FASLG

Gene Summary

Gene:FASLG; Fas ligand (TNF superfamily, member 6)
Aliases: APTL, FASL, CD178, CD95L, ALPS1B, CD95-L, TNFSF6, APT1LG1
Location:1q23
Summary:This gene is a member of the tumor necrosis factor superfamily. The primary function of the encoded transmembrane protein is the induction of apoptosis triggered by binding to FAS. The FAS/FASLG signaling pathway is essential for immune system regulation, including activation-induced cell death (AICD) of T cells and cytotoxic T lymphocyte induced cell death. It has also been implicated in the progression of several cancers. Defects in this gene may be related to some cases of systemic lupus erythematosus (SLE). Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor ligand superfamily member 6
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (39)
Pathways:What pathways are this gene/protein implicaed in?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosome 1
  • DNA Sequence Analysis
  • Cancer Gene Expression Regulation
  • Rectal Cancer
  • p53 Protein
  • Antineoplastic Agents
  • BCL2 protein
  • Viral Matrix Proteins
  • Case-Control Studies
  • Bladder Cancer
  • Neutropenia
  • Stomach Cancer
  • Apoptosis
  • Microsatellite Instability
  • Adenocarcinoma
  • Transfection
  • Gene Expression
  • Survival Rate
  • Ligands
  • Proto-Oncogenes
  • Skin Cancer
  • Genetic Therapy
  • T-Lymphocytes
  • Caspases
  • Immunohistochemistry
  • Mutation
  • Paraffin Embedding
  • Sjogren's Syndrome
  • Genetic Predisposition
  • Tumor Escape
  • Fas Ligand Protein
  • Neoplasm Proteins
  • bcl-X Protein
  • Membrane Glycoproteins
  • FAS (CD95)
  • Risk Factors
  • Messenger RNA
  • RNA Splicing
  • Young Adult
  • bcl-2-Associated X Protein
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FASLG (cancer-related)

Abu-Dahab R, Abdallah MR, Kasabri V, et al.
Mechanistic studies of antiproliferative effects of Salvia triloba and Salvia dominica (Lamiaceae) on breast cancer cell lines (MCF7 and T47D).
Z Naturforsch C. 2014 Nov-Dec; 69(11-12):443-51 [PubMed] Related Publications
Ethanol extracts obtained from two Salvia species, S. triloba and S. dominica, collected from the flora of Jordan, were evaluated for their antiproliferative activity against MCF7 and T47D breast cancer cell lines by the sulforhodamine B assay. The ethanol extracts were biologically active with IC50 values of (29.89 ±0.92) and (38.91 ±2.44) μg/mL for S. triloba against MCF7 and T47D cells, respectively, and (5.83 ±0.51) and (12.83 ±0.64) μg/mL for S. dominica against MCF7 and T47D cells, respectively. Flow cytometry analysis and the annexinV-propidium iodide (PI) assay revealed apoptosismediated, and to a lesser extent necrosis-induced, cell death by the S. triloba and S. dominica ethanolic extracts in T47D cells. The mechanism of apoptosis was further investigated by determining the levels of p53, p21/WAF1, FasL (Fas ligand), and sFas (Fas/APO-1). The extract from S. triloba induced a more pronounced enrichment in cytoplasmic mono- and oligonucleosomes than that from S. dominica (p < 0:05) in T47D cells. In response to the extract from S. dominica, but not from S. triloba, the proapoptotic efficacy was specifically regulated by p21. Extracts from both Salvia spp. did not enhance p53 levels, and apoptosis induced by them was not caspase-8- or sFas/FasL-dependent. Thus, our findings indicate that S. triloba and S. dominica ethanolic extracts may be useful in breast cancer management/treatment via proapoptotic cytotoxic mechanisms.

Ferreira AF, de Oliveira GL, Tognon R, et al.
Apoptosis-related gene expression profile in chronic myeloid leukemia patients after imatinib mesylate and dasatinib therapy.
Acta Haematol. 2015; 133(4):354-64 [PubMed] Related Publications
BACKGROUND/AIMS: We investigated the effects of tyrosine kinase inhibitors (TKIs) on the expression of apoptosis-related genes (BCL-2 and death receptor family members) in chronic myeloid leukemia (CML) patients.
METHODS: Peripheral blood mononuclear cells from 32 healthy subjects and 26 CML patients were evaluated before and after treatment with imatinib mesylate (IM) and dasatinib (DAS) by quantitative PCR.
RESULTS: Anti-apoptotic genes (c-FLIP and MCL-1) were overexpressed and the pro-apoptotic BIK was reduced in CML patients. Expression of BMF, A1, c-FLIP, MCL-1, CIAP-2 and CIAP-1 was modulated by DAS. In IM-resistant patients, expression of A1, c-FLIP, CIAP-1 and MCL-1 was upregulated, and BCL-2, CIAP-2, BAK, BAX, BIK and FASL expression was downregulated.
CONCLUSION: Taken together, our results point out that, in CML, DAS interferes with the apoptotic machinery regulation. In addition, the data suggest that apoptosis-related gene expression profiles are associated with primary resistance to IM.

Kumar R, Verma V, Sharma V, et al.
A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors.
Toxicol Appl Pharmacol. 2015; 283(3):187-97 [PubMed] Related Publications
Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P<0.01) and increased expression of ER-β target TNF-α (P<0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization.

