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FAS

Fas cell surface death receptor;FAS;Fas cell surface death receptor

APO-1 cell surface antigen|CD95 antigen|Delta Fas/APO-1/CD95|FAS 827dupA|FAS receptor variant 9|FASLG receptor|Fas (TNF receptor superfamily, member 6)|Fas AMA|TNF receptor superfamily member 6|apoptosis antigen 1|apoptosis-mediating surface antigen FAS|t

10q24.1

protein-coding

OBJECTIVE: To investigate the correlations between Fas-1377 and -670 polymorphisms and survival in Chinese women with breast cancer. METHODS: Polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP) was used to detect the polymorphism of Fas gene in 310 breast cancer patients with a long-term follow-up (median 10.5 years, range 0.2 - 16.1 years). Survival curves were analyzed by Kaplan-Meier method. RESULTS: The polymorphism of neither Fas-1377 nor Fas-670 was significantly correlated with the overall survival in this series of 310 cases (P > 0.05). However, among 146 patients without lymph node metastasis, the 5-year overall survival (OS) rate was significantly lower in the patients with Fas-1377 AA genotype than that in the patients with Fas-1377 GA or GG genotype (OS: 66.7% vs. 95.4%, P = 0.03). Among 117 patients with lymph node metastasis, both the Fas-1377 and Fas-670 polymorphisms were not significantly correlated with OS (P = 0.42). CONCLUSION: Among breast cancer patients without lymph node metastasis, patients with Fas-1377 AA genotype may have a worse survival, while patients with Fas-1377 GA or GG genotype may not be so.

Single-nucleotide polymorphisms of the FAS -1377G/A, FAS -670A/G, and FASL -844T/C genes may alter transcriptional activity of these genes. Recent evidence suggests an association of these polymorphisms with an increased risk of cervical cancer, so we explored this relationship. Genotypes of 155 patients with cervical cancer and 160 healthy control subjects were determined using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Associations with cancer risk were estimated using two-sided logistic regression. We observed a significantly increased risk of lymph node metastasis associated with the FAS -1377 GA or AA polymorphism [odds ratio (OR) = 4.16, 95% confidence interval (CI) = 1.10 to 15.74; P = 0.036]. In addition, the FAS -670AG or GG genotype showed an increased incidence of node metastasis, but these findings were not statistically significant (OR = 3.67, 95%

BACKGROUND AND AIM: Our purpose is to study the clinical significance of Fas/FasL expression in colon cancer and liver metastases (LM). MATERIAL AND METHODS: The expression of Fas/FasL in 68 patients with colon cancer was examined immunohistochemically and correlated to the clinicopathological features of the tumors. RESULTS: High expression of FasL, was observed in stage D and in LM (p=0.024). Fas expression was reduced in stage D tumors and in LM, when compared to earlier stages of disease (p=0.024). LM had also shown a decreased expression of Fas (p=0.016). tumors with low FasL expression upregulate more often their Fas expression (p = 0.028). No correlation could be established regarding the patients survival. CONCLUSIONS: Low expression of Fas and high expression of FasL are more often in colon tumor stage D and in liver metastasis; these imply tumor aggression, resistance against apoptosis, and could be held as negative prognostic factors.

AIM: To investigate the relation of Fas and Fas ligand (FasL) protein expression with carcinogenesis and metastasis of gastric carcinoma. METHODS: Immunohistochemistry was used to detect Fas and FasL protein expression in 64 gastric carcinoma tissue samples and 20 normal gastric tissue samples. Relation between FasL and Fas expression, age and gender of gastric cancer patients, and pathological subtype and lymph node metastasis of gastric cancer was analyzed. RESULTS: The Fas expression level was significantly higher in normal gastric tissue samples than in gastric carcinoma tissue samples (85.0% vs 25.0%, P < 0.001), while the FasL expression level was significantly lower in normal gastric tissue samples than in gastric carcinoma tissue samples (30.0% vs 81.3%, P < 0.001). The Fas expression level was significantly higher in invasive lymph nodes than in non-invasive lymph nodes (82.9% vs 56.5%, P < 0.003) and in well-differentiated gastric carcinoma tissue samples than in poorly-differentiated gastric carcinoma tissue samples (50.0% vs 18.0%, P = 0.015). The FasL expression level was significantly lower in well-differentiated gastric carcinoma tissue samples than in poorly- differentiated gastric carcinoma tissue samples (42.9% vs 84.0%, P = 0.021). The Fas and FasL expression levels (25.0% and 81.3%) were significantly different in gastric carcinoma tissue samples (P < 0.001), but had a non-linear correlation (P = 0.575). CONCLUSION: Abnormal Fas and FasL expressions in gastric carcinoma and lymph node tissues are involved in carcinogenesis and metastasis of gastric cancer.

