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Sonic Hedgehog Pathway Is Upregulated in Adamantinomatous Craniopharyngiomas

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Sonic Hedgehog Pathway Is Upregulated in Adamantinomatous Craniopharyngiomas D C Gomes and others SHH in adamantinomatous 172:5 603–608 Clinical Study craniopharyngiomas Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas D C Gomes1,2, S A Jamra1, L F Leal1, L M Colli1, M L Campanini1, R S Oliveira1, C E Martinelli Jr1, P C L Elias1, A C Moreira1, H R Machado1, F Saggioro1, L Neder1, M Castro1 and S R Antonini1 Correspondence should be addressed 1School of Medicine of Ribeirao Preto, University of Sao Paulo, Avenida Bandeirantes, 3900 – Monte Alegre, to S R Antonini CEP 14049-900, Ribeirao Preto, Sao Paulo, Brazil and 2Federal University of Uberlandia, Uberlandia, Email Minas Gerais, Brazil [email protected] Abstract Objectives: Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/b-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs. Design: To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/b-catenin mutations and patients outcomes. Patients and methods: In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, b-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed. Results: The aCPs presented higher mRNA expression of SHH (C400-fold change (FC); P!0.01), GLI1 (C102-FC; P!0.001), and GLI3 (C5.1-FC; P!0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P!0.01 and PZ0.02 respectively). CTNNB1/b-catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (C4.3-FC; PZ0.02 and C10.2-FC; European Journal of Endocrinology PZ0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation. Conclusions: The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/b-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP. European Journal of Endocrinology (2015) 172, 603–608 Introduction Craniopharyngiomas are epithelial tumors that are significant morbidity related to their local invasion of classified as papillary craniopharyngiomas or adamanti- CNS structures (4) and to the surgical approach itself (1). nomatous craniopharyngiomas (aCPs) and account for Almost 80% of aCPs show aberrant accumulation of 1.2–4.0% of primary brain tumors in children (1). aCPs b-catenin in the cytoplasm and nucleus (5, 6).Inaddition, are embryonic tumors that result from the transforma- the prevalence of CTNNB1 (b-catenin) mutations in aCPs tion of embryonic squamous cell nests of the involuted has been shown to vary from 16 to 100%, including in our craniopharyngeal duct (1, 2) and represent 90% of all own series (5,7,8,9,10). In a previous study, a mouse craniopharyngiomas, occurring mainly in children (1). expressing a degradation-resistant mutant form of aCPs present benign histological features classified by b-catenin in early Rathke’s pouch progenitor cells demon- WHO as grade I tumors (3).However,theypresent strated that cells that accumulated b-catenin formed www.eje-online.org Ñ 2015 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-14-0934 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 09:33:57PM via free access Clinical Study D C Gomes and others SHH in adamantinomatous 172:5 604 craniopharyngiomas clusters resembling human aCPs. These tumors arise from an association between the CTNNB1 gene mutation and the activation of b-catenin in pituitary progenitors during SHH signaling activity in aCPs. embryogenesis based on the observation that these clusters expressed the stem cell markers SOX2, SOX9, and p27KIP1 (11, 12). Recently, it was demonstrated that the activation Subjects and methods of oncogenic b-catenin in Sox2 positive stem cell in the Patients adult pituitary results in tumors resembling human aCP (13). Of note, mutated Sox2-positive cells were not the cell- This study was approved by the Local Ethics Committee of-origin of the tumors, but they gave rise to b-catenin- (protocol no. 2009/1188), and informed written consent accumulating clusters with tumor-inducing activities (13). was obtained from the patients or from their parents. The Hedgehog (HH) pathway is also involved in Eighteen patients with aCPs diagnosed at the University pituitary formation during early vertebrate embryogenesis. Hospital of the Ribeirao Preto Medical School, University Its activation is triggered by HH ligand binding to a receptor of Sao Paulo, were enrolled in the study. The diagnosis