Nallapalle SR, Daripally S, Prasad VT
Promoter polymorphism of FASL confers protection against female-specific cancers and those of FAS impact the cancers divergently.
Tumour Biol. 2015; 36(4):2709-24 [PubMed] Related Publications
We investigated risk association of FAS (-1377 G>A and -670 A>G) and FASL (-844 T>C) promoter polymorphisms with breast, ovarian, cervical, and endometrial cancers and report that the FASL -844 CC genotype was protective against breast, ovarian, cervical, and endometrial cancers (P ≤ 0.01). On the other hand, FAS -1377 GA and AA variants increased risk of breast cancer. However, the GA variant of FAS -1377 was also found to be a risk factor for cervical cancer. In contrast, FAS -670 AG variant significantly lowered risk of breast cancer. Further, we also observed that risk association of co-occurrence of FAS and/or FASL variants with the cancers varied as compared to the presence of individual polymorphisms. Although risk and protective haplotypes of FAS SNPs were observed across the cancer phenotypes, the association of the haplotypes was significant for breast cancer alone with a 3-fold enhanced risk. The protective effect of the FASL CC genotype seen in this study suggests that similar biomolecular mechanisms involving FASL might play a role in female-specific cancers.

Wang J, Hansen K, Edwards R, et al.
Mitochondrial division inhibitor 1 (mdivi-1) enhances death receptor-mediated apoptosis in human ovarian cancer cells.
Biochem Biophys Res Commun. 2015; 456(1):7-12 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of a variety of cancers including ovarian cancer. However, the inherent or acquired resistance of tumor cells to TRAIL limits the potential application of TRAIL-mediated therapy. In this study, we identified that mitochondrial division inhibitor-1 (mdivi-1) is able to enhance the sensitivity of human ovarian cancer cells to death receptor ligands including TRAIL, FAS ligands, and TNF-α. Importantly, the combination of TRAIL and mdivi-1 has no apparent cytotoxic effect on non-transformed human cells, indicating a significant therapeutic window. We identified that caspase-8 and not the modulation of TRAIL receptors is required for the combination effect of TRAIL and mdivi-1. We further demonstrated that the enhanced efficacy of combination of mdivi-1 and death ligands is not dependent on the originally reported target of mdivi-1, Drp1, and is also not dependent on the two important pro-apoptotic Bcl-2 family proteins Bax and Bak. Thus, our study presents a novel strategy in enhancing the apoptotic effect of death receptor ligands and provides a new effective TRAIL-based combination approach for treating human ovarian cancer.

Zhang YC, Guo LQ, Chen X, et al.
The role of death receptor 3 in the biological behavior of hepatocellular carcinoma cells.
Mol Med Rep. 2015; 11(2):797-804 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Death receptor 3 (DR3) belongs to the tumor necrosis factor (TNF) receptor superfamily, primarily found in lymphoid tissues. Reports have determined that DR3 may also be distributed in numerous types of tumors. Therefore, it is thought that DR3 may have an important role in the process of tumorigenesis. The aim of the present study was to observe the effect of silencing DR3 expression on hepatocarcinoma cell growth, apoptosis and invasion in order to elucidate the role of DR3 in tumor development. The hepatocarcinoma cell lines (HepG2, Huh7, SMMC7721 and Bel‑7402) and normal human liver cells (HL‑7702) were transfected with three stealth RNA interference (RNAi) sequences that target the DR3 gene. Reverse transcription quantitative polymerase chain reaction was used to detect the expression levels of DR3 in hepatocarcinoma cell lines and normal liver HL‑7702 cells. MTT assay and flow cytometry (FCM) were used to determine the rates of cell proliferation and apoptosis, respectively. Following silencing of the DR3 gene, western blot analysis was used to determine the protein expression of P53, Fas, Caspase8, nuclear factor kappa‑light‑chain‑enhancer of activated B cells (NF‑κB) and Caspase3. DR3 messenger RNA (mRNA) expression in hepatocarcinoma cell lines was significantly increased compared with that in the normal liver cell line. Three targeted DR3 gene small interfering RNAs significantly inhibited DR3 gene expression in Bel‑7402 cells at the nucleic acid level. AF02670.1_stealth_883 and cocktail demonstrated the most efficient inhibition of DR3 gene expression at 48 and 72 h following transfection, with mRNA inhibition rates of 89.46 and 92.75%, and 90.53 and 94.25% (P<0.01), respectively. Cell viability was significantly reduced by AF02670.1_stealth_883 and RNAi cocktail at 24, 48 and 72 h following transfection. The inhibition rates of cell proliferation were 50.76 and 61.76% (P<0.05) at 72 h following transfection. FCM revealed that AF02670.1_stealth_883 and RNAi cocktail also induced apoptosis in Bel‑7402 cells at 72 h following transfection. Reduction of NF‑κB and P53 levels was observed (P<0.05) in Bel‑7402 cells following DR3 silencing, whereas levels of Fas, Caspase3 and Caspase8 were markedly elevated (P<0.05). DR3 expression levels in hepatocellular carcinoma cells were significantly higher than those in normal cells. DR3 silencing effectively inhibited proliferation and invasion of hepatocellular carcinoma cells in vitro. However, silencing of the DR3 gene affect levels of apoptosis antigen‑3 ligand in cells, therefore indicating that it may be involved with other pathways that regulate apoptosis in HCCs. In conclusion, the results of the present study indicated that DR3 may be a promising therapeutic target molecule for further study of hepatocellular carcinoma gene therapy.

Sullivan EM, Jeha S, Kang G, et al.
NK cell genotype and phenotype at diagnosis of acute lymphoblastic leukemia correlate with postinduction residual disease.
Clin Cancer Res. 2014; 20(23):5986-94 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
PURPOSE: Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy.
EXPERIMENTAL DESIGN: The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically with postinduction MRD status.
RESULTS: The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype were 2.85 times the odds in those with Tel-A/A genotype (P = 0.035). MRD-positive patients were more likely to have KIR2DL5A (P = 0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (P = 0.0074 and P = 0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (P = 0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (P = 0.038). Collectively, five NK cell-related factors (Tel-B-associated KIR2DL5A, NKp46, FASL, granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity.
CONCLUSIONS: Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control.

