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Microarray analysis shows multiple signaling pathways are involved in basal cell carcinoma growth

ABSTRACT: BACKGROUND: Basal cell carcinoma (BCC) is the most common form of human cancer. Though the genetic mutation and subsequent aberrant signaling role of the Hedgehog pathway in BCC development is understood, little is known about the downstream genetic mechanisms underlying BCC growth. The characterization of molecular events would improve our understanding of carcinogenesis and may define new therapeutic intervention opportunities. OBJECTIVE: To identify differential gene expression associated with tumorigenesis promotion and to define common signaling pathways significant in BCC survival and growth. METHODS: Microarray analysis, using a 21K expanded sequence verified cDNA set was performed on tissues obtained from previously untreated patients undergoing Mohs surgical resection (8 superficial BCC, 8 nodular BCC, 7 morphea form, 8 normal skin). Significantly differentially expressed genes were identified by analysis of microarray results in various data sets and subsequently screened for signaling pathway involvement. Selected genes were validated using real-time PCR analysis using an expanded set of 31 BCC samples. RESULTS: The global gene expression profiles in BCCs and normal skin were distinguishable by unpaired T test. 2429 genes were at least 1.5 fold differentially expressed between BCC (all morphological types) and normal skin (p < 0.01). Multiple singaling pathways were activated, but the hedgehog, WNT, MAPK and calcium signal transduction pathways predominated. CONCLUSION: Our findings may have important implications for understanding the pathogenesis of BCC and suggest targeting of the WNT and MAPK pathways with therapeutic intervention. Keywords: disease state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE6520 | GEO | 2006/12/15

SECONDARY ACCESSION(S): PRJNA98793

REPOSITORIES: GEO

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Project description:Hair follicles (HF) and BCCs can be regarded as ordered and disordered skin appendages respectively and may utilize similar molecular mechanisms of growth. We wanted to examine the similarities and differences in gene expression patterns between BCCs and HF to define common growth mechanisms and gene expression patterns that distinguish an ordered skin appendage from a disordered skin growth. Nodular BCCs (n= 8) and non-follicular skin epithelium (n=8) were obtained. Scalp hair follicle root sheath was micro dissected from between the sebaceous gland duct and the lower one third of the HF (n=7). Microarray analysis was performed using 21K cDNA arrays and selected genes were validated using qPCR and histochemistry staining. Two differentially expressed gene sets were identified by significance analysis of microarray (SAM) in BCC and HF verses skin epithelium respectively. Based on these two lists, we conducted multiple signaling pathway analyses. The results indicated that Notch, hedgehog, and WNT signaling pathways were involved in regulating formation of both HF and BCCs. However, Notch signaling, including tumor suppressor genes Notch 1, Notch 2, Jagged ligands (JAG 1, 2), notch signaling inhibitor NUMB, Lunatic Fringe (LFNG), Deltex proteins (DTX 1, 2) which serve as important signaling components downstream of Notch, and Notch target genes HES1 ,RBPSUHL, hairless protein and HES7, all showed selective differential activation in BCCs compared to HF. The components of the notch signaling pathway may be potential new targets in the development of new therapeutic approaches to BCCs. samples of human hair follicles (n=7) were collected from scalp biopsies of normal individuals undergoing cosmetic procedures while nodular BCCs (n=8) and normal skin (n=8) were obtained from patients undergoing surgical resection. Only patients that had not been treated with preoperative chemotherapy or other therapeutic approaches were selected. All samples were provided by the Department of Dermatology and Skin Science, University of British Columbia with approval from the University Clinical Research Ethics Board. Hair follicles were microdissected to remove the lower one third, including the hair bulb, leaving the root sheaths including the bulge region. Normal skin samples were microdissected to isolate skin epithelium from the dermal component. All nodular BCC samples and normal skin epithelium were taken from the facial area of donors. Collected samples were immediately stored in an RNA stabilization reagent (Qiagen Inc, Mississauga, ON). BCC morphological subtypes were described and clinically classified during surgery and clinical diagnoses were confirmed by formalin-fixed, paraffin embedded histological assessment of the tumors. Human Operon v.2.1 (21K) glass arrays were produced (based on human 70mers from Operon Biotechnologies Inc, Huntsville, AL) by the Microarray Facility of the Prostate Centre at Vancouver General Hospital, Vancouver, Canada [17, 18]. RNAs were amplified using the SenseAmp Plus kit (Genisphere Inc, Hatfield, PA). The calculated A 260/280 ratio was used to determine the appropriate amount of sense RNA for labeling. Total RNA from test samples and universal human reference RNA (Stratagene, Cedar Creek, TX) were differentially labeled with Cy5 and Cy3 respectively, with the 3DNA array detection 350 kit (Genisphere Inc, Hatfield, PA) and cohybridized to cDNA microarrays. Following overnight hybridization and washing, arrays were imaged using a ScanArray Express scanner (PerkinElmer, Boston, MA).

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Microarray analysis shows multiple signaling pathways are involved in basal cell carcinoma growth

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