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http://purl.uniprot.org/citations/24301457http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/24301457http://www.w3.org/2000/01/rdf-schema#comment"

Background

Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma (PDAC). This study investigated genes encoded by this cytoband.

Methods

We studied mRNA/protein expression in radically resected (n = 130) and metastatic patients (n = 50). The role of CYB5A was tested in 11 PDAC cell lines and five primary cultures through retrovirus-mediated upregulation and small interfering RNA using wound-healing, invasion, annexin-V, electron microscopy, and autophagic assays, as well as autophagy genes and kinases arrays. CYB5A+ orthotopic models (n = 6 mice/group) were monitored by Firefly and Gaussia-luciferase bioluminescence, magnetic resonance imaging, and high-frequency ultrasound. Data were analyzed by t test, Fisher exact-test, log-rank test and Cox proportional hazards models. All statistical tests were two-sided.

Results

Both resected and metastatic patients with low mRNA or protein expression of CYB5A had statistically significantly shorter survival (eg, median = 16.7 months, 95% confidence interval [CI] = 13.5 to 19.9; vs median = 24.8 months, 95% CI = 12.8 to 36.9; P = .02, two-sided log-rank test; n = 82 radically resected PDACs), and multivariable analyses confirmed prognostic relevance. Moreover, we characterized a novel function to CYB5A, autophagy induction, concomitant with reduced proliferation and migration/invasion of PDAC cells. Network analysis of proautophagic pathways suggested CYB5A interaction with TRAF6, which was confirmed by TRAF6 downregulation after CYB5A reconstitution (-69% in SU.86.86-CYB5A+; P = .005, two-sided t test). CYB5A silencing had opposite effects, restoring TRAF6 expression and wound healing. In vivo studies showed that CYB5A induced autophagy while inhibiting tumor growth/metastasis and increasing survival (median = 57 days, 95% CI = 52 to 61; vs median = 44 days, 95% CI = 21 to 57; P = .03, two-sided log-rank test).

Conclusions

These results define CYB5A as a novel prognostic factor for PDAC that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.org/dc/terms/identifier"doi:10.1093/jnci/djt346"xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Lee J.H."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Wang Y."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Wang Q."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Giaccone G."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Peters G.J."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Lagerweij T."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Vasile E."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Wurdinger T."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Funel N."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Boggi U."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Giovannetti E."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Avan A."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"Caretti V."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/author"van der Velde A."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/name"J Natl Cancer Inst"xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/pages"djt346"xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/title"Role of CYB5A in pancreatic cancer prognosis and autophagy modulation."xsd:string
http://purl.uniprot.org/citations/24301457http://purl.uniprot.org/core/volume"106"xsd:string
http://purl.uniprot.org/citations/24301457http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/24301457
http://purl.uniprot.org/citations/24301457http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/24301457
http://purl.uniprot.org/uniprot/#_A0A384ME44-mappedCitation-24301457http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/24301457
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