Abstract
Currently there is a lack of targeted therapies that lead to long-term attenuation or regression of disease in patients with advanced clear cell renal cell carcinoma (ccRCC). Our group has implemented a high-throughput genetic analysis coupled with a high-throughput proliferative screen in order to investigate the genetic contributions of a large cohort of overexpressed genes at the functional level in an effort to better understand factors involved in tumor initiation and progression. Patient gene array analysis identified transcripts that are consistently elevated in patient ccRCC as compared to matched normal renal tissues. This was followed by a high-throughput lentivirus screen, independently targeting 195 overexpressed transcripts identified in the gene array in four ccRCC cell lines. This revealed 31 'hits' that contribute to ccRCC cell proliferation. Many of the hits identified are not only presented in the context of ccRCC for the first time, but several have not been previously linked to cancer. We further characterize the function of a group of hits in tumor cell invasion. Taken together these findings reveal pathways that may be critical in ccRCC tumorigenicity, and identifies novel candidate factors that could serve as targets for therapeutic intervention or diagnostic/prognostic biomarkers for patients with advanced ccRCC.
Highlights
Renal Cell Carcinoma (RCC) is among the top ten most common solid tumors in the United States
In this study we utilized a high-throughput gene array of patient clear cell subtype of RCC (ccRCC) tissues and matched normal samples followed by a high-throughput shRNA screen in an effort to identify genes transcripts that are overexpressed in tumor samples, and to ascertain those that promote ccRCC cell proliferation
Our findings reveal tumor-specific upregulation of factors that influence tumor cell growth, and angiogenesis, inflammation, and cell migration
Summary
Renal Cell Carcinoma (RCC) is among the top ten most common solid tumors in the United States. The clear cell subtype of RCC (ccRCC) manifests in the majority of all cases, accounting for approximately 80% [2]. The prognosis for patients who present with localized disease is relatively good, and treatment typically involves surgical resection of the tumor. Patients who present with advanced and metastatic disease have markedly worse prognoses, with overall survival rates dropping to 50% for stage III and
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