Role of the nuclear receptor PPARy in clear cell renal and bladder urotheial carcinoma / Danielle J. Sanchez.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Sanchez, Danielle J., author.

Contributor:

Simon, Celeste, degree supervisor.

Seale, Patrick, degree committee member.

Susztak, Katalin, degree committee member.

Wellen, Kathryn, degree committee member.

Lazar, Mitchell, degree committee member.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

ix, 107 leaves : color illustrations ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2019.

Summary:

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARy) has a well-characterized role in the developmental process of adipogenesis and transcriptional regulation of lipid metabolism. However, its expression patterns and functions in various cancer subtypes are less understood. My studies investigate the role of PPARy in two distinct cancers of the urinary tract: clear cell renal cell carcinoma (ccRCC) and bladder urothelial carcinoma (UC). In ccRCC, I hypothesized that PPARy activity contributes to the aberrant lipid accumulation phenotype characteristic of this disease, thereby promoting tumor progression. Through ChIP-seq, I demonstrated that PPARy and its heterodimeric DNA binding partner retinoid X receptor (RXR) occupy both adipose-shared and ccRCC-specific sites throughout the genome. However, based on a number of in vitro and in vivo assays evaluating ccRCC viability, proliferation, migration, and effects on lipid metabolism, I concluded that PPARy was dispensable for these processes and ccRCC progression. I also studied the role of PPARy in UC, a cancer which displays copy number amplification and mRNA overexpression of PPARG or RXRA in ~30% of tumors. In contrast to the results obtained in ccRCC, I demonstrated that genetic and pharmacological inhibition of PPARy reduces tumor growth via cell cycle arrest. Furthermore, I identified a candidate list of PPARy-regulated genes in UC based on ChIP- and RNA-seq analyses of cell culture models, as well as gene expression data from primary patient samples. Together, my studies illuminate the remarkable cell type-specific functions of PPARy in urinary tract cancers, and provide rationale for the pharmacological targeting of its transcriptional effectors in a subset of tumors.

Notes:

Ph. D. University of Pennsylvania 2019.

Department: Cell and Molecular Biology.

Supervisor: M. Celeste Simon.

Includes bibliographical references.

Other Format:

Online version: Sanchez, Danielle J. Role of the nuclear receptor PPARy in clear cell renal and bladder urotheial carcinoma.

OCLC:

1126790147