Fas signaling was reported to participate in cell apoptosis. However, this pathway has also been shown to promote tumor cell motility, leading to the hypothesis that Fas signaling may induce epithelial-mesenchymal transition (EMT) to promote metastasis. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signaling on colorectal and gastric cancer cells were tested using motility assay, immunofluorescence, RT-PCR and immunoblot analyses. Fas signaling downregulated epithelial markers, upregulated mesenchymal markers and promoted motility in gastrointestinal (GI) cancer cells. FasL treatment also increased the expression of EMT transcriptional factors in the nucleus and induced a spindle shape cell morphology in these cells. Knockdown of Snail or Twist expression significantly decreased FasL-induced motility. The ERK1/2 pathway was activated by Fas signaling and is required for FasL-induced EMT and motility. Moreover, oxaliplatin, a chemotherapeutic agent, induced EMT partly through Fas signaling. Evaluation of human GI clinical specimens showed that FasL expression increased whereas E-cadherin expression decreased during GI cancer progression. Both markers were significantly inversely correlated. Tissue samples with a non-EMT phenotype were mainly distributed in patients with early cancer stages, whereas samples with an EMT phenotype were mostly distributed in patients with advanced cancer stages. A non-EMT phenotype significantly correlated with better prognosis. Altogether, these data indicate that Fas signaling may induce EMT to promote tumor motility and metastasis in GI cancer in vivo and in vitro.

BACKGROUND: FAS and its ligand, FASL, have important roles in the neoplasia-immunity relationship. In melanoma, the importance of FAS and FASL remains controversial, despite a group of studies. In this study, we aimed to demonstrate the distribution of FAS/FASL in melanotic lesions and to investigate the correlation between tumor infiltrating lymphocytes and macrophages. METHODS: Ten intra-dermal nevi, 12 primary malignant melanoma, and eight skin and 15 lymph node metastases were included in this study. FAS and FASL were studied in all of the groups using classical labeled streptavidin-biotin immunohistochemical method. tumor infiltrating lymphocyte status and macrophage number demonstrated by CD68 immunostain were also evaluated in primary melanoma and skin metastases. RESULTS: FAS positivity was detected in all of the cases. FASL expressions were seen in 60% of the intra-dermal nevus and in all of the other groups. There were significant differences in FASL between nevus and primary melanoma, nevus and skin metastasis, and nevus and lymph node metastasis. There were strong positive correlations between FAS expression and intra-neoplastic macrophage score and between FASL and density of lymphocyte infiltration in skin metastases. CONCLUSION: Although FAS and FASL expression is a constant feature of melanotic lesions, its diagnostic importance is very limited because of the different results obtained in the past studies. The correlation between FAS status and macrophage number and between FASL status and lymphocyte number in skin metastasis but not in primary lesions might point to diverse FAS/FASL interaction between neoplastic cells and macrophages in the different microenvironments.

metastatic spinal cancer is characterized by the maintenance of normal disc structure until the vertebral body is severely destroyed by cancer cells. Anatomic features of the discs have been thought to be the main factor which confer the discs their resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local infiltration of cancer cells into the discs. The purpose of this study was to investigate whether Fas ligand (FasL) produced by disc cells can kill Fas-bearing breast cancer cells by Fas and FasL interaction. Two human breast cancer cells (MCF-7 and MDA-MB-231) were obtained and cultured (1 x 10(6) cells/well), and the expression of Fas was investigated by western blot analysis. Annulus fibrosus cells were isolated and cultured, and the presence of FasL was quantified in the supernatants of three different numbers of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) by ELISA assay. The MCF-7 and MDA-MB-231 cancer cells were cultured with supernatants of annulus fibrosus cells for 48 h. As controls, MCF-7 and MDA-MB-231 cancer cells were also cultured by themselves for 48 h. Finally, we determined and quantified the apoptosis rates of MCF-7 and MDA-MB-231 cancer cells by Annexin V-FITC and PI and TUNEL at 48 h, respectively. The expression of Fas was identified in MCF-7 and MDA-MB-231 cancer cells. The mean concentrations of FasL in supernatants of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) were 10.8, 29.6, and 56.4 pg/mL, respectively. After treatment with the supernatant of three different numbers of annulus fibrosus cells, the mean apoptosis rate of MCF-7 cancer cells was increased (2.8%, P < 0.01; 6.7%, P < 0.001; 31.0%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (1.1%). The mean apoptosis rate of MDA-MB-231 cancer cells was also increased (5.7%, P < 0.01; 11.1%, P < 0.001; 25.3%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (2.1%). TUNEL also demonstrated direct evidence of apoptosis of MCF-7 and MDA-MB-231 cancer cells. Our results demonstrate that Fas-bearing cancer cells undergo apoptosis by FasL produced by disc cells, which may be considered as a potential biochemical explanation for the disc's resistance to metastatic cancer.

