UC Davis

Kidney cancer or renal cell carcinoma (RCC) is the 6th most common type of cancer in men and the 9th common cancer in women in the United States and claims nearly 15,000 lives annually. 75% of total RCC cases are clear-cell renal cell carcinoma (ccRCC) which is refractory to the conventional chemotherapy and there is currently no effective cure against ccRCC except for surgical removal. While Fuhrman nuclear grading has been widely used as a prognostic tool for ccRCC, its subjective nature hinders precise and reliable patient-specific prognosis. The overarching aim of this dissertation is to characterize the molecular components of Fuhrman nuclear grades to understand the molecular underpinning of ccRCC chemoresistance and to identify proteomic and metabolomic signatures of ccRCC that can be harnessed to establish novel diagnostic tools complimentary to the Fuhrman nuclear grading and to identify potential novel grade-defined pharmacological targets. This dissertation first aims to characterize the molecular mechanisms behind the ccRCC chemoresistance using Roscovitine (Seliciclib) as an example of conventional chemotherapy via cyclin dependent kinase (CDK) inhibition. Second, Fuhrman nuclear grade-defined proteomes are characterised to identify a set of proteins that can be used as diagnostic biomarkers and grade-specific pharmacological ccRCC targets. Third, the potential role of Argininosuccinate Synthetase (ASS1), whose expression was suppressed across all Fuhrman grades, in ccRCC pathogenesis is investigated. Additionally, in order to establish novel diagnostic criteria, this study aims to characterize the grade-dependent subcellular localization of novel ccRCC biomarker proteins that are found to behave as moonlighting proteins.