumors. In this study, we investigated the expression pattern of miR-210 in clear cell RCCs and other tumor types, and correlated its expression with HIFs and clinicopathologic characteristics.
Design: Forty-three tumor samples and corresponding normal kidney from 39 patients were evaluated. Samples included 21 sporadic clear cell RCCs, fifteen CCRCC arising in VHL syndrome, and 2 clear cell tumors in BHD patients. Three hybrid oncocytic tumors, one papillary type I and one tumor with sarcomatoid differentiation were also included for analysis. miR-210 and HIF-1A mRNA expression were evaluated by Real-Time PCR. A two-fold change compared to the adjacent normal kidney was considered significant. In some cases, IHC evaluation for HIF1-a was also included. Only HIF1-A nuclear accumulation was considered positive staining.
Results: Seventy-six per cent of tumors showed at least a 2-fold increase compared with normal kidney (p<0.05). On average, sporadic clear cell tumors showed an 8.1 fold increase compared to 12.1, 13.9 and 3.5 fold-change in clear cell VHL, sarcomatoid, and papillary tumors respectively. Clear cell tumors in BHD patients showed a 2-fold decrease, while no change was seen in hybrid oncocytic tumors. A higher increase on miR-210 levels was seen in patients with advanced disease (p<0.05) and with larger tumors. Low transcript levels (>2 fold-downregulation) for HIF1-a were seen in 13 sporadic cases and only two showed an increase in HIF1-a mRNA. Similarly, 11 out of 15 of VHL cases (73%) showed at least a 2-fold decrease in transcript levels. In the cases where HIF1-a mRNA was elevated, a good correlation with IHC findings was obtained.
Conclusions: The hallmark of clear cell kidney tumors is the activation of the hypoxia pathway. Our results demonstrate that miR-210 is part of the hypoxic phenotype of these tumors. While miR-210 overexpression correlates with poor prognostic factors, the data also suggest that miR-210 could be used as a biomarker for the noninvasive evaluation of tumor hypoxia in renal cell carcinomas.
Category: Genitourinary (including renal tumors)
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 100, Wednesday Morning