Up-regulation of Sonic Hedgehog Pathway in Adamantinomatous Craniopharyngiomas

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 17-28-Adrenal Tumors & Pheochromocytoma
Basic/Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-19
Soraya Regina Abu Jamra*1, Debora Cristiane Gomes1, Leticia Ferro Leal1, Carlos Eduardo Jucá1, Ricardo Santos Oliveira1, Carlos Eduardo Martinelli1, Ayrton Custodio Moreira1, Helio Rubens Machado2, Fabiano Pinto Saggioro1, Luciano Neder1, Margaret De Castro1 and Sonir Roberto Antonini1
1School of Medicine of Ribeirao Preto-University of Sao Paulo, Ribeirao Preto-SP, Brazil, 2School of Medicine of Ribeirao Preto-University of Sao Paulo, Ribeirao Preto SP, Brazil
Background/Objectives: The pathogenesis of adamantinomatous craniopharyngiomas (ACP) is still partially understood. Mutations in beta-catenin are the only known cause of ACP and we found frequent beta-catenin accumulation both in beta-catenin mutated and wild-type (WT) ACP. Recently, a b-catenin mutant mouse model of ACP (ACP b-Cat) was generated. ACP b-Cat cells express high levels of Sonic Hedgehog (SHH). The SHH pathway is involved in central nervous system development but the role of SHH pathway in ACP has not been investigated to date. Here, we evaluated the expression pattern of SHH pathway genes in ACP.

Patients and Methods: Fourteen ACP patients, including 8 children (57% male; median age 15.5 yrs) were analyzed. Pituitary hormone deficiency and b-catenin mutations were found in 86% and 50% of these cases, respectively.  The mRNA expression levels of SHH pathway genes (SHH, PTCH, SMO, GLI1, GLI2, GLI3, SUFU and ZIC2) was evaluated by qPCR. SMO, GLI1, GLI3 and SUFU protein expression was evaluated by immunohistochemistry (IHC). Seven normal pituitaries tissues were used as controls.

Results: Compared to normal pituitaries, ACP presented extremely higher mRNA levels of SHH (fold: 4.6x103; p<0.01) and GLI1 (fold: 1.2x103; p<0.001) and higher GLI3 mRNA levels (fold: 17; p<0.001). Interestingly, ACP GLI2 mRNA expression level was not different of normal pituitaries (fold: 2.6; p=0.09). PTCH, SMO, ZIC2 and SUFU ACP mRNA levels were similar to normal pituitaries. Moreover, compared to beta-catenin WT, beta-catenin mutated ACPs presented higher expression of GLI1 (fold: 32; p=0.04) and SMO(fold: 5; p=0.03). We did not find association between abnormal ACP SHH pathway genes expression and age at diagnosis or disease progression, suggesting that SHH pathway abnormalities may occur at an early stage of tumor formation. IHC showed that normal pituitaries (4 adults; 3 children) present focal and weak expression of SMO, GLI1, GLI3 and SUFU. SMO, GLI1, GLI3 and SUFU immunostaining was found in 90%, 80%, 92% and 67% of the ACP evaluated.

Conclusions: Increased expression of SHH pathway genes suggests that SHH pathway is up-regulated in human ACP and may play an important role in the pathogenesis of these tumors.

Nothing to Disclose: SRA, DCG, LFL, CEJ, RSO, CEM, ACM, HRM, FPS, LN, MD, SRA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: FAPESP and CNPq