Chaves Neto AH, Pelizzaro-Rocha KJ, Fernandes MN, Ferreira-Halder CV
Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O.
Tumour Biol. 2015; 36(2):595-604 [PubMed] Related Publications
Riboflavin (vitamin B2) is a precursor for coenzymes involved in energy production, biosynthesis, detoxification, and electron scavenging. Previously, we demonstrated that irradiated riboflavin (IR) has potential antitumoral effects against human leukemia cells (HL60), human prostate cancer cells (PC3), and mouse melanoma cells (B16F10) through a common mechanism that leads to apoptosis. Hence, we here investigated the effect of IR on 786-O cells, a known model cell line for clear cell renal cell carcinoma (CCRCC), which is characterized by high-risk metastasis and chemotherapy resistance. IR also induced cell death in 786-O cells by apoptosis, which was not prevented by antioxidant agents. IR treatment was characterized by downregulation of Fas ligand (TNF superfamily, member 6)/Fas (TNF receptor superfamily member 6) (FasL/Fas) and tumor necrosis factor receptor superfamily, member 1a (TNFR1)/TNFRSF1A-associated via death domain (TRADD)/TNF receptor-associated factor 2 (TRAF) signaling pathways (the extrinsic apoptosis pathway), while the intrinsic apoptotic pathway was upregulated, as observed by an elevated Bcl-2 associated x protein/B-cell CLL/lymphoma 2 (Bax/Bcl-2) ratio, reduced cellular inhibitor of apoptosis 1 (c-IAP1) expression, and increased expression of apoptosis-inducing factor (AIF). The observed cell death was caspase-dependent as proven by caspase 3 activation and poly(ADP-ribose) polymerase-1 (PARP) cleavage. IR-induced cell death was also associated with downregulation of v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue (avian)/protein serine/threonine kinase B/extracellular signal-regulated protein kinase 1/2 (Src/AKT/ERK1/2) pathway and activation of p38 MAP kinase (p38) and Jun-amino-terminal kinase (JNK). Interestingly, IR treatment leads to inhibition of matrix metalloproteinase-2 (MMP-2) activity and reduced expression of renal cancer aggressiveness markers caveolin-1, low molecular weight phosphotyrosine protein phosphatase (LMWPTP), and kinase insert domain receptor (a type III receptor tyrosine kinase) (VEGFR-2). Together, these results show the potential of IR for treating cancer.

Zhu L, Derijard B, Chakrabandhu K, et al.
Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death.
Cancer Lett. 2014; 354(2):355-64 [PubMed] Related Publications
Fas and PI3K/Akt signaling pathways pivotally impact on cancer cell death and survival respectively and are considered as promising targets for innovative anticancer therapies. To better characterize the combination effect of PI3K/Akt inhibitors and Fas agonists and understand the profile of the interaction between PI3K/Akt and Fas signaling, we qualitatively and quantitatively evaluated the combination effect of PI3K/Akt inhibitors LY294002, Akt inhibitor VIII and FasL. At the concentration that can block cell cycle progression and DNA synthesis but not elicit apoptosis, these inhibitors potentiate FasL to induce apoptosis. At higher concentrations, when the PI3K/Akt inhibitors induce apoptosis, they synergize FasL to induce apoptosis. In addition, PI3K/Akt inhibition significantly facilitates the Fas-mediated apoptotic signaling. Understanding the combination effects between PI3K/Akt inhibition and Fas activation not only leads to rational design of effective combination therapy of PI3K/Akt inhibitors but also improve our knowledge about the impact of PI3K-Akt pathway on Fas signaling and the potential modulation of innate immune system by PI3K-Akt-targeting drugs in anticancer treatment.

Gibot L, Chabaud S, Bouhout S, et al.
Anticancer properties of chitosan on human melanoma are cell line dependent.
Int J Biol Macromol. 2015; 72:370-9 [PubMed] Related Publications
PURPOSE: Chitosan, a natural macromolecule, is widely used in medical and pharmaceutical fields because of its distinctive properties such as bactericide, fungicide and above all its antitumor effects. Although its antitumor activity against different types of cancer had been previously described, its mechanism of action was not fully understood.
MATERIALS AND METHODS: Coating of chitosan has been used in cell cultures with A375, SKMEL28, and RPMI7951 cell lines. Adherence, proliferation and apoptosis were investigated.
RESULTS: Our results revealed that whereas chitosan decreased adhesion of primary melanoma A375 cell line and decreased proliferation of primary melanoma SKMEL28 cell line, it had potent pro-apoptotic effects against RPMI7951, a metastatic melanoma cell line. In these latter cells, inhibition of specific caspases confirmed that apoptosis was effected through the mitochondrial pathway and Western blot analyses showed that chitosan induced an up regulation of pro-apoptotic molecules such as Bax and a down regulation of anti-apoptotic proteins like Bcl-2 and Bcl-XL. More interestingly, chitosan exposure induced an exposition of a greater number of CD95 receptor at RPMI7951 surface, making them more susceptible to FasL-induced apoptosis.
CONCLUSION: Our results indicate that chitosan could be a promising agent for further evaluations in antitumor treatments targeting melanoma.

