Oncotarget

Research Papers:

Global gene expression of histologically normal primary skin cells from BCNS subjects reveals "single-hit" effects that are influenced by rapamycin

Amruta Phatak, Mohammad Athar, James A. Crowell, David Leffel, Brittney-Shea Herbert, Allen E. Bale and Levy Kopelovich _

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Oncotarget. 2019; 10:1360-1387. https://doi.org/10.18632/oncotarget.26640

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Abstract

Amruta Phatak1, Mohammad Athar2, James A. Crowell3, David Leffel4, Brittney-Shea Herbert1, Allen E. Bale5 and Levy Kopelovich6

1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

2Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA

3NCI-DCTD-DTP, Bethesda, MD, USA

4Department of Dermatology, Yale School of Medicine, New Haven, CT, USA

5Department of Genetics, Yale School of Medicine, New Haven, CT, USA

6Department of Medicine, Weill Cornell Medical College, New York, NY, USA

Correspondence to:

Levy Kopelovich, email: kopelovichl@gmail.com

Allen E. Bale, email: allen.bale@yale.edu

Keywords: Gorlin syndrome; basal cell carcinoma; patched; HH signaling; rapamycin

Received: December 09, 2018    Accepted: January 11, 2019    Published: February 15, 2019

ABSTRACT

Studies of dominantly heritable cancers enabled insights about tumor progression. BCNS is a dominantly inherited disorder that is characterized by developmental abnormalities and postnatal neoplasms, principally BCCs. We performed an exploratory gene expression profiling of primary cell cultures derived from clinically unaffected skin biopsies of BCNS gene-carriers (PTCH1 +/-) and normal individuals. PCA and HC of untreated keratinocytes or fibroblasts failed to clearly distinguish BCNS samples from controls. These results are presumably due to the common suppression of canonical HH signaling in vitro. We then used a relaxed threshold (p-value <0.05, no FDR cut-off; FC 1.3) that identified a total of 585 and 857 genes differentially expressed in BCNS keratinocytes and fibroblasts samples, respectively. A GSEA identified pancreatic β cell hallmark and mTOR signaling genes in BCNS keratinocytes, whereas analyses of BCNS fibroblasts identified gene signatures regulating pluripotency of stem cells, including WNT pathway. Significantly, rapamycin treatment (FDR<0.05), affected a total of 1411 and 4959 genes in BCNS keratinocytes and BCNS fibroblasts, respectively. In contrast, rapamycin treatment affected a total of 3214 and 4797 genes in normal keratinocytes and normal fibroblasts, respectively. The differential response of BCNS cells to rapamycin involved 599 and 1463 unique probe sets in keratinocytes and fibroblasts, respectively. An IPA of these genes in the presence of rapamycin pointed to hepatic fibrosis/stellate cell activation, and HIPPO signaling in BCNS keratinocytes, whereas mitochondrial dysfunction and AGRN expression were uniquely enriched in BCNS fibroblasts. The gene expression changes seen here are likely involved in the etiology of BCCs and they may represent biomarkers/targets for early intervention.


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