Background Gastric cancer (GC) is a highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer-associated deaths worldwide. Although many genes have been implicated in its development, many cases remain genetically unexplained. Hence, there is an urgent need to find new disease-related genes.
Methods A transgenic Drosophila model was used to screen for novel genes putatively involved in GC. The authors evaluated the expression of the most interesting candidates in GC cell lines and primary tumours by semi-quantitative reverse transcription PCR, dissected the molecular mechanisms responsible for the deregulation of the most relevant one, and analysed its functional role in vitro and in a chicken embryo model.
Results Six candidate genes were identified, of which cytoplasmic polyadenylation element binding protein 1 (CPEB1) was downregulated in all GC cell lines and in 11 of 12 primary GC tumours. The pivotal CPEB1 promoter CpG site was determined, and it was found that methylation at this 79th CpG site was associated with CPEB1 silencing in GC cell lines and primary tumours. It was also discovered that methylation of this site was significantly more prevalent in diffuse type GC (p=0.007) and in cases with lymph node metastases (p=0.042). In vitro, CPEB1 impaired invasion. Its antiangiogenic role was also discovered, which was associated with downregulation of MMP14 and VEGFA.
Conclusions The first evidence of CPEB1 involvement in GC is presented, along with the molecular mechanism underlying the regulation of its expression and its potential role in invasion and angiogenesis.
- cancer genetics
- RNA expression
- cell biology
- cell adhesion molecules
- colorectal diseases
- colorectal carcinoma
- colorectal cancer screening
- mutation screening
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Funding Supported by: The Portuguese Foundation for Science and Technology (FCT) (Projects: PTDC/SAU-ONC/110294/2009; PhD grants: SFRH/BD/29777/2006-JC, SFRH/BD/40090/2007-GC; Post-Doc grants: SFRH/BPD/48765/2008-JSC; Salary support from Program Ciência 2007 and 2008-CO, JP, MTP and PSP). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT. Also supported by grants BFU2009-07044 and ‘From Genes to Shape’ (Consolider-Ingenio) from the Spanish MICINN to FC.investigation.
Competing interests None.
Patient consent All samples were obtained with informed consent and in compliance with the Helsinki Declaration (http://www.wma.net/e/policy/b3.htm). Written consent was obtained from every patient affected by primary GC. These consents are archived at the Department of General Surgery and Surgical Oncology (Hospital Santa Maria alle Scotte, Siena, Italy). In accord with the Italian D.L. n. 196 of the 30 June 2003, namely the Privacy Law, we cannot distribute personal information such as name, health condition, and specific information on patients. Therefore information has been sufficiently anonymised, meaning that neither the patient nor anyone else can identify the patient with certainty.
Ethics approval The study protocol was reviewed and approved by the appropriate ethics committees.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We are happy to share our data without any patent protection or conflict of interest.