Wu J, Salva KA, Wood GS
c-CBL E3 ubiquitin ligase is overexpressed in cutaneous T-cell lymphoma: its inhibition promotes activation-induced cell death.
J Invest Dermatol. 2015; 135(3):861-8 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Mycosis fungoides and Sézary syndrome are two major forms of cutaneous T-cell lymphoma (CTCL) characterized by resistance to apoptosis. A central pathway for T-cell apoptosis is activation-induced cell death, which is triggered through the T-cell receptor (TCR). This results in upregulation of FAS ligand (FASL) and subsequent apoptosis through the FAS death receptor pathway. It has been known for more than a decade that TCR signaling is defective in CTCL; however, the underlying mechanism has not been apparent. In this report, we show that the E3 ubiquitin ligase, c-CBL, is overexpressed in CTCL and that its knockdown overcomes defective TCR signaling, resulting in phosphorylation of PLC-g1, calcium influx, ROS generation, upregulation of FASL, and extrinsic pathway apoptosis in CTCL cells expressing adequate FAS. In CTCL cells with suboptimal FAS expression, FAS can be upregulated epigenetically by derepression of the FAS promoter using methotrexate, which we showed previously has activity as a DNA methylation inhibitor. Using these combined strategies, FAS-low as well as FAS-high CTCL cells can be killed effectively.

Beach JA, Nary LJ, Hovanessian R, Medh RD
Correlation of glucocorticoid-mediated E4BP4 upregulation with altered expression of pro- and anti-apoptotic genes in CEM human lymphoblastic leukemia cells.
Biochem Biophys Res Commun. 2014; 451(3):382-8 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
In Caenorhabditiselegans, motorneuron apoptosis is regulated via a ces-2-ces-1-egl-1 pathway. We tested whether human CEM lymphoblastic leukemia cells undergo apoptosis via an analogous pathway. We have previously shown that E4BP4, a ces-2 ortholog, mediates glucocorticoid (GC)-dependent upregulation of BIM, an egl-1 ortholog, in GC-sensitive CEM C7-14 cells and in CEM C1-15mE#3 cells, which are sensitized to GCs by ectopic expression of E4BP4. In the present study, we demonstrate that the human ces-1 orthologs, SLUG and SNAIL, are not significantly repressed in correlation with E4BP4 expression. Expression of E4BP4 homologs, the PAR family genes, especially HLF, encoding a known anti-apoptotic factor, was inverse to that of E4BP4 and BIM. Expression of pro- and anti-apoptotic genes in CEM cells was analyzed via an apoptosis PCR Array. We identified BIRC3 and BIM as genes whose expression paralleled that of E4BP4, while FASLG, TRAF4, BCL2A1, BCL2L1, BCL2L2 and CD40LG as genes whose expression was opposite to that of E4BP4.

Ferrari L, Pistocchi A, Libera L, et al.
FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation.
Oncotarget. 2014; 5(14):5712-24 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Chordoma is a rare malignant tumor that recapitulates the notochord phenotype and is thought to derive from notochord remnants not correctly regressed during development. Apoptosis is necessary for the proper notochord development in vertebrates, and the apoptotic pathway mediated by Fas and Fasl has been demonstrated to be involved in notochord cells regression. This study was conducted to investigate the expression of FAS/FASL pathway in a cohort of skull base chordomas and to analyze the role of fas/fasl homologs in zebrafish notochord formation. FAS/FASL expression was found to be dysregulated in chordoma leading to inactivation of the downstream Caspases in the samples analyzed. Both fas and fasl were specifically expressed in zebrafish notochord sorted cells. fas and fasl loss-of-function mainly resulted in larvae with notochord multi-cell-layer jumps organization, larger vacuolated notochord cells, defects in the peri-notochordal sheath structure and in vertebral mineralization. Interestingly, we observed the persistent expression of ntla and col2a1a, the zebrafish homologs of the human T gene and COL2A1 respectively, which are specifically up-regulated in chordoma. These results demonstrate for the first time the dysregulation of FAS/FASL in chordoma and their role in notochord formation in the zebrafish model, suggesting their possible implication in chordoma onset.

Yamanashi H, Hashizume O, Yonekawa H, et al.
Administration of an antioxidant prevents lymphoma development in transmitochondrial mice overproducing reactive oxygen species.
Exp Anim. 2014; 63(4):459-66 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Because of the difficulty to exclude possible involvement of nuclear DNA mutations, it has been a controversial issue whether pathogenic mutations in mitochondrial DNA (mtDNA) and the resultant respiration defects are involved in tumor development. To address this issue, our previous study generated transmitochondrial mice (mito-mice-ND6(13997)), which possess the nuclear and mtDNA backgrounds derived from C57BL/6J (B6) strain mice except that they carry B6 mtDNA with a G13997A mutation in the mt-Nd6 gene. Because aged mito-mice-ND6(13997) simultaneously showed overproduction of reactive oxygen species (ROS) in bone marrow cells and high frequency of lymphoma development, current study examined the effects of administrating a ROS scavenger on the frequency of lymphoma development. We used N-acetylcysteine (NAC) as a ROS scavenger, and showed that NAC administration prevented lymphoma development. Moreover, its administration induced longevity in mito-mice-ND6(13997). The gene expression profiles in bone marrow cells indicated the upregulation of the Fasl gene, which can be suppressed by NAC administration. Given that natural-killer (NK) cells mediate the apoptosis of various tumor cells via enhanced expression of genes encoding apoptotic ligands including Fasl gene, its overexpression would reflect the frequent lymphoma development in bone marrow cells. These observations suggest that continuous administration of an antioxidant would be an effective therapeutics to prevent lymphoma development enhanced by ROS overproduction.

