Basic sciencec-FLIP expression in bladder urothelial carcinomas: its role in resistance to Fas-mediated apoptosis and clinicopathologic correlations
Section snippets
Patients
Fifty-three consecutive patients with primary invasive (N0M0) UC presenting at Asklepeion Voula Hospital in Athens between 1985 and 1995, for whom sufficient paraffin-embedded tissue was available, were enrolled in the present investigation. Of the 53 patients, 45 were men and 8 were women (median age 72 years, range 35 to 90). By the time this study was undertaken, 15 patients had died of their disease after a median survival of 12 months (range 7 to 39) and 2 patients had been lost to
Fas gene mutation detection
Using PCR-SSCP, a normal banding pattern was obtained for the vast majority of the samples (48 of 53; 91%). In 5 cases in which an aberrant banding pattern was observed, direct sequencing revealed a normal coding sequence of Fas exon 9. Therefore, none of the 53 UC samples tested showed evidence of mutations by PCR-SSCP and direct sequencing.
Fas, FasL, and c-FLIP expression
Immunoreactivity (defined as expression in 10% or more of neoplastic cells) was detected for Fas, FasL, and c-FLIP in 72%, 66%, and 81% of cases,
Comment
In vitro studies have indicated that despite Fas expression in UC cell lines, poorly differentiated cells are insensitive to either recombinant Fas ligand or agonistic apoptosis-inducing monoclonal antibody against Fas,12 raising the idea that bladder cancer cells must have acquired effective mechanisms to neutralize Fas signaling. The high frequency of Fas and FasL coexpression, an apparently counterintuitive combination of factors with deleterious effects on cell survival, documented in the
Conclusions
The results of the present investigation demonstrated that Fas, FasL, and c-FLIP are frequently expressed and coexpressed in bladder carcinoma, supporting the suspected involvement of c-FLIP as a mechanism to counteract apoptosis driven by Fas/FasL coexpression. c-FLIP gained further importance in this regard because we were unable to demonstrate structural alterations of the Fas death domain in our samples. More importantly, c-FLIP emerged for the first time as an independent prognostic
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2023, Biomedicine and PharmacotherapyRegulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks
2022, Trends in CancerCitation Excerpt :Taken together, the role of c-FLIP in DR-mediated apoptosis is multifaceted and controlled by a number of intricate mechanisms. Defects in apoptosis regulation are a classical feature of cancer cells [25,26], which often have abnormal c-FLIP expression [27–33]. A great deal of progress has been made in structural and functional c-FLIP research, however, several molecular features of c-FLIP-mediated assembly of macromolecular complexes have not yet been entirely determined [22,34,35].
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2015, Advances in Virus ResearchThe role of c-FLIP in cisplatin resistance of human bladder cancer cells
2013, Journal of UrologyTargeting c-FLIP in cancer
2013, Cancer LettersCitation Excerpt :Overexpression of c-FLIP is associated with an increased resistance to apoptosis mediated by Fas and TRAIL, and studies have demonstrated that in some tissue types, high levels of c-FLIP expression correlates with a more aggressive tumour [29]. Studies of patients with colorectal carcinoma [30], cervical carcinoma [31], Burkitt’s lymphoma [32], non-Hodgkin’s lymphoma [33], and bladder urothelial carcinomas [18] have demonstrated that elevated levels of c-FLIP in tumour tissue is correlated with a poor prognosis. To our knowledge only one study suggested that c-FLIP levels did not have any correlation with survival in ovarian cancers [34].