p53 and MDM2 in renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney cancer and follows an unpredictable disease course. To improve prognostication, a better understanding of critical genes associated with disease progression is required. The objective of this review was to focus attention on 2 such genes, p53 and murine double minute 2 (MDM2), and to provide a comprehensive summary and critical analysis of the literature regarding these genes in RCC. Information was compiled by searching the PubMed database for articles that were published or e-published up to April 1, 2009. Search terms included renal cancer, renal cell carcinoma, p53, and MDM2. Full articles and any supplementary data were examined; and, when appropriate, references were checked for additional material. All studies that described assessment of p53 and/or MDM2 in renal cancer were included. The authors concluded that increased p53 expression, but not p53 mutation, is associated with reduced overall survival/more rapid disease progression in RCC. There also was evidence that MDM2 up-regulation is associated with decreased disease-specific survival. Two features of RCC stood out as unusual and will require further investigation. First, increased p53 expression is tightly linked with increased MDM2 expression; and, second, patients who have tumors that display increased p53 and MDM2 expression may have the poorest overall survival. Because there was no evidence to support the conclusion that p53 mutation is associated with poorer survival, it seemed clear that increased p53 expression in RCC occurs independent of mutation. Further investigation of the mechanisms leading to increased p53/MDM2 expression in RCC may lead to improved prognostication and to the identification of novel therapeutic interventions. Cancer 2010;116:780-90. V C 2010 American Cancer Society.KEYWORDS: renal cancer, renal cell carcinoma, p53, murine double minute 2.The latest available figures from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program predict that there will be 49,096 new cases of kidney cancer (renal cancer and cancer of the renal pelvis) and 11,033 deaths from the disease in the United States in 2009. 1 In the United Kingdom, the latest figures for 2007 indicate that 7380 individuals were diagnosed with the disease and that 3752 died from it. 2 Advances in our understanding of the molecular biology of renal cell carcinoma (RCC) have helped classify this heterogeneous disease and led to the development of several new ''von Hippel-Lindau (VHL) pathway''-targeted molecular drug treatments. 3 Nevertheless, patients with metastatic disease still have an extremely short life expectancy. 3 Certainly other molecular pathways must contribute to the poor prognosis observed for those who have advanced RCC. The objective of the current review was to turn the molecular focus back to 1 of the most important genes in cancer biology, p53, and its counterpart, murine double minute 2 (MDM2), and to describe and critically review what is known of their ro...

Choosing the right cell line for renal cell cancer research

“…Varied expression of the protein is visible in cell lines, which corresponds with in vivo data, as p53 over-expression occurs in later stages of the disease [157] and to some extent correlates with poor prognosis [158]. A relatively high expression of p53 was observed in ACHN, Caki-2, UOK121, and UM-RC-6 and low in A-498 (although mutated) [159, 160].…”

IMP3, a Promising Prognostic Marker in Clear Cell Renal Cell Carcinoma

“…Mutations of p53 or functional inactivation of the intact p53 gene are common in many human cancers and over-expression of p53 is associated with poor prognosis in a variety of cancers. Recent studies have reported that mutations of p53 were found in 0% to 44% of renal malignant tumors and higher p53 expression levels were associated with poor prognosis in CCRCC 17,18,19…”

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

“…Another study revealed that MDM2 promoted p53 deacetylation via recruitment of the HDAC1 complex [16]. In kidney, MDM2 is associated with tubular epithelial cell death [17], podocyte mitotic catastrophe [18], kidney development [19] and renal cell carcinoma [20]. Our previous study demonstrated that MDM2 participated in fibroblast activation and TIF via a p53-independent pathway [21].…”