Singh TD, Lee HW, Lee SW, et al.
Noninvasive imaging of apoptosis induced by adenovirus-mediated cancer gene therapy using a caspase-3 biosensor in living subjects.
Mol Imaging. 2014; 13 [PubMed] Related Publications
We attempted to visualize the serial induction of caspase-3-dependent apoptosis mediated by Fas ligand/tumor necrosis factor-related apoptosis-inducing ligand (FasL/TRAIL) adenoviral gene therapy in mice bearing human glioma xenografts using a caspase-3 biosensor and monitored its therapeutic effects. Human D54 glioma cells expressing both the caspase-3 sensor and the Renilla luciferase (Rluc) gene were established (referred to as D54-CR cells). The bioluminescence imaging (BLI) signals of the caspase-3 sensor in the D54-CR cells were increased in a time- and virus dose-dependent manner by Ad-TRAIL or Ad-FasL transduction. Fluorescence-activated cell sorting (FACS) analysis revealed an increase in both cleaved caspase-3 or poly(ADP-ribose) polymerase (PARP) and annexin V- and propidium iodide-positive cells depending on the dosage of administered virus. Ad-FasL treatment resulted in a significant increase in the BLI activity of the caspase-3 sensor in the D54-CR tumors, which were ≈ 8.2, ≈ 12.9, and ≈ 46.6 times higher than those of control at 12 hours, 24 hours, and 96 hours posttreatment, respectively. In contrast, a significant reduction in Rluc activity, as a surrogate marker of cell viability, was detected in the tumors treated with Ad-FasL but not in those treated with Ad-null. Overall, the activation of caspase-3-dependent apoptosis induced by Ad-FasL/Ad-TRAIL gene therapy was successfully monitored by a sensitive imaging platform for caspase-3 activation.

Xu Y, Deng Q, He B, et al.
The diplotype Fas -1377A/-670G as a genetic marker to predict a lower risk of breast cancer in Chinese women.
Tumour Biol. 2014; 35(9):9147-61 [PubMed] Related Publications
This study was designed to reveal the effects of Fas and FasL polymorphisms of interest on breast cancer risk. A total of 439 patients with breast cancer and 439 controls were enrolled in this study. The genotypes Fas -1377G/A, Fas -670A/G, and FasL -844 T/C were detected by MassARRAY. The protein expressions of estrogen receptor, progesterone receptor, and CerbB-2 were determined by immunohistochemistry. Among the 439 patients, Fas mRNA levels in 22 samples of breast cancer and adjacent normal tissues were detected by real-time polymerase chain reaction, and the soluble Fas and Fas ligand concentrations of 180 patients were measured by enzyme-linked immunosorbent assay. The Fas -1377GA, Fas -1377AA, Fas -670AG, Fas -670GG, and FasL -844TC genotypes were associated with a reduced risk of breast cancer. Haplotype analysis indicated that Fas -1377G/-670A was associated with an increased risk of breast cancer, whereas Fas -1377A/-670A was associated with the opposite effect. Furthermore, gene-gene interaction analysis revealed that the Fas -1377GA/AA (-670AG/GG) and FasL -844CC or TC/TT genotypes were associated with a decreased risk of breast cancer. Meanwhile, -1377GG and -670AA genotypes were associated with higher soluble Fas concentrations than other genotypes. We conclude that Fas and FasL polymorphisms can affect breast cancer risk and that Fas polymorphisms are likely to affect breast cancer risk by regulating the soluble Fas concentration.

Meng XW, Koh BD, Zhang JS, et al.
Poly(ADP-ribose) polymerase inhibitors sensitize cancer cells to death receptor-mediated apoptosis by enhancing death receptor expression.
J Biol Chem. 2014; 289(30):20543-58 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Recombinant human tumor necrosis factor-α-related apoptosis inducing ligand (TRAIL), agonistic monoclonal antibodies to TRAIL receptors, and small molecule TRAIL receptor agonists are in various stages of preclinical and early phase clinical testing as potential anticancer drugs. Accordingly, there is substantial interest in understanding factors that affect sensitivity to these agents. In the present study we observed that the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and veliparib sensitize the myeloid leukemia cell lines ML-1 and K562, the ovarian cancer line PEO1, non-small cell lung cancer line A549, and a majority of clinical AML isolates, but not normal marrow, to TRAIL. Further analysis demonstrated that PARP inhibitor treatment results in activation of the FAS and TNFRSF10B (death receptor 5 (DR5)) promoters, increased Fas and DR5 mRNA, and elevated cell surface expression of these receptors in sensitized cells. Chromatin immunoprecipitation demonstrated enhanced binding of the transcription factor Sp1 to the TNFRSF10B promoter in the presence of PARP inhibitor. Knockdown of PARP1 or PARP2 (but not PARP3 and PARP4) not only increased expression of Fas and DR5 at the mRNA and protein level, but also recapitulated the sensitizing effects of the PARP inhibition. Conversely, Sp1 knockdown diminished the PARP inhibitor effects. In view of the fact that TRAIL is part of the armamentarium of natural killer cells, these observations identify a new facet of PARP inhibitor action while simultaneously providing the mechanistic underpinnings of a novel therapeutic combination that warrants further investigation.

Nihal M, Wu J, Wood GS
Methotrexate inhibits the viability of human melanoma cell lines and enhances Fas/Fas-ligand expression, apoptosis and response to interferon-alpha: rationale for its use in combination therapy.
Arch Biochem Biophys. 2014; 563:101-7 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Melanoma, a highly aggressive form of cancer, is notoriously resistant to available therapies. Methotrexate (MTX), an antifolate, competitively inhibits DNA synthesis and is effective for several types of cancer. In cutaneous T-cell lymphoma (CTCL), MTX increases Fas death receptor by decreasing Fas promoter methylation by blocking the synthesis of SAM, the principal methyl donor for DNMTs, resulting in enhanced Fas-mediated apoptosis. The objective of this study was to explore the effects of MTX in human melanoma. MTX variably inhibited the survival of melanoma cells and induced apoptosis as evident by annexin V positivity and senescence associated β-galactosidase activity induction. Furthermore, MTX caused increased transcript and protein levels of extrinsic apoptotic pathway factors Fas and Fas-ligand, albeit at different levels in different cell lines. Our pyrosequencing studies showed that this increased expression of Fas was associated with Fas promoter demethylation. Overall, the ability of MTX to up-regulate Fas/FasL and enhance melanoma apoptosis through extrinsic as well as intrinsic pathways might make it a useful component of novel combination therapies designed to affect multiple melanoma targets simultaneously. In support of this concept, combination therapy with MTX and interferon-alpha (IFNα) induced significantly greater apoptosis in the aggressive A375 cell line than either agent alone.

