Expression of DICER, BIM, and PTEN in Malignant Melanoma: Role in Survival Mechanism and Adjuncts in Risk Stratification
Thanh T Ha, Elizabeth M Hyjek, Christopher R Shea, Vesna Petronic-Rosic, Thomas Krausz. University of Chicago, Chicago, IL
Background: Malignant melanomas (MM) are notoriously chemoresistant. The MITF-DICER-BIM and PTEN-BIM pathways are proposed to confer survival advantage in aggressive melanomas. MITF, the master regulator of melanocyte survival, upmodulates DICER, a critical microRNA processor. BIM, an inducer of apoptosis, is abrogated in the presence of DICER but upregulated by PTEN. In vitro, massive apoptosis occurs when BIM is overexpressed in the absence of DICER, whereas BIM suppression in the absence of PTEN confers resistance to BRAF inhibitors. The present study investigates whether these pathways are operative in clinical MM specimens and whether immunohistochemical (IHC) staining for these proteins is associated with metastatic status.
Design: Ten cases of nevi and twenty cases of MM (ten with and ten without metastasis) were identified from our institution's pathology archive (2006-2011). Cases were excluded if there was no sentinel lymph node biopsy or if the paraffin block was unavailable or contained insufficient tissue. Four-μm-thick sections of each lesion were immunolabeled for DICER, BIM, and PTEN. Staining intensity was scored as: nil, moderate (1+), or strong (2+).
Results: Nevi showed nil BIM expression but moderate (1+) staining with DICER and diffusely uniform strong (2+) staining with PTEN. BIM and DICER expression was increased compared to nevi in 55% and 45% of MM cases (n=20), respectively. Increased BIM and DICER expression was not associated with metastatic disease status. Contrary to the MITF-DICER-BIM model, BIM expression appeared unaffected by DICER status. However, BIM expression appeared directly correlated with PTEN in 60% of cases, suggesting multiple levels of regulation for BIM in vivo. Finally, PTEN expression was reduced in 55% of MM cases. The majority of these cases had metastasis (73%). Conversely, strong PTEN staining was more frequently seen in localized disease (78%).
Conclusions: Mechanisms of MM survival are complex and likely to involve multiple pathways not always evident in in vitro models. Although limited by a small sample size and heterogeneous sample subtypes, our results suggest that immunohistochemical staining for PTEN in primary MM holds promise as a useful adjunct for prognostication and risk stratification. Larger studies with long-term follow-up are warranted to confirm these findings and identify downstream PTEN targets for possible therapeutic application.
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 110, Wednesday Afternoon