BACKGROUND: FAS-670 A/G single nucleotide polymorphism has been demonstrated to affect the expression of FAS gene by altering the transcriptional activity of FAS gene promoter. Downregulation of FAS with resultant resistance to death signals has been found in many cancers. We carried out a case-control study to investigate the biological significance of this polymorphism in nasopharyngeal carcinoma (NPC). METHODS: FAS-670 A/G polymorphism was examined in a Chinese population of 237 patients with NPC and 264 control subjects using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: There were no significant differences in the genotype or allele distribution of FAS-670 A/G polymorphism between cases and controls. FAS-670 (AG+GG) genotype and G allele showed significant associations with an increasing risk of lymph node metastasis (OR=2.08, P=0.01; OR=1.67, P=0.011, respectively) and distant metastasis (OR=3.87, P=0.015; OR=1.81, P=0.03, respectively) of NPC patients. In addition, FAS-670 (AG+GG) genotype showed an increasing incidence of advanced clinical stage, but this finding was not statistically significant (OR=1.79, P=0.066). CONCLUSION: The FAS-670 G allele could be used as a genetic risk marker for the metastasis of NPC patients.

Many types of cancer cells are resistant to Fas-mediated apoptosis by several mechanisms, including the mutations of the genes involved in Fas-mediated apoptosis. In this study, to explore the possibility that the mutations of the genes involved in the proximal pathway of Fas-mediated apoptosis (Fas, FADD, caspase 8 and caspase 10) are involved in cancer metastasis, we have analysed somatic mutation and deletion of these genes in 80 non-small cell lung cancers (NSCLCs) with (n=43) and without (n=37) metastasis to the regional lymph nodes. We found 12 mutations (four Fas, four FADD, and four caspase 10 mutations) in 11 of 80 NSCLCs (13.8%). Interestingly, of these mutations, most mutations (10 out of 12) were detected in the NSCLCs with metastasis, and the frequency in the metastasis lesions (23%) was higher than that in the primary lesions of the NSCLCs without metastasis (5.4%). Furthermore, transfection study revealed that the tumor-derived mutants have decreased apoptosis inductions compared to the wild types. These data suggest that the inactivating mutations of the genes in the proximal pathway of Fas-mediated apoptosis may lead to a decreased cancer cell death and play a role in the metastasis of NSCLC.

The ability of osteosarcoma cells to form lung metastases has been inversely correlated to cell surface Fas expression. Downregulation of Fas allows osteosarcoma cells to circumvent FasL-mediated apoptosis upon entrance into the FasL(+) lung microenvironment. However, the mechanism of Fas regulation remains unclear. Here, we show that miRNA plays a role in the downregulation of Fas expression in osteosarcoma. expression levels of several members of the miR-17-92 cluster including miR-20a and miR-19a were found to be higher in metastatic low-Fas-expressing LM7 cells than in the parental nonmetastatic high-Fas-expressing SAOS-2 cells. We also found an inverse correlation between Fas and miR-20a expression in all 8 cell lines derived from patient samples. Overexpression of miR-20a consistently resulted in the downregulation of Fas expression in SAOS-2 cells and thus in decreased sensitivity to FasL. Conversely, inhibiting miR-20a in LM7 cells increased Fas expression and their sensitivity to FasL. Mice injected with LM7 stably transfected with anti-miR-20a had fewer metastases than those with control plasmids. Taken together, our findings suggest that miR-20a, encoded by miR-17-92, downregulates Fas expression in osteosarcoma, thus contributing to the metastatic potential of osteosarcoma cells by altering the phenotype and allowing survival in the FasL(+) lung microenvironment.

metastatic spinal cancer is characterized by the maintenance of normal disc structure until the vertebral body is severely destroyed by cancer cells. Anatomic features of the discs have been thought to be the main factor which confer the discs their resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local infiltration of cancer cells into the discs. The purpose of this study was to investigate whether Fas ligand (FasL) produced by disc cells can kill Fas-bearing breast cancer cells by Fas and FasL interaction. Two human breast cancer cells (MCF-7 and MDA-MB-231) were obtained and cultured (1 x 10(6) cells/well), and the expression of Fas was investigated by western blot analysis. Annulus fibrosus cells were isolated and cultured, and the presence of FasL was quantified in the supernatants of three different numbers of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) by ELISA assay. The MCF-7 and MDA-MB-231 cancer cells were cultured with supernatants of annulus fibrosus cells for 48 h. As controls, MCF-7 and MDA-MB-231 cancer cells were also cultured by themselves for 48 h. Finally, we determined and quantified the apoptosis rates of MCF-7 and MDA-MB-231 cancer cells by Annexin V-FITC and PI and TUNEL at 48 h, respectively. The expression of Fas was identified in MCF-7 and MDA-MB-231 cancer cells. The mean concentrations of FasL in supernatants of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) were 10.8, 29.6, and 56.4 pg/mL, respectively. After treatment with the supernatant of three different numbers of annulus fibrosus cells, the mean apoptosis rate of MCF-7 cancer cells was increased (2.8%, P < 0.01; 6.7%, P < 0.001; 31.0%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (1.1%). The mean apoptosis rate of MDA-MB-231 cancer cells was also increased (5.7%, P < 0.01; 11.1%, P < 0.001; 25.3%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (2.1%). TUNEL also demonstrated direct evidence of apoptosis of MCF-7 and MDA-MB-231 cancer cells. Our results demonstrate that Fas-bearing cancer cells undergo apoptosis by FasL produced by disc cells, which may be considered as a potential biochemical explanation for the disc's resistance to metastatic cancer.