Kumazaki M, Shinohara H, Taniguchi K, et al.
Propolis cinnamic acid derivatives induce apoptosis through both extrinsic and intrinsic apoptosis signaling pathways and modulate of miRNA expression.
Phytomedicine. 2014 Jul-Aug; 21(8-9):1070-7 [PubMed] Related Publications
Propolis cinnamic acid derivatives have a number of biological activities including anti-oxidant and anti-cancer ones. In this study, we aimed to elucidate the mechanism of the anti-cancer activity of 3 representative propolis cinnamic acid derivatives, i.e., Artepilin C, Baccharin and Drupanin in human colon cancer cell lines. Our study demonstrated that these compounds had a potent apoptosis-inductive effect even on drug-resistant colon cancer cells. Combination treatment of human colon cancer DLD-1 cells with 2 of these compounds, each at its IC20 concentration, induced apoptosis by stimulating both intrinsic and extrinsic apoptosis signaling pathways. Especially, Baccharin plus Drupanin exhibited a synergistic growth-inhibitory effect by strengthening both intrinsic and extrinsic apoptotic signaling transduction through TRAIL/DR4/5 and/or FasL/Fas death-signaling loops and by increasing the expression level of miR-143, resulting in decreased expression levels of the target gene MAPK/Erk5 and its downstream target c-Myc. These data suggest that the supplemental intake of these compounds found in propolis has enormous significance with respect to cancer prevention.

Yang Q, Xu E, Dai J, et al.
miR-21 regulates N-methyl-N-nitro-N'-nitrosoguanidine-induced gastric tumorigenesis by targeting FASLG and BTG2.
Toxicol Lett. 2014; 228(3):147-56 [PubMed] Related Publications
MicroRNAs (miRNAs) are recently discovered regulators of gene expression and are important in the regulation of many cellular events. Evidence collected to date shows that miRNAs are altered after exposure to environmental toxicants. However, the role that miR-21 plays in the gastric tumorigenesis induced by environmental carcinogens remains largely unknown. The aim of this study was to characterize the regulatory role of miR-21 in the carcinogenic processes following exposure to the N-nitroso carcinogen N-methyl-N-nitro-N'-nitrosoguanidine (MNNG). We found a progressive dose- and time-dependent increase in miR-21 expression following treatment with MNNG. Dysregulated miR-21 affected both cell growth in GES-1 cells and the gastric tumorigenesis induced with MNNG. These data demonstrate the involvement of miR-21 in the malignant transformation and tumorigenesis activated by MNNG. We also established that the Fas ligand (FASLG) and B-cell translocation gene 2 (BTG2), regulated by miR-21, contribute to the transformation induced by MNNG in GES-1 cells. This is the first study to show that miR-21 is involved in chemical carcinogenesis in vivo and in vitro. The regulation by miR-21 of the gastric carcinogenesis induced by MNNG highlights the functional roles of miRNAs in chemical carcinogenesis, and offers a new explanation of the mechanisms underlying chemical carcinogenesis.

Liu XL, Meng YH, Wang JL, et al.
FOXL2 suppresses proliferation, invasion and promotes apoptosis of cervical cancer cells.
Int J Clin Exp Pathol. 2014; 7(4):1534-43 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
FOXL2 is a transcription factor that is essential for ovarian function and maintenance, the germline mutations of which give rise to the blepharophimosis ptosis epicanthus inversus syndrome (BPES), often associated with premature ovarian failure. Recently, its mutations have been found in ovarian granulosa cell tumors (OGCTs). In this study, we measured the expression of FOXL2 in cervical cancer by immunohistochemistry and its mRNA level in cervical cancer cell lines Hela and Siha by RT-PCR. Then we overexpressed FOXL2 in Hela cells and silenced it in Siha cells by plasmid transfection and verified using western blotting. When FOXL2 was overexpressed or silenced, cells proliferation and apoptosis were determined by Brdu assay and Annexin V/PI detection kit, respectively. In addition, we investigated the effects of FOXL2 on the adhesion and invasion of Hela and Siha cells. Finally, we analyzed the influences of FOXL2 on Ki67, PCNA and FasL by flow cytometry. The results showed that FOXL2 was highly expressed in cervical squamous cancer. Overexpressing FOXL2 suppressed Hela proliferation and facilitated its apoptosis. Silencing FOXL2 enhanced Siha proliferation and inhibited its apoptosis. Meanwhile, silencing FOXL2 promoted Siha invasion, but it had no effect on cells adhesion. In addition, overexpressing FOXL2 decreased the expression of Ki67 in Hela and Siha cells. Therefore, our results suggested that FOXL2 restrained cells proliferation and enhanced cells apoptosis mainly through decreasing Ki67 expression.

Verim L, Timirci-Kahraman O, Akbulut H, et al.
Functional genetic variants in apoptosis-associated FAS and FASL genes and risk of bladder cancer in a Turkish population.
In Vivo. 2014 May-Jun; 28(3):397-402 [PubMed] Related Publications
BACKGROUND: The present study aimed to evaluate the role of functional polymorphisms of apoptosis-associated Fatty acid synthase (FAS) and fatty acid synthase ligand (FASL) genes in bladder cancer susceptibility as first presentation in a Turkish population.
PATIENTS AND METHODS: Genotypes of 91 patients with bladder cancer and 101 healthy controls were evaluated for the polymorphism of FAS-1377 G/A and FASL-844 T/C genes by polymerase chain reaction and restriction fragment length polymorphism analysis.
RESULTS: The frequency of the FAS-1377 G allele was significantly higher in patients with bladder cancer compared to controls (p<0.001). A significantly increased risk for developing bladder cancer was found for the group bearing a T allele for FASL-844 compared to the homozygous FASL-844 CC genotype (p=0.027). FAS-1377 GG genotype and FASL-844 T allele were found to be independently associated with an increased risk of bladder cancer. Additionally, gene-gene interaction analysis revealed that the frequency of FAS-1377AA with FASL-844TC was significantly lower in patients with bladder cancer in comparison to those of controls (p<0.001). Extensive studies for gene-gene interaction are still needed.
CONCLUSION: Our study provides new evidence that FAS-1377 G and FASL-844 T alleles may be used as low-penetrant risk factors for bladder cancer development in a Turkish population.

