Apoptosis plays an essential role in cell homeostasis. One of the major apoptotic mechanisms is the receptor-mediated pathway in which Fas acts a central part. Fas is a cell surface receptor which interacts with its natural ligand FASL to initiate the death signal cascade, which results in apoptotic cell death [76].
The most basic requirement for normal functioning of the death receptor pathways is that the receptor is expressed on the tumor cell surface to allow receptor ligand interaction. Several events could lead to evasion of Fas-mediated apoptosis: downregulation of Fas and upregulation of FasL expression in tumor cells are some examples; others, such as hypermethylation or mutation of FAS gene are also known [79].
Other mechanisms that help cancer cells to evade the cytotoxic T cell attack are soluble decoy receptors. These receptors are thought to be released from the tumors and act as competitive inhibitors for membrane bound receptors, effectively shielding the tumor from attack. FasL “counter-attack” is a proposed theory of apoptosis evasion, through Fas/FasL pathway [71].
The importance of functional polymorphisms analysis as been suggested, in order to elucidate and identify individual susceptibility for cancer development and treatment response [16, 123].
Several studies have investigated the association between FAS–670A/G and the FASL–844T/C polymorphisms and the risk of human cancers [103-109, 141, 142]. Although some studies have found no significant association of the FAS–670A/G polymorphism with the risk of several types of human cancers, even so these studies only evaluated FAS–670 polymorphism [141, 142]. One group
their studies showed that these polymorphisms increased the risk of esophageal and lung cancer and proposed that this association displayed a multiplicative gene-gene interaction [106, 109]. However, they reported that in cases of cervical cancer, only the FASL–844T/C polymorphism was associated with the risk of cervical cancer [107]. In addition, Sibley and co-workers [103] reported tha,t of two FAS promoter polymorphisms, only the FAS-1377G/A polymorphism, but not FAS–670A/G, was associated with a significantly increased risk of acute myeloid leukaemia in a study performed in the United Kingdom. Krippl and collegues [104]
also reported that the FAS -1377 G/A polymorphism increased the risk of breast cancer; however, neither the FAS–670A/G nor the FASL–844T/C were associated with risk of breast cancer in a Caucasian population. These previous studies suggest that polymorphisms in the FAS and FASL genes may increase the susceptibility to some types of human cancers, although it is unclear which of the polymorphisms has the main effect in disease development. By contrast, Lai and his group [105] reported an oppositely directed association of the FAS–670A/G polymorphism with cervical cancer in a Taiwanese population: they found that the FAS–670 A allele was associated with a significantly increased risk of cervical cancer.
No studies have been reported regarding the evaluation of FAS and FASL polymorphisms in prostate cancer patients. This is the first study to analyze a possible association between FAS and FASL polymorphisms and altered susceptibility to prostate cancer. However, no statically significant association was found between the studied polymorphisms and individual prostate cancer risk.
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Although the reason for the different findings considering the FAS and FASL polymorphisms in human cancers from different studies is unclear, there are several possible explanations for this. First, it may be the result of the different ethnicities of the studied populations. The allelic and genotype frequencies of the FAS and FASL polymorphisms vary greatly in different ethnic groups [104-106].
Therefore, the genetic effect of the FAS and FASL polymorphisms on the susceptibility to human cancer may be diverse in different ethnic populations.
Second, it may be due to different molecular mechanisms underlying the development of different cancers. In addition, inadequate study design such as non-random sampling, limited sample size and the pitfalls arising from unknown confounders also need be considered.
The frequency of FAS genotypes in the normal control population was analyzed. These results show that the general population has a profile for FAS–
670A/G polymorphism similar to other Caucasian European and non-European populations. Interestingly, differences were found in the genotype frequencies in comparison to what is reported for Han Chinese populations, and also with Indian and Brazilian populations. When a similar comparison between FASL–844T/C polymorphism was performed between Portuguese and other normal population, different genotype frequencies were found regarding Asian and USA populations.
However, similar genotype frequencies were found with other European populations, with an exception of a control group from Denmark.
In the selection of subjects, the evaluation of potential selection bias was
were randomly selected. Thus, it was considered that these results represent the FAS and FASL polymorphisms genotype frequencies in an approximate estimate of the genetic profile of the Portuguese population.
The results revealed that FAS–670A/G polymorphism may influence the prostate cancer development. Individuals carrying AG and GG genotypes present statistically significant protection (OR=0.30; CI: 0.20–0.44 and OR=0.22; CI: 0.12–
0.41, respectively) for extra-capsular invasion in prostate cancer patients. These results demonstrate a protective effect for the onset of extra-capsular invasion in G allele carriers (OR=0.28; CI: 0.19–0.41).
Previous studies reported that the G allele reduces the transcriptional activity of FAS gene [101, 102], consequently reducing the expression of Fas protein. Furthermore, several studies suggested that the reduction of Fas membrane receptor would reduce apoptosis and be associated with a malignant potential [108, 140, 142]. Recently published studies have been reported, indicanting lines of evidence that reinforces the results that were found in this study [89, 155-157].
Fas exist as membrane bound and soluble forms with opposite roles on triggering apoptosis. They derive from the same gene by alternative splicing.
Membrane Fas receptor triggers apoptosis and, on other hand, sFas, which lacks transmembrane domain, binds to Fas ligand antagonizing Fas/FasL apoptotic pathway [36, 37].
