There are presently about 39,000 new cases of renal cancer in the United States each year, resulting in over 13,000 deaths. Traditional radiation and chemo-therapies are ineffective. Early detection is also difficult because of a lack of early symptoms. 40-50% of patients develop metastatic disease, for whom the 5-year survival rate is only ~10%. Such grim statistics point to an urgent need for better understanding of the kidney cancer biology. One important characteristic of kidney cancer is its strong association with lesions in one gene, the von Hippel-Lindau (VHL) tumor suppressor gene. The gene is named after the familial VHL disease. Up to 70% of the carriers of germ line VHL mutations develop renal cell carcinoma of the clear-cell type (ccRCC). In addition, loss of VHL function, including somatic mutations and epigenetic defects, is found in 70-90% of sporadic ccRCC. The best-documented function of VHL is its E3 ubiquitin ligase activity that targets the alpha subunit of the hypoxia-inducible factor (HIF-a). However, VHL also possess multiple HIF-independent functions. It is not known how loss of the complex spectrum of VHL functions collectively contribute to the initiation of ccRCC. The uncertainties are further compounded by a lack of VHL cancer model in mouse. Our studies in the past funding period have elucidated a novel epithelial-to-mesenchymal transition (EMT) pathway that has been implicated in kidney injury and fibrosis. Most importantly, using a new conditional knockout strategy, we have, for the first time, developed a genuine mouse ccRCC model that recapitulates features of kidney inflammation and fibrosis, leading to metastatic ccRCC. This model should allow us to elucidate the earliest event in ccRCC and point to potential preventive and curative strategies for this deadly disease.
Four Specific Aims are proposed to characterize the new VHL cancer model:
Aim 1. To determine the tissue origin and the role of VHL-HIF axis in VHL knockout lesions.
Aim 2. To elucidate the molecular and cellular mechanisms of EMT signaling in VHL mutant cells.
Aim 3. To elucidate the mechanism of inflammation in VHL mutant kidney.
Aim 4. To profile the gene expression pattern associated with VHL tumor progression.
Mutations in VHL tumor suppressor gene are the cause of a majority of kidney cancers, but the exact tumorigenic mechanism of this deadly disease is still unknown. We recently developed a VHL mutant mouse model that for the first time, generated kidney cancer and suggested an intriguing possibility of inflammation prior to tumor development. Our proposed study should shed lights on the process of kidney cancer formation and point to preventive and curative strategies.
|Bader, Hannah L; Hsu, Tien (2016) Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model. BMC Cancer 16:797|
|Lin, Chih-Hung; Dammai, Vincent; Adryan, Boris et al. (2015) Interaction between Nm23 and the tumor suppressor VHL. Naunyn Schmiedebergs Arch Pharmacol 388:143-52|
|Pritchett, T L; Bader, H L; Henderson, J et al. (2015) Conditional inactivation of the mouse von Hippel-Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney. Oncogene 34:2631-9|
|Ignesti, Marilena; Barraco, Marilena; Nallamothu, Gouthami et al. (2014) Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23. BMC Biol 12:12|
|Liby, Tiera A; Spyropoulos, Perry; Buff Lindner, Haley et al. (2012) Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells. Int J Cancer 130:532-43|
|Bader, Hannah L; Hsu, Tien (2012) Systemic VHL gene functions and the VHL disease. FEBS Lett 586:1562-9|
|Hsu, T (2012) Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: insights from model organisms. Oncogene 31:2247-57|
|Hsu, Tien (2011) NME genes in epithelial morphogenesis. Naunyn Schmiedebergs Arch Pharmacol 384:363-72|
|Hsouna, Anita; Nallamothu, Gouthami; Kose, Nurgun et al. (2010) Drosophila von Hippel-Lindau tumor suppressor gene function in epithelial tubule morphogenesis. Mol Cell Biol 30:3779-94|
|Duchi, Serena; Fagnocchi, Luca; Cavaliere, Valeria et al. (2010) Drosophila VHL tumor-suppressor gene regulates epithelial morphogenesis by promoting microtubule and aPKC stability. Development 137:1493-503|
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