Patient samples of renal cell carcinoma show reduced expression of TRAF1 compared with normal kidney and functional studies in vitro indicate TRAF1 promotes apoptosis: potential for targeted therapy

Abstract

The tumour necrosis factor (TNF) receptor-associated factor (TRAF) family of proteins links the TNF receptor superfamily to cell signalling cascades. TRAF1 is involved in regulation of apoptosis, proliferation, differentiation and stress responses. It has a role in development of several malignancies, but no information for renal cell carcinoma (RCC) is available. Expression profiles for TRAF1 were investigated in 121 samples of human RCC of various subtypes plus paired normal kidney prepared in tissue microarrays, in comparison with apoptosis (morphology, ApopTag) and mitosis (morphology, proliferating cell nuclear antigen/PCNA). TRAF1 function was tested in vitro in RCC ACHN cells. TRAF1 short interfering RNA (siRNA) was used to inhibit expression of TRAF1 in ACHN cells untreated or treated with cancer therapies known to induce apoptosis (20 Gy X-irradiation and/or 500 IU/mL interferon-alpha). In patient samples, TRAF1 localised to proximal tubular epithelium in normal kidney and was significantly decreased in clear cell RCC as one group (p < 0.01) and all other RCC subclassifications grouped together (p < 0.05). There was little apoptosis identified in any RCC samples. In vitro, TRAF1 siRNA caused significant reduction in TRAF1 expression and a concurrent decrease in apoptosis and increase in proliferative activity (both p < 0.05) in the ACHN RCC cells treated with radiation and interferon-alpha. TRAF1 may have a pro-apoptotic, anti-mitotic role in RCC. The low TRAF1 expression in untreated RCC patient samples compared with normal kidney, and the localisation of TRAF1 to the proximal tubular epithelium from which many RCC originate, may indicate a potential for targeted therapy in RCC.