Regulation of the Type I Interferon Pathway by Cancer Genes in Clear Cell Renal Cell Carcinoma
Abstract
Kidney cancer is one of the ten most common cancers diagnosed in the United States, the majority of which are clear cell renal cell carcinoma (ccRCC). While early stage ccRCC has a favorable prognosis, advanced stage disease remains incurable due to late diagnosis and acquired treatment resistance. Increased knowledge of the molecular pathways disrupted in ccRCC will help guide the development of novel therapeutic strategies. Genetically, ccRCC exhibits loss of the von Hippel-Lindau tumor suppressor gene (VHL), leading to constitutive hypoxia inducible factor (HIF) transcriptional activity. Loss of the BRCA1-associated protein 1 (BAP1) tumor suppressor is observed in 13 percent of patients and is associated with poor prognosis, yet its precise role in ccRCC is not well understood. In this thesis, the impact of the VHL-HIF axis and BAP1 on signaling pathways leading to ccRCC tumor progression are examined and a new treatment strategy is explored. This work builds on previous studies in the lab implicating VHL and HIF in the regulation of interferon stimulated gene factor 3 (ISGF3), a heterotrimeric transcription factor that mediates the type I interferon (IFN) response. Using VHL–/– isogenic cell lines and mouse xenograft models, we show that VHL re-expression or HIF2α suppression reduce ISGF3 activity by downregulating IFN-β transcript levels. Suppression of IFN-β enhances tumor growth in Ren-02 xenografts, suggesting it functions as a tumor suppressor. Moreover, we demonstrate that BAP1 stimulates ISGF3 activity via upregulation of IFN-β and stimulator of interferon genes (STING) signaling. We confirm the tumor suppressor function of BAP1 in Ren-02 xenografts and show that ISGF3 expression in the cancer cells or systemic STING activation via intraperitoneal agonist treatment reduce the growth of BAP1-deficient tumors. Altogether, our results provide evidence for type I IFN pathway dysregulation as a central feature of ccRCC, as several cancer genes implicated in the disease modulate its tumor suppressive activity, and we demonstrate a novel function of BAP1 in ccRCC that can be therapeutically targeted.
Subject Area
Molecular biology|Oncology|Biology
Recommended Citation
Langbein, Lauren E, "Regulation of the Type I Interferon Pathway by Cancer Genes in Clear Cell Renal Cell Carcinoma" (2022). ProQuest ETD Collection - Thomas Jefferson University. AAI30242033.
https://jdc.jefferson.edu/dissertations/AAI30242033