Sehgal L, Mathur R, Braun FK, et al.
FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma.
Leukemia. 2014; 28(12):2376-87 [PubMed] Related Publications
Impaired Fas-mediated apoptosis is associated with poor clinical outcomes and cancer chemoresistance. Soluble Fas receptor (sFas), produced by skipping of exon 6, inhibits apoptosis by sequestering Fas ligand. Serum sFas is associated with poor prognosis of non-Hodgkin's lymphomas. We found that the alternative splicing of Fas in lymphomas is tightly regulated by a long-noncoding RNA corresponding to an antisense transcript of Fas (FAS-AS1). Levels of FAS-AS1 correlate inversely with production of sFas, and FAS-AS1 binding to the RBM5 inhibits RBM5-mediated exon 6 skipping. EZH2, often mutated or overexpressed in lymphomas, hyper-methylates the FAS-AS1 promoter and represses the FAS-AS1 expression. EZH2-mediated repression of FAS-AS1 promoter can be released by DZNeP (3-Deazaneplanocin A) or overcome by ectopic expression of FAS-AS1, both of which increase levels of FAS-AS1 and correspondingly decrease expression of sFas. Treatment with Bruton's tyrosine kinase inhibitor or EZH2 knockdown decreases the levels of EZH2, RBM5 and sFas, thereby enhancing Fas-mediated apoptosis. This is the first report showing functional regulation of Fas repression by its antisense RNA. Our results reveal new therapeutic targets in lymphomas and provide a rationale for the use of EZH2 inhibitors or ibrutinib in combination with chemotherapeutic agents that recruit Fas for effective cell killing.

Zheng ZZ, Ming YL, Chen LH, et al.
Compound K-induced apoptosis of human hepatocellular carcinoma MHCC97-H cells in vitro.
Oncol Rep. 2014; 32(1):325-31 [PubMed] Related Publications
An intestinal bacterial metabolite of ginseng protopanaxadiol saponin, 20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol (compound K), has been reported to induce apoptosis in a variety of cancer cells. However, the precise mechanisms induced by compound K in human hepatocellular carcinoma (HCC) cells remain unclear. In order to examine possible apoptotic mechanisms, we investigated the anticancer effect of compound K in MHCC97-H. MTT assay showed that compound K inhibited the proliferation of MHCC97-H cells with a relatively low toxicity in normal hepatoma cells. Cell cycle progression and cell staining showed an increase in apoptotic sub-G1 fraction. Treatment of MHCC97-H with compound K also induced a reduction in mitochondrial membrane potential (Δψm) and DNA damage. Further study showed that compound K upregulated Fas, FasL, Bax/Bcl-2 ratio and downregulated pro-caspase-9, pro-caspase-3 in a dose-dependent manner, and it also inhibited Akt phosphorylation. These results suggest that compound K significantly inhibits cell proliferation and induces apoptosis in MHCC97-H cells through Fas- and mitochondria-mediated caspase-dependent pathways in human HCC cells.

Ham S, Kim KH, Kwon TH, et al.
Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells.
Oncol Rep. 2014; 31(6):2683-91 [PubMed] Related Publications
Luteolin, a flavonoid extracted from a number of plants with recognized anticancer, anti-inflammatory and anti-oxidative activities, inhibits angiogenic processes and modulates multidrug resistance. However, the efficacy and mechanisms of action of this flavonoid agent are still undergoing study. In order to elucidate whether luteolin exhibits an anticancer effect in cervical cancer cells, HeLa cells were incubated with luteolin and apoptosis was assessed by observing nuclear morphological changes, and performing Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Cell cycle analysis, western blotting, RT-PCR and mitochondrial membrane potential measurements were also carried out. Luteolin showed a significant dose-dependent cytotoxic effect only in human papillomavirus (HPV)-positive cervical cancer cells, when compared to its effect on HPV-negative cervical cancer C33A cells. Expression levels of human papilloma virus E6 and E7 oncogenes were suppressed, those of related factors pRb and p53 were recovered and E2F5 was increased by luteolin treatment. Furthermore, luteolin enhanced the expression of death receptors and death receptor downstream factors such as Fas/FasL, DR5/TRAIL and FADD in HeLa cells, and activated caspase cascades. In particular, luteolin enhanced the activity of caspase-3 and -8 in a dose-dependent manner. Activation of caspase-3 induced caspase-8 activity and vice versa. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and inhibited Bcl-2 and Bcl-xL expression. In conclusion, luteolin exerts anticarcinogenic activity through inhibition of E6 and E7 expression and cross-activation of caspase-3 and -8. Taken together, these results suggest that luteolin induces inactivation of HPV-18 oncogene expression and apoptosis by activating the intrinsic and extrinsic pathways.

