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Altered Expression of PRKX, WNT3 and WNT16 in Human Nodular

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Altered Expression of PRKX, WNT3 and WNT16 in Human Nodular ANTICANCER RESEARCH 36 : 4545-4552 (2016) doi:10.21873/anticanres.11002 Altered Expression of PRKX , WNT3 and WNT16 in Human Nodular Basal Cell Carcinoma NATALIA GURGEL DO CARMO 1,2 , LUIS HENRIQUE TOSHIHIRO SAKAMOTO 3, ROBERT POGUE 1, CINTIA DO COUTO MASCARENHAS 1, SIMONE KARST PASSOS 4, MARIA SUELI SOARES FELIPE 1,2 and ROSÂNGELA VIEIRA DE ANDRADE 1 1Program of Genomic Sciences and Biotechnology, Catholic University of Brasília, Brasília, DF, Brazil; 2Program of Molecular Pathology, University of Brasília, Brasília, DF, Brazil; 3Domingos A. Boldrini Center for Hematological Investigation, Campinas, SP, Brazil; 4Dermatology Service, Asa Norte Regional Hospital, Brasília, DF, Brazil Abstract. Background/Aim: Nodular and superficial are the differences in their biological behavior, such as tumor most common subtypes of basal cell carcinoma (BCC). growth pattern, potential for recurrence and metastasis, Signaling pathways such as Hedgehog (HH) and Wingless histological pattern and genetic factors. In addition, it is (WNT) signaling are associated with BCC phenotypic important to consider extrinsic factors, such as site of origin, variation. The aim of the study was to evaluate of the therapeutic choice and immunological state of the person expression profiles of 84 genes related to the WNT and HH with the tumor (3). Nodular BCC is the most common signaling pathways in patients with nodular and superficial biopsied subtype; it usually manifests as a single lesion and BCC. Materials and Methods: A total of 58 BCCs and 13 mostly affects head and neck areas (8). Histologically, the samples of normal skin were evaluated by quantitative real- tumor is a well-defined structure with precise contours; it time polymerase chain reaction (qPCR) to detect the gene- presents basaloid cells of nodular mass separated from the expression profile. Results: qPCR array showed segregation dermis by a typical artefact of separation (8-10). Superficial in BCC subtypes compared to healthy skin. PRKX, WNT3 BCC can be seen as multiple lesions. It is the second most and WNT16 were significantly (p<0.05) altered: PRKX was common biopsied subtype, affecting mostly the trunk and up-regulated, and WNT3 and WNT16 were down-regulated shoulder areas. It is seen as a tumoral focus, which goes in nodular BCC. Conclusion: PRKX, WNT3 and WNT16 from the epidermis to papillary dermis, showing peripheral genes, belonging to the WNT signaling pathway, are involved refraction around the tumor (8, 9). in the tumorigenic process of nodular BCC. The wingless (WNT), hedgehog (HH), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like Basal cell carcinoma (BCC) is a common skin tumor in growth factor (IGF) and transforming growth factor beta humans (1). It presents slow growth and if left untreated can (TGF β) signaling pathways are related to development be locally destructive (2-4). It does not have a high mortality mechanism of skin stem cells (11). WNT and HH have gained rate, although it is responsible for substantial morbidity, notorious attention in skin cancer, especially in BCC. The HH imposing a growing burden on healthcare services (4, 5). signaling pathway is known to be activated in most BCCs and Significant biological BCC subtypes are nodular, superficial, mutations in HH genes, especially Patched 1 ( PTCH1 ) and infiltrative, sclerodermiform, micronodular and mixed BCC Smoothened, frizzled class receptor ( SMO ), are pivotal to the forms (4, 6, 7). Histological BCC subtypes may display development of BCC (3, 12, 13). Target genes in which expression is up-regulated directly by HH signaling are PTCH1 , GLI family zinc finger 1 ( GLI1 ), GLI2 , protein kinase cAMP-activated catalytic subunit alpha ( PRKACA ) Correspondence to: Rosângela Vieira de Andrade, Ph.D., SGAN and hedgehog-interacting protein ( HHIP ) (2, 4, 14). AKT 916, Módulo B, Universidade Católica de Brasília (UCB) - Campus serine/threonine kinase 1 ( AKT1 ), IGF binding protein 4 II, Bloco C, 2˚ andar, Sala - 217, Bairro: Asa Norte, CEP 70790- (IGFBP4 ), IGFBP2 , secreted frizzled-related protein 2 160, Brasília, DF, Brazil. Tel: +55 6134487268, Fax: +55 6133474797, e-mail: [email protected] (SFRP2 ), bone morphogenetic protein receptor type 2 (BMPR2 ), leucine-rich repeat containing G protein-coupled Key Words: Basal cell carcinoma, WNT, Hedgehog, differential receptor 5 ( GPR49 ) and platelet-derived growth factor gene expression. receptor-alpha ( PDGFR α) have been reported to be up- 0250-7005/2016 $2.00+.40 4545 ANTICANCER RESEARCH 36 : 4545-4552 (2016) regulated in BCC (4, 15, 16). There is evidence that WNT Table I. Clinical features of nine patients whose samples were used in