Abstract
The pituitary tumor transforming gene (PTTG1) is a recently discovered oncogene implicated in malignant progression of both endocrine and nonendocrine malignancies. Clear cell renal cell carcinoma (ccRCC) is cytogenetically characterized by chromosome 3p deletions that harbor the ccRCC-related von Hippel-Lindau, PBRM1, BAP1, and SETD2 tumor suppressor genes, along with chromosome 5q amplifications where the significance has been unclear. PTTG1 localizes to the chromosome 5q region where amplifications occur in ccRCC. In this study, we report a functional role for PTTG1 in ccRCC tumorigenesis. PTTG1 was amplified in ccRCC, overexpressed in tumor tissue, and associated with high-grade tumor cells and poor patient prognosis. In preclinical models, PTTG1 ablation reduced tumorigenesis and invasion. An analysis of gene expression affected by PTTG1 indicated an association with invasive and metastatic disease. PTTG1-dependent expression of the RhoGEF proto-oncogene ECT2 was observed in a number of ccRCC cell lines. Moreover, ECT2 expression correlated with PTTG1 expression and poor clinical features. Together, our findings reveal features of PTTG1 that are consistent with its identification of an oncogene amplified on chromsome 5q in ccRCC, where it may offer a novel therapeutic target of pathologic significance in this disease.
Highlights
Renal cell carcinoma (RCC) is the most common type of kidney cancer and accounts for approximately 39,000 new cases and 13,000 deaths per year within the United States [1]
In order to study the importance of the PTTG1 oncogene in vitro and in vivo, we examined the level of PTTG1 protein expression in several Clear cell renal cell carcinoma (ccRCC) and other kidney-derived cell lines (Fig. 3A)
We show that PTTG1, a recently described oncogene, is located in this region of amplification
Summary
Renal cell carcinoma (RCC) is the most common type of kidney cancer and accounts for approximately 39,000 new cases and 13,000 deaths per year within the United States [1]. The oncogenic potential of PTTG1 was initially shown by its ability to transform NIH3T3 fibroblasts upon overexpression. This was later substantiated in HEK293 cells in which overexpression of PTTG1 resulted in increased cell proliferation, anchorage-independent growth in soft agar, and tumor formation in nude mice [25]. We show that PTTG1 overexpression in ccRCC is associated with patient survival and assess its putative role as a promoter of disease progression. We show that this 5q oncogene is genetically amplified in ccRCC and contributes to the oncogenic transformation of renal cancer cells, as well as, the progression of ccRCC from localized to invasive disease. We show that PTTG1 regulates the expression of the Rho-GEF ECT2, another novel proto-oncogene that exhibits significant overexpression in aggressive ccRCC
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