Sporadic clear cell renal cell cancer and the HIFs [electronic resource].

Dondeti, Vijay R.
95 p.
Molecular biology.
Local subjects:
Penn dissertations -- Cell and molecular biology. (search)
Cell and molecular biology -- Penn dissertations. (search)
System Details:
Mode of access: World Wide Web.
Sporadic clear cell Renal Cell Carcinoma (ccRCC) is the most common type of adult kidney cancer. The most prevalent genomic copy number aberrations in ccRCC are 3p deletions and 5q amplifications. The tumor suppressor von-Hippel Lindau (VHL), located on 3p, is frequently inactivated in ccRCC and leads to constitutive activation of the hypoxia inducible factors, HIF1alpha and HIF2alpha. Although more than 30% of ccRCC tumors show 5q amplifications, little is known about potential candidate genes on 5q. We performed an integrated genomic analysis of 54 sporadic ccRCC samples using high-density copy number and gene expression data and identified two putative 5q targets, STC2 (stanniocalcin 2), a secreted glycoprotein, and VCAN (versican), a proteoglycan. We demonstrated that STC2 and VCAN are both amplified and overexpressed, and promote carcinogenesis by inhibiting cell death. This integrated genomic analysis also was applied to investigate VHL-deficient subtypes of ccRCC, one of which expresses both HIF1alpha and HIF2alpha (H1H2) and the other expressing only HIF2alpha (H2). Our analysis revealed that the H1H2 group has a more aberrant genome (on average) than the H2 group, and that H1H22 and H2 tumors each have a distinct pattern of genomic aberrations. We are the first to identify and functionally validate two potentially important targets on 5q in ccRCC and have further established that ccRCC can be classified into subtypes based on HIFalpha expression with each subtype having its own specific pattern of copy number alterations. We also created inducible HIF2alpha knockdown cells and developed an orthotopic xenotransplant model to study the role of HIF2alpha in tumor maintenance. This orthotopic model can be extended to study other targets of interest such as STC2 and VCAN.
Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2011.
Source: Dissertation Abstracts International, Volume: 72-12, Section: B, page: 7177.
Advisers: M. Celeste Simon; Katherine L. Nathanson.
Includes supplementary digital materials.
Local notes:
School code: 0175.
Nathanson, Katherine L., advisor
Simon, M. Celeste, advisor
University of Pennsylvania.
Contained In:
Dissertation Abstracts International 72-12B.
Access Restriction:
Restricted for use by site license.
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