Abstract
BackgroundDecreased expression of the interferon-stimulated, putative tumour suppressor gene XAF1 has been shown to play a role during the onset, progression and treatment failure in various malignancies. However, little is yet known about its potential implication in the tumour biology of clear-cell renal cell cancer (ccRCC).MethodsThis study assessed the expression of XAF1 protein in tumour tissue obtained from 291 ccRCC patients and 68 normal renal tissue samples, utilizing immunohistochemistry on a tissue-micro-array. XAF1 expression was correlated to clinico-pathological tumour features and prognosis.ResultsNuclear XAF1 expression was commonly detected in normal renal- (94.1%) and ccRCC (91.8%) samples, without significant differences of expression levels. Low XAF1 expression in ccRCC tissue, however, was associated with progression of tumour stage (p = 0.040) and grade (p < 0.001). Low XAF1 tumour levels were also prognostic of significantly shortened overall survival times in univariate analysis (p = 0.018), but did not provide independent prognostic information.ConclusionThese data suggest down-regulation of XAF1 expression to be implicated in ccRCC progression and implies that its re-induction may provide a therapeutic approach. Although the prognostic value of XAF1 in ccRCC appears to be limited, its predictive value remains to be determined, especially in patients with metastatic disease undergoing novel combination therapies of targeted agents with Interferon-alpha.
Highlights
Decreased expression of the interferon-stimulated, putative tumour suppressor gene XAF1 has been shown to play a role during the onset, progression and treatment failure in various malignancies
Transcriptional down-regulation of XAF1 expression has been reported to occur in Renal cell carcinoma (RCC) [21] and low XAF1 mRNA tumour levels have been linked to impaired prognosis in RCC patients [26]
The intensity of XAF1 expression in tumour tissue seemed to be more variable than in benign renal parenchyma, the median immunoreactive score (IRS) of 50 did not differ statistically significant from that observed in normal renal tissue
Summary
Decreased expression of the interferon-stimulated, putative tumour suppressor gene XAF1 has been shown to play a role during the onset, progression and treatment failure in various malignancies. XIAP-independent pathways of apoptosis-sensitization by XAF1 have been identified, e.g. the promotion of cytochrome c release, the prolonged activation of p53 protein and its target gene expression as well as the degradation of the IAP-family member survivin [20,21,22]. XAF1 is ubiquitously expressed in normal human tissues, but at comparably low or undetectable levels in numerous cancer cell lines with high XIAP expression on the other hand [17,18]. These data suggest that either down-regulation of XAF1 or up-regulation of XIAP expression may promote the survival of tumour cells [17,23]. This study was done to examine XAF1 protein expression in a large cohort of ccRCC patients and to investigate the impact of XAF1 expression on clinico-pathological parameters and outcome
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