activation is a downstream consequence of HH signaling in the quantitative real-time polymerase chain reaction array. tumors (17, 18). Activation of the WNT pathway, typically Sample Gender Age, Histological Anatomic caused by gene mutations, leads to increased transcription of no. years type site genes related to growth, proliferation, differentiation, apoptosis, genetic stability, migration and angiogenesis 1 Male 85 Nodular BCC Chest (17,19). It has also been reported that genes such as cyclin 2 Female 97 Nodular BCC Face 3 Female 50 Nodular BCC Pinna D2 ( CCND2 ), calcium/calmodulin-dependent protein kinase 4 Male 50 Superficial BCC Lap II gamma ( CAMK2G ), casein kinase 2 alpha 2 ( CSNK2A2 ), 5 Female 47 Superficial BCC Pre-sternum and frizzled receptors such as FZD7, FZD8 and FZD2 were 6 Female 94 Superficial BCC Nasal dorsum deregulated in BCC (4). Larsimont et al. used a mouse model 7 Male 73 Control tissue Armpit of BCC to show early expression of SRY sex-determining 8 Female 53 Control tissue Armpit 9 Female 78 Control tissue Armpit region Y-box 9 ( SOX9 ) during tumorigenesis in a WNT- β- catenin-dependent manner. Deletion of SOX9 and constitutive BCC: Basal cell carcinoma. activation of HH signaling prevents BCC development (20). In the present study, the objectives were to focus on differential expression of genes belonging to the WNT and HH signaling pathways in patients with superficial and Reverse Transcription Kit (Thermo Fisher Scientific) according to 2 nodular BCC. Using quantitative real-time polymerase chain the manufacturer’s instructions. The RT RNA QC PCR Array reaction (qPCR) array techniques and validation assay by (Qiagen) was used for quality control. qPCR, we identified alterations in the gene expression qPCR array. In order to analyze the gene-expression profile, we used patterns of human nodular BCC. the Human Hedgehog Signaling RT 2 Profiler™ PCR Array version 3.0 (Qiagen) according to the manufacturer’s instructions. This array Materials and Methods contains 84 genes from the HH and WNT signaling pathways including genes involved in cell differentiation and multicellular Human tissue specimens. The first part of the present study involved organism development. Five housekeeping genes [beta-2- the analysis of six BCC samples (three nodular and three superficial) microglobulin ( B2M ), hypoxanthine phosphoribosyltransferase 1 and three healthy human epithelial tissue biopsies (normal skin), (HPRT1 ), ribosomal protein L13a ( RPL13A ), glyceraldehyde-3- totaling nine distinct samples (Table I). Tissue biopsies were obtained phosphate dehydrogenase ( GAPDH ), actin beta ( ACTB )] and controls from the Service of Dermatology at the Asa Norte Regional Hospital were also included on each array for genomic DNA contamination between 2011 and 2014 in Brazil. Normal tissue biopsies were detection, RNA quality, and general PCR performance. Genorm collected from patients who underwent surgery for general software (available at http:// medgen.ugent.be/~jvdesomp/genorm/), dermatological purposes but not for neoplasm. The samples were integrated by qbasePLUS software version 2.1 (Biogazelle NV, ® collected and immediately transferred to RNA later (Invitrogen, Life Zwijnaarde, Belgium) was used to identify the best housekeeping Technologies) and stored at −80˚C until required for analysis. BCC genes to analyze the gene expression profiles. qPCR array was tumor types were confirmed by histopathological tests. The second part carried out using Step One Plus (Thermo Fisher Scientific). of the present study involved 48 samples of nodular BCC and 10 samples of healthy human skin, obtained from the same source. All Validation assay by qPCR. The differential gene expression pattern pathologies (or lack thereof) were confirmed by histological was validated using qPCR with TaqMan ® probes for 10 selected examination. Samples with ambiguous histopathology were excluded. genes (casein kinase 1 delta ( CSNK1D ), PRKACA , protein kinase The study received approval from the Ethical Committee of the cAMP-activated catalytic subunit beta ( PRKACB ), protein kinase X- Catholic University of Brasilia (no. CEP/UCB 112/2009). The patients linked ( PRKX ), WNT inhibitory factor 1 ( WIF1 ), WNT2B, WNT3, gave their written consent for use of their biopsy samples for this study. WNT10A, WNT10B and WNT16 ) based on the expression pattern and the hierarchical cluster, p-value and fold-change values. ACTB RNA extraction and analysis and cDNA synthesis. Tissue disruption and GAPDH genes were used as housekeeping genes for reference. was carried out using a TissueLyser II (Qiagen, Hilden, Germany) We compared 48 samples of human nodular BCCs with 10 samples with 5 mm steel beads, RNase-Free, 20 Hz, 3×3 min. Total RNA of healthy human epithelial tissue biopsies obtained in the same was isolated using
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