miRNA Markers of Aggressive Behavior of Papillary Thyroid Carcinoma
MN Nikiforova, JE Dipaola, LM Aspden, YE Nikiforov. University of Pittsburgh Medical Center, Pittsburgh, PA
Background: Papillary thyroid carcinoma (PTC) is a relatively indolent tumor, although in 10-15% of cases it can develop recurrence or distant metastases and may cause tumor-related death. The aggressive biological behavior can not always be predicted based on histopathologic features. microRNAs (miRNAs) are dysregulated in various tumors types, and some of them serve as markers of tumor progression. In this study, we searched for miRNA markers of more aggressive behavior of PTCs.
Design: First, six PTCs with either local tumor recurrence or distant metastases (aggressive group) were matched by sex, age, and mutational status (4 BRAF positive, 1 RET/PTC positive and 1 with no mutations) with 6 PTCs with no complications on similar length follow-up (non-aggressive group) and studied for expression of 328 human mature miRNAs with Flexmir MicroRNA Human Panel (Exiqon) on Luminex 200. Next, 12 additional PTCs (4 aggressive and 8 non-aggressive) were analyzed for expression of specific miRNAs using real-time PCR on ABI 7500.
Results: Overall, the tumors in aggressive PTC group and non-aggressive PTC group revealed relatively similar miRNA expression profiles, with most highly overexpressed miRNAs being miR-146b, miR-221, and miR-222 and most downregulated miRNAs being miR-153, miR-448, miR-325, miR-382 and miR-495. However, the levels of miR-221 and miR-222 expression were 2.3 and 2.5 fold higher in aggressive group as compared to non-aggressive group. This correlates with the recent finding of miR-221 and miR-222 association with progression and metastatic behavior in melanoma. In addition, miR-155, miR-205, miR-337 were significantly more overexpressed in aggressive PTCs (2-4 fold difference) and miR-376a, miR-376b, miR-422a, and miR-130b were downregulated only in aggressive PTCs. Several miRNAs targeting the MET gene, including miR-34b, miR-206, miR-1 and miR-198 were expressed at significantly lower levels in aggressive tumors, which may provide a mechanism for MET overexpression found in PTCs.
Conclusions: We identified several miRNAs that were differentially expressed in aggressive PTCs as compared to non-aggressive tumors. Among those were miR-221 and miR-222, recently implicated in aggressive behavior of other tumor types, and several miRNAs targeted the MET gene. These data suggest that a panel of miRNAs may be used to predict a more aggressive behavior of PTCs.
Tuesday, March 10, 2009 8:45 AM
Platform Session: Section H1, Tuesday Morning