Fouqué A, Debure L, Legembre P
The CD95/CD95L signaling pathway: a role in carcinogenesis.
Biochim Biophys Acta. 2014; 1846(1):130-41 [PubMed] Related Publications
Apoptosis is a fundamental process that contributes to tissue homeostasis, immune responses, and development. The receptor CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance, and various lineages of malignant cells exhibit loss-of-function mutations in this pathway; therefore, CD95 was initially classified as a tumor suppressor gene. However, more recent data indicate that in different pathophysiological contexts, this receptor can transmit non-apoptotic signals, promote inflammation, and contribute to carcinogenesis. A comparison with the initial molecular events of the TNF-R signaling pathway leading to non-apoptotic, apoptotic, and necrotic pathways reveals that CD95 is probably using different molecular mechanisms to transmit its non-apoptotic signals (NF-κB, MAPK, and PI3K). As discussed in this review, the molecular process by which the receptor switches from an apoptotic function to an inflammatory role is unknown. More importantly, the biological functions of these signals remain elusive.

Mills LD, Zhang L, Marler R, et al.
Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression.
J Biol Chem. 2014; 289(23):16516-25 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways.

Zhang T, Wang X, He D, et al.
Metformin sensitizes human bladder cancer cells to TRAIL-induced apoptosis through mTOR/S6K1-mediated downregulation of c-FLIP.
Anticancer Drugs. 2014; 25(8):887-97 [PubMed] Related Publications
Metformin, an oral antidiabetic agent, has been reported to potentiate chemotherapeutic-induced cytotoxicity. In this study, we investigated the effects and molecular mechanisms of metformin in sensitizing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human bladder cancer cells. Metformin alone did not induce apoptosis, but markedly potentiated TRAIL-induced apoptosis in 253J and RT4 bladder cancer cells. To elucidate the underlying mechanism, we examined the modulatory effects of metformin on the key components of the TRAIL signaling pathway and found that metformin did not alter the expression levels of death receptor 4 (DR4) and death receptor 5 (DR5), but significantly reduced the cellular Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme (FLICE) inhibitory protein (c-FLIP) levels, contributing toward the sensitization to TRAIL. Further experiments showed that metformin did not affect the mRNA level, proteasomal degradation, and protein stability of c-FLIPL. However, metformin inhibited the mTOR/S6K1 pathway in 253J and RT4 cells, which usually regulates protein translation; moreover, knockdown of S6K1 effectively reduced the levels of c-FLIPL, indicating that metformin downregulates c-FLIP through inhibition of the mTOR/S6K1 pathway. In addition, AMP-activated protein kinase (AMPK) inhibitor compound C did not prevent the inhibitory effects of metformin on the mTOR/S6K1 pathway and metformin-mediated sensitization to TRAIL. Taken together, our results indicate that metformin sensitizes human bladder cancer cells to TRAIL-induced apoptosis through downregulation of c-FLIP, which is mediated by the mTOR/S6K1 pathway, but independent of AMPK; furthermore, these findings provide a rationale for the combined application of metformin with TRAIL in the treatment of bladder cancer.

Wu MF, Yang J, Xiang T, et al.
miR-21 targets Fas ligand-mediated apoptosis in breast cancer cell line MCF-7.
J Huazhong Univ Sci Technolog Med Sci. 2014; 34(2):190-4 [PubMed] Related Publications
Over-expression of Fas ligand (FasL) on tumor cell surface can induce the apoptosis of specific activated tumor infiltrating lymphocytes (TILs) via the Fas/FasL pathway, leading to the formation of a site of immune privilege surrounding the tumor mass for escaping immune surveillance and promoting tumor proliferation, invasion and metastasis. The blocking effect of miR-21 on FasL-mediated apoptosis in breast cancers was investigated in this study. The expression levels of miR-21 and FasL in human breast carcinoma cell lines were detected by using RT-PCR and Western blotting. FasL as a target gene of miR-21 was identified by Luciferase assay. The apoptosis of Jurkat T lymphocytes induced by MCF-7 cells was determined by flow cytometry. It was found that in four human breast cancer cell lines, FasL expression level in MCF-7 cells was the highest, while miR-21 was down-regulated the most notably. After miR-21 expression in MCF-7 cells was up-regulated, FasL was identified as a target gene of miR-21. When the effector/target (E/T) ratio of MCF-7 cells and Jurkat cells was 10:1, 5:1 and 1:1, the inhibitory rate of apoptosis of Jurkat T lymphocytes induced by MCF-7 cells was 95.81%, 93.16% and 91.94%, respectively. It is suggested that in breast cancers miR-21 expression is negatively associated with FasL expression, and FasL is a target gene of miR-21. miR-21 targeting and regulating FasL-mediated apoptosis will bring us the possibility of a new tumor immunotherapy via breaking tumor immune privilege.

Chen SK, Chung CA, Cheng YC, et al.
Toll-like receptor 6 and connective tissue growth factor are significantly upregulated in mitomycin-C-treated urothelial carcinoma cells under hydrostatic pressure stimulation.
Genet Test Mol Biomarkers. 2014; 18(6):410-6 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) is the most common histologic subtype of bladder cancer. The administration of mitomycin C (MMC) into the bladder after transurethral resection of the bladder tumor (TURBT) is a common treatment strategy for preventing recurrence after surgery. We previously applied hydrostatic pressure combined with MMC in UC cells and found that hydrostatic pressure synergistically enhanced MMC-induced UC cell apoptosis through the Fas/FasL pathways. To understand the alteration of gene expressions in UC cells caused by hydrostatic pressure and MMC, oligonucleotide microarray was used to explore all the differentially expressed genes.
RESULTS: After bioinformatics analysis and gene annotation, Toll-like receptor 6 (TLR6) and connective tissue growth factor (CTGF) showed significant upregulation among altered genes, and their gene and protein expressions with each treatment of UC cells were validated by quantitative real-time PCR and immunoblotting.
CONCLUSION: Under treatment with MMC and hydrostatic pressure, UC cells showed increasing apoptosis using extrinsic pathways through upregulation of TLR6 and CTGF.

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