RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer

Abstract

RASSF2, a member of the RASSF1 family, has recently been identified as a potential tumour suppressor. We examined methylation status in multiple regions which included the CpG island and spanned the transcription start site of RASSF2 in 10 gastric cancer cell lines, as well as 78 primary gastric cancers and corresponding non-neoplastic gastric epithelia. Hypermethylation of RASSF2 in at least one of the regions examined was detected in seven (70%) of the 10 cell lines; two (20%) exhibited hypermethylation in all the regions examined including the transcription start site and lost expression of RASSF2 mRNA, which could, however, be restored by 5-aza-2 0 deoxycytidine treatment, while the other five (50%) cell lines exhibited hypermethylation at the 5 0 -and/or 3 0 -edge, with four of them expressing RASSF2 mRNA. In primary gastric cancers and corresponding non-neoplastic gastric epithelia, frequencies of RASSF2 methylation ranged from 29% (23 out of 78) to 79% (62 out of 78) and 3% (two out of 78) to 60% (47 out of 78), respectively, at different CpG sites examined. Methylation was frequently observed at the 5 0 -and 3 0 -edges, and became less frequent near the transcription start site in both the primary gastric cancers and corresponding non-neoplastic gastric epithelia. Hypermethylation near the transcription start site was mostly cancer-specific. We thus showed that RASSF2 is silenced by hypermethylation near the transcription start site in gastric cancer. Hypermethylation was found initially to occur at the 5 0 -and 3 0 -furthest regions of the CpG island in non-neoplastic gastric epithelia, to gradually spreads near the transcription start site to shut down RASSF2 expression, and ultimately to constitute a field-defect placing tissue increased risk for development of gastric cancer.

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…FUS1 was originally identified as a PAP that potentiates and inhibits the mitogenic effect of PDGF-A and PDGF-B, respectively (Fischer and Schubert, 1996) suggesting the protein may indeed play A high-stringency motif scan (scansite.mit.edu) identifies a predicted PKC and PKA kinase site (Ser50) and an ERK binding motif. Myristoylation of FUS1 has also been described (Endoh et al, 2005). ERK, extracellular signal-regulated kinase; PKA, protein kinase A; PKC, protein kinase C.…”

“…The feasibility of using RASSF2A methylation as a biomarker for CRCs, perhaps in combination with other genes, is an area of current research in our laboratory. RASSF2A methylation has also been found in gastric cancer at frequencies ranging from 29 to 79% and in 51% of NPC primary tumours (Endoh et al, 2005;Zhang et al, 2007). In NPC tumours RASSF2A methylation correlates with increased metastatic potential (Zhang et al, 2007).…”

Ectopic expression of RASSF2 and its prognostic role for gastric adenocarcinoma patients

“…On the other hand, Endoh et al (25) carried out the first detailed investigation and determined that frequent silencing of RASSF2 was associated with promoter hypermethylation in gastric cancer. Their study revealed that methylation frequencies of RASSF2 varied in the regions upstream and downstream of the transcription start site.…”

Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma

“…13,17,18 Although the exact mechanisms about how RASSF2 functions in human cancers were largely unknown, inactivation of RASSF2 in kidney cells showed an advanced growth during transformation, 18 and in vitro expression of RASSF2 could induce apoptosis and cell cycle arrest in lung cancer cells. 9 In our study, we further confirmed the ability of RASSF2 to induce cell cycle arrest and inhibit colony formation in NPC cells.…”