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Correlation of global micro RNA expression with basal cell carcinoma subtype

ABSTRACT: Basal cell carcinomas (BCCs) are the most common cancers in the US. Histologic appearance distinguishes several subtypes, each of which can have a different biologic behavior. In this study global miRNA expression was quantified by high throughput sequencing in nodular BCCs, a subtype that is slow growing, and infiltrative BCCs, aggressive tumors that extend through the dermis and invade structures such as cutaneous nerves. Principal components analysis correctly classified seven out of eight infiltrative tumors on the basis of miRNA expression. The remaining tumor, on pathology review, contained a mixture of nodular and infiltrative elements. Nodular tumors did not cluster tightly, likely reflecting broader histopathologic diversity in this class, but trended toward forming a group separate from infiltrative BCCs. qPCR assays were developed for six of the miRNAs that showed significant differences between the BCC subtypes, and five of these six were validated in a replication set of four infiltrative and three nodular tumors. The expression level of miR-183, a miRNA that inhibits invasion and metastasis in several types of malignancies, was consistently lower in infiltrative than nodular tumors and could be one element underlying the difference in invasiveness. These results represent the first miRNA profiling study in BCCs and demonstrate that miRNA gene expression may be involved in tumor pathogenesis and particularly in determining the aggressiveness of these malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33665 | GEO | 2012/02/01

SECONDARY ACCESSION(S): PRJNA148721

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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Correlation of global micro RNA expression with basal cell carcinoma subtype

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