Jiang and colleagues [156] have found a Fas elevated expression with a cytoplasmatic staining pattern in high-grade prostatic intraepithelial neoplasia (PIN)
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and prostatic adenocarcinomas compared with adjacent benign prostate tissue.
These results suggest an elevated expression of sFas in prostate cancer cells.
It was reported that serum sFas is elevated in prostate cancer and associated with poor prognosis in metastatic and advanced diseases [89, 157].
Serum sFas is also elevated in bladder cancer and is associated with poor prognosis [43] and predicts early recurrences in patients with bladder cancer [58].
Another study in bladder cancer suggests that sFas is likely to be produced and released by bladder urothelial cell carcinoma (UCC) cells and that urine sFas levels could be an independent predictor of presence and invasiveness of bladder cancer [158]. Other studies have found association between sFas expression or serum levels in cancer patients of bile duct carcinoma [159], breast carcinoma [44, 160], colon carcinoma [41], gastric carcinoma [42], gynecological malignancies [161] and melanoma [45].
A recent published study supports the proposed hypothesis; Mahfoudh and colleagues [162] shown that serum sFas levels could be related to FAS–670A/G polymorphism and they demonstrated that FAS–670 A allele appear to reduce sFas concentrations in healthy population serum [162].
According to the found results and reinforced by the evidence of the sFas’
role in apoptosis and its higher levels in various types of cancer, especially prostate cancer, we hypothesized that the reduction of the expression of Fas caused by G allele would reduce sFas expression levels preventing the anti-apoptotic effect of this protein.
Other important result found in this work, is related with FASL
with T carrier genotypes (TT+TC), which present higher PSA levels (OR=0.28; CI:
0.19–0.41), being evident a protective effect of CC genotype.
FASL–844 CC genotype was associated with higher basal expression levels of FasL [49] and this death ligand is expressed in T-cells membrane or in some tumors cells [96-100]. Few studies reported that prostatic tumor cells have FasL overexpression in their surface membrane. However, assuming that the effect of FASL–844 polymorphism could be associated with a higher expression of FasL in T cell population, it might confer them a more effective apoptosis induction in tumor cells.
Elevated PSA levels are associated with a higher number of prostate cells and an enhanced proliferation rate [132], therefore, in these cells apoptosis may not be so efficient in the control and maintenance of cell homeostasis.
Consequently, patients with FASL–844 CC genotype, which might have a more effective apoptosis induction by T cell, controling prostatic cell proliferation, and thus, reducing PSA levels.
The interaction between FAS and FASL polymorphisms is biologically plausible because these two molecules are a receptor-ligand system, and apoptotic cell death needs both normal Fas and normal FasL. Therefore, if a cell carries functional polymorphisms in both genes that have an effect on their expression level, an additive effect is to be expected. Hence, a possible gene–
gene interaction between FAS and FASL polymorphisms and their role in increasing prostate cancer risk was also analysed.
In this analysis, from the evaluated criteria, only a protective effect was found for advanced disease (OR=0.32; CI: 0.20–0.49) in simultaneously FASL–
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844 T carrier (TT+TC) and FAS–670 G carrier (AG+GG) patients. Although, a protection was also found (OR=0.45; CI: 0.26–0.78) for patients with FASL–844 CC genotype and FAS–670 G carriers.
These results could indicate that, in prostate cancer, FAS and FASL polymorphisms may not have an interaction, as appointed by other studies in different cancer models. On the other hand, these results could be explained by the fact that the influence of G allele in disease status might be the reduction of sFas levels, controlling the anti-apoptotic effect of this soluble form, and liberating FasL to induce apoptosis independently of its expression level, which is influenced by FASL polymorphism.
These results might help understating the role of FAS and FASL polymorphism in the development of prostate cancer.
6. CONCLUSIONS AND
FUTURE PERSPECTIVES
This study reinforces several lines of evidence suggesting that genetic analysis of functional polymorphisms may help to understand cancer development and progression.
According to the results of the present study, FAS–670A/G and FASL–
844T/C are not related with prostate cancer risk. On other hand, FAS–670 G allele might be a protection factor for advanced disease in prostate cancer, as well as FASL–844 CC genotype could have influence in PSA levels. These two polymorphisms may not interact with each other in prostate cancer carcinogenesis.
Furthermore, the genotype frequencies of the studied polymorphisms were very similar to previously reported results in other Caucasian European populations.
Overall, FAS and FASL polymorphisms may not influence prostate cancer individual susceptibility. However these polymorphisms seem to be involved in prostate cancer development.
Regarding the results found in this study, it might be important to evaluate Fas and FasL expression in prostate cancer cells, as well as to measure sFas and sFasL levels in serum of prostate cancer patients, thus evidencing the influence of FAS and FASL polymorphisms in the expression of Fas and FasL proteins.
The analysis of other described FAS promoter polymorphisms (FAS–
1377G/A), which might have a powerful influence in Fas transcription alone or interacting with FAS–670A/G, is essential to evaluate their role in prostate cancer susceptibility and development. However, is also important to confirm the results that were found in a higher number of individuals; and correlate the genotype
Apoptosis is a complex process that involves several mechanisms and different molecules; therefore it is essential to evaluate functional polymorphisms that influence other proteins involved in Fas/FasL pathways, as well as other apoptotic pathways, in order to comprehend the apoptotic process.
Finally, it is important to expand this study to other types of cancer, to subsequently understand the role of polymorphisms and Fas/FasL pathways in cancer.
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