complex formed by the transmembrane protein patched 1 considered clinical, hormonal, ophthalmological, and (PTCH1). In the presence of the ligand, the frizzled class neural system imaging findings, as previously described receptor, smoothened (SMO), is released from PTCH1 (8), and it was confirmed by histopathology after surgery. nZ inhibition, and activates the transcription factors glioma- Normal anterior pituitaries ( 7), which were obtained from adults who died from natural causes and underwent associated oncogene family zinc finger, GLI1, GLI2, and routine autopsy, were chosen as control tissue considering GLI3 (14). After the appearance of Rathke’s pouch, Sonic HH the probable embryonic common origin of aCPs (17). (SHH) expression is excluded from this region but remains in surrounding areas (15). Moreover, the SHH pathway plays an important role in adult stem cell maintenance, and GLI1 Quantitative real-time PCR expression is considered as a marker of SHH-responsive cells The tumoral and normal pituitary tissues were micro- and as a marker of progenitor/stem cells (16). The expression dissected by an experienced pathologist (F Saggioro) and of the stem cell markers, SOX2 and OCT4, has been observed frozen at K70 8C until RNA extraction using TRIzol reagent in human aCPs (17). (Invitrogen). RNA was quantified by spectrometry, and its Andoniadou et al. (11) used the b-catenin mutant integrity was evaluated by the 260:280-nm absorbance ratio transgenic mice model to demonstrate the co-expression and by agarose gel electrophoresis. The cDNA synthesis was b European Journal of Endocrinology of SHH mRNA in the cluster of cells expressing -catenin performed using the High-Capacity cDNA Reverse Tran- in tumors resembling aCPs. Furthermore, increased mRNA scription Kit and MultiScribe enzyme (Applied Biosystems). expression of SHH was found in cells that accumulate The relative mRNA expression was analyzed by b-catenin. In situ hybridization performed in a small quantitative real-time PCR using specific TaqMan assays SHH PTCH1 number of human aCP sections revealed and (Applied Biosystems): SHH (Hs00179843_m1), PTCH1 expression in epithelial nodules, whereas PTCH1 was also (Hs00181117_m1), SMO (Hs01090242_m1), GLI1 (Hs01 found in palisade cells (11). Interestingly, there are reports 110766_m1), GLI2 (Hs01119974_m1), GLI3 (Hs00 of aCPs in patients with PTCH1 mutations (Gorlin 609233_m1), and SUFU (Hs00171981_m1). The values were syndrome), and over-active SHH signaling occurs in normalized based on the mean expression ofthe endogenous numerous human cancers (18, 19). These data support a controls, GUSB (4326320E) and PGK1 (4326318E). The role for pituitary stem cells in the oncogenesis of human reactions were performed according to the manufacturer’s aCPs. Thus, we hypothesized that crosstalk between recommendation, and the relative mRNA expression values K Wnt/b-catenin and SHH pathways, which are important were determined using the 2 DDCt method (20). during normal pituitary development, could contribute to the imbalance in intracellular signaling in the molecular Immunohistochemical analyses pathogenesis of aCPs. In this study, we have analyzed the expression of In addition to routine hematoxylin–eosin staining, several components of the SHH pathway in human aCPs, immunohistochemical (IHC) was performed according to in which CTNNB1 mutations were identified or not. Our the availability of formalin-fixed, paraffin-embedded aCPs findings revealed a significant increase in the main in 14 samples using the primary antibodies anti-SMO components of the SHH pathway and the presence of (sc-13943), anti-GLI1 (sc-20687), anti-GLI3 (sc-20688), www.eje-online.org Downloaded from Bioscientifica.com at 09/29/2021 09:33:57PM via free access Clinical Study D C Gomes and others SHH in adamantinomatous 172:5 605 craniopharyngiomas anti-SUFU (sc-28847), anti-b-catenin (sc-7963; Santa overall follow-up of the patients was 75.3 months (8–248 Cruz Biotechnology, Inc.) and Ki67 (NCL-Ki67-MM1; months). The clinical data for the patients are presented Novocastra, Newcastle, UK). The staining was developed in Supplementary Table 1, see section on supplementary with 3,30-diaminobenzidine-tetrahydrochloride (DAB; data given at the end of this article. A portion of these Vector Laboratories, Inc., Burlingame, CA, USA) and clinical
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