FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation

Ferrari, Luca; Pistocchi, Anna; Libera, Laura; Boari, Nicola; Mortini, Pietro; Bellipanni, Gianfranco; Giordano, Antonio; Cotelli, Franco; Riva, Paola

doi:10.18632/oncotarget.2145

Cited by 12 publications

(10 citation statements)

References 59 publications

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“…It was shown previously that many intracellular signaling pathways actively participate in tumorigenesis [ 33 – 36 ]. Other pathways, in turn, are silenced in the transformed cells and tissues [ 37 – 38 ].…”

Section: Resultsmentioning

confidence: 99%

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

et al. 2014

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Identification of reliable and accurate molecular markers remains one of the major challenges of contemporary biomedicine. We developed a new bioinformatic technique termed OncoFinder that for the first time enables to quantatively measure activation of intracellular signaling pathways basing on transcriptomic data. Signaling pathways regulate all major cellular events in health and disease. Here, we showed that the Pathway Activation Strength (PAS) value itself may serve as the biomarker for cancer, and compared it with the “traditional” molecular markers based on the expression of individual genes. We applied OncoFinder to profile gene expression datasets for the nine human cancer types including bladder cancer, basal cell carcinoma, glioblastoma, hepatocellular carcinoma, lung adenocarcinoma, oral tongue squamous cell carcinoma, primary melanoma, prostate cancer and renal cancer, totally 292 cancer and 128 normal tissue samples taken from the Gene expression omnibus (GEO) repository. We profiled activation of 82 signaling pathways that involve ~2700 gene products. For 9/9 of the cancer types tested, the PAS values showed better area-under-the-curve (AUC) scores compared to the individual genes enclosing each of the pathways. These results evidence that the PAS values can be used as a new type of cancer biomarkers, superior to the traditional gene expression biomarkers.

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Section: Resultsmentioning

confidence: 99%

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

et al. 2014

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“…The zebrafish is a powerful tool for a variety of studies from early dorso/venrtal patterning to late development (Varga et al, ; Bellipanni et al, ; Valenti et al, ; Della Noce et al, ) and for modeling complex syndromes and diseases (Malafoglia et al, ; Malafoglia et al, ; Ferrari et al, ). In the present study we have used zebrafish to model a group of congenital maformations named cohesinopathies.…”

Section: Discussionmentioning

confidence: 99%

CyclinD1 Down‐Regulation and Increased Apoptosis Are Common Features of Cohesinopathies

Fazio

Gaston‐Massuet

Bettini

et al. 2015

Journal Cellular Physiology

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Genetic variants within components of the cohesin complex (NIPBL, SMC1A, SMC3, RAD21, PDS5, ESCO2, HDAC8) are believed to be responsible for a spectrum of human syndromes known as "cohesinopathies" that includes Cornelia de Lange Syndrome (CdLS). CdLS is a multiple malformation syndrome affecting almost any organ and causing severe developmental delay. Cohesinopathies seem to be caused by dysregulation of specific developmental pathways downstream of mutations in cohesin components. However, it is still unclear how mutations in different components of the cohesin complex affect the output of gene regulation. In this study, zebrafish embryos and SMC1A-mutated patient-derived fibroblasts were used to analyze abnormalities induced by SMC1A loss of function. We show that the knockdown of smc1a in zebrafish impairs neural development, increases apoptosis, and specifically down-regulates Ccnd1 levels. The same down-regulation of cohesin targets is observed in SMC1A-mutated patient fibroblasts. Previously, we have demonstrated that haploinsufficiency of NIPBL produces similar effects in zebrafish and in patients fibroblasts indicating a possible common feature for neurological defects and mental retardation in cohesinopathies. Interestingly, expression analysis of Smc1a and Nipbl in developing mouse embryos reveals a specific pattern in the hindbrain, suggesting a role for cohesins in neural development in vertebrates.

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“…Apoptotic mechanisms are involved in notochord formation, and apoptosis is deregulated in chordoma. 16 Loss of heterozygosity in the 1p36 region has been indicated as a possible negative prognostic factor by Longoni et al 27 In 27 chordoma samples from the 45 patients described above, we investigated the LOH in 1p36. Stratifying patients according to LOH status at 1p36 on survival analysis, we observed that all events (recurrence or death) clustered in the group of patients with 1p36 LOH.…”

Section: Biological Prognostic Factorsmentioning

confidence: 99%

Skull base chordomas: clinical outcome in a consecutive series of 45 patients with long-term follow-up and evaluation of clinical and biological prognostic factors

Boari

Gagliardi

Cavalli

et al. 2016

JNS

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OBJECTIVE Skull base chordomas (SBCs) are rare dysembryogenetic invasive tumors with a variable tendency for recurrence. According to previous studies, the recurrence rate seems to be affected by both clinical variables and tumor biological features. The authors present the results of treatment of SBCs in a large series of patients and investigate the role of 1p36 chromosomal region loss of heterozygosity (LOH) as a prognostic factor. METHODS Between 1990 and 2011, 45 patients were treated for SBCs. The mean follow-up was 76 months (range 1–240 months). An LOH analysis was performed in 27 cases. Survival analysis was performed to determine clinical and biological parameters correlating with clinical outcome. RESULTS The 5- and 10-year overall survival rates were 67% and 57%, respectively. Five- and 10-year progression-free survival rates were 58% and 44%, respectively. Multivariate analysis showed that extent of resection, adjuvant radiation therapy, and absence of rhinopharynx invasion were positive independent predictors of overall survival. The latter 2 variables and a younger patient age were positive independent predictors of progression-free survival. Twenty-one patients showed 1p36 LOH. All events of recurrence and death clustered in the group of patients with 1p36 LOH; however, this biological marker was not statistically significant on multivariate analysis. CONCLUSIONS Resection is the treatment of choice in primary and recurrent SBC. Patient age, rhinopharynx invasion at diagnosis, extent of tumor removal, and postoperative radiation therapy influence SBC prognosis. Genetic analysis, even while showing interesting results, did not reveal 1p36 LOH as an independent predictor of clinical outcome.

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FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation

Cited by 12 publications

References 59 publications

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

CyclinD1 Down‐Regulation and Increased Apoptosis Are Common Features of Cohesinopathies

Skull base chordomas: clinical outcome in a consecutive series of 45 patients with long-term follow-up and evaluation of clinical and biological prognostic factors

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