Prognostic value of apoptosis inducing factor in uveal melanoma

Abstract

In malignant tumors including uveal melanoma there is a continuous effort in search for additional and relevant factors with predictive value and possible therapeutic indications. In the present work we evaluated the 5-year mortality in a group of patients with surgically treated uveal melanoma and its relation to selected demographic, clinical and histopathological parameters, including the expression of apoptosis inducing factor (AIF) in the neoplastic tissue.We analyzed retrospectively the clinical data of patients with uveal melanoma treated surgically (enucleation, endoresection, exenteration) in the period from 2001 to 2007 (n=54). Immunohistochemical detection of AIF expression in formalin fixed and in paraffin embedded tissue samples was evaluated semiquantitatively, intensity and percentage multiplicative Quick Score (QS) was calculated and compared between patients with over 5 year (n=32) and less than 5 year (n=22) survival. In the analyzed group of 54 patients the 5 year mortality was 41 %. We confirmed the negative prognostic significance of some of the known prognostic factors as the tumor size and volume, T3 and T4 stage in the TNM classification and the mixed histological type of the tumor. Immunohistochemistry performed on 49 melanoma specimens showed AIF cytoplasmic positivity, no nuclear translocation was detected. The cut-off value of AIF expression QS ≥ 4 (18) in tumor cells separated the 5 year survival of patients (P = 0.018), odds ratio 5.2 (1.24 - 21.73). Moderate and strong expression of AIF in tumor cells also correlated with less favorable prognosis. Confocal microscopy proved colocalization of AIF with mitochondrial marker in neoplastic cells.The prognosis of patients with uveal melanoma can be more accurate with inclusion of immunohistochemical detection of AIF expression. Increased expression of the AIF protein appears as a new negative prognostic factor predicting the 5 year survival.

AIF promotes a JNK1-mediated cadherin switch independently of respiratory chain stabilization

“…The NADH-oxidase activity of AIF has been studied in vitro (30), but the biochemical consequences of AIF-mediated redox control within cells and the contribution of AIF to cell signaling have remained largely unclear. A number of studies have indicated that AIF is up-regulated in tumors, albeit typically not more than 2-fold (9,10,(23)(24)(25)(26)(27)(28)(29). The ability of AIF to regulate cellular redox signaling provides further insight into overexpression levels, which may explain why AIF elevation in cancer rarely exceeds 2-fold compared with normal cells (9, 10).…”

“…A cellular context in which these AIF activities are critical is the environment of tumor cells, which exhibit an elevated dependence upon metabolic and redox balance for growth and survival (22). Numerous studies have demonstrated AIF overexpression in cancer (9,10,(23)(24)(25)(26)(27)(28)(29), suggesting an ability of tumors to exploit AIF activity during pathogenesis. Indeed, we and others have shown that AIF is critical to the growth and/or survival of pancreatic (10), prostate (9), and colorectal (11) cancers.…”

“…The observation that AIF promotes ROS formation (30) raises the possibility that this activity functions as a trigger for one or more ROS-sensitive signaling pathways that influence tumorigenesis. Concomitantly, AIF is often elevated in cancer (9,10,(23)(24)(25)(26)(27)(28)(29) and may therefore serve as a contributory factor to promote tumorigenic redox signaling. Relative to healthy tissues, cancer cells elevate ROS to levels that benefit tumorigenesis by activating oxidative stress-associated prosurvival and proliferative signaling pathways (31), such as those driven by the activities of the mitogen-activated protein kinase (MAPK) family of proteins (32).…”

Prognostic Value of Apoptosis-Inducing Factor (AIF) in Germ Cell Tumors

“…These results suggested tissue-specific function of AIF and indicated that AIF downregulation might play an important role in early stages of kidney tumor development [30]. Association between AIF expression and disease prognosis has been observed in various malignant tumors [23,28,29,31,32]. However, currently, prognostic value of AIF in testicular GCTs (TGCTs) remains unknown.…”

“…Since reduced cell survival correlated with decreased expression of mitochondrial complex I protein subunits, the authors stressed the importance of prosurvival function of AIF required for aggressive growth of the neoplasm [22]. AIF overexpression was also found in uveal melanoma [23], carcinoma of the stomach [24], colon [25], skin [26] and pancreas, chronic lymphocytic leukemia (CLL), and diffuse large B-cell lymphoma (DLBCL) [27][28][29]. On the other hand, downregulation of AIF is a rare event in malignant tumors.…”