Identification of ARHGEF17, DENND2D, FGFR3, and RB1 mutations in melanoma by inhibition of nonsense‐mediated mRNA decay

Bloethner, Sandra; Mould, Arne W.; Stark, Mitchell; Hayward, Nicholas K.

doi:10.1002/gcc.20598

Cited by 22 publications

(20 citation statements)

References 39 publications

(49 reference statements)

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“…Rab GTPases regulate tumorigenesis via trafficking-mediated events, and some function in a trafficking-independent manner [22,[37][38][39][40]. Additionally, it is known that several members of the Rab GTPase family affect exosome secretion via the trans-Golgi network or by inducible vesicular trafficking [35,41].…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer

et al. 2014

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Background Patients with advanced gastric cancer (GC) have an adverse prognosis even after curative resection. Development of novel diagnostic and therapeutic approaches for GC is urgently required. Methods The expression and methylation status of DENN/MADD domain-containing protein 2D (DEN-ND2D), a member of the membrane trafficking proteins, were evaluated in 12 GC cell lines and 112 pairs of surgical specimens. Subgroup analysis based on tumor differentiation, location, and morphology was also performed. Expression and distribution of DENND2D protein were determined by immunohistochemistry. Results The majority of GC cell lines (75 %) and tissues (79 %) showed reduced expression of DENND2D mRNA compared with noncancerous gastric tissues. GC tissues showed a significantly lower mean expression level of mRNA and a higher frequency of promoter hypermethylation of DENND2D than corresponding noncancerous tissues. No significant differences in DENND2D mRNA expression and methylation status were found between GC subtypes categorized by tumor differentiation, location, and morphology. The expression patterns of DENND2D protein were confirmed to be consistent with those of DENND2D mRNA. Downregulation of DENND2D mRNA in GC tissues was significantly associated with factors related to more advanced GC and subsequent adverse prognosis. Among 72 patients who underwent R0 resection, downregulation of DENND2D mRNA in GC tissues was an independent prognostic factor and associated with early recurrence. Conclusions Our results suggested that DENND2D is a putative tumor suppressor gene regulated by promoter hypermethylation in GC. Downregulation of DENND2D can serve as a novel tumor biomarker to predict progression and early recurrence of all types of GC.

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Section: Discussionmentioning

confidence: 99%

Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer

et al. 2014

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“…The DENND2 family is the only example where the DENN domain is located within the C-terminal region (20,29). Each DENND2 protein acts as a GEF for Rab9a/b.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of DENND2D through promoter hypermethylation is an adverse prognostic factor in squamous cell carcinoma of the esophagus

et al. 2013

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Abstract. Esophageal cancer ranks sixth in cancer mortality worldwide and patients with esophageal squamous cell carcinoma (ESCC) have a poor prognosis with a 5-year survival rate of less than 10%. Elucidation of the mechanisms of carcinogenesis and tumor progression in esophageal cancer is urgently required to develop targets for therapy and prognostic biomarkers. In the present study, the expression and regulatory mechanism of the differentially expressed in normal and neoplastic cells domain containing 2D (DENND2D), which is a regulator of Rab GTPases, were investigated to explore its potential as a tumor suppressor gene for ESCC. The level of DENND2D mRNA expression in ESCC cell lines and surgical specimens was determined using a quantitative real-time reverse transcription-polymerase chain reaction assay, and the relationship between the expression levels of DENND2D mRNA and clinicopathological factors was evaluated. The expression and distribution of DENND2D were determined using immunohistochemistry. DNA methylation analysis was performed to determine the regulatory mechanism of DENND2D expression in ESCC. The level of DENND2D mRNA expression was reduced in 8/9 ESCC cell lines and in 59/65 surgical specimens, and the mean expression levels were significantly lower in cancerous tissues compared to corresponding normal tissues (P<0.001). The expression pattern of DENND2D protein and mRNA was consistent. Downregulation of DENND2D mRNA in ESCC tissues was identified as an independent prognostic factor in multivariate analysis (Hazard ratio, 2.194; P=0.039). The DENND2D promoter was methylated in 5/9 ESCC cell lines, and DNA demethylation reactivated DENND2D mRNA expression. Hypermethylation of DENND2D was frequently detected in ESCC tissues (64.6%) and was significantly associated with downregulation of DENND2D mRNA expression (P=0.008). Taken together, our data suggest that DENND2D is a candidate tumor suppressor gene that was inactivated by promoter hypermethylation in patients with ESCC and may serve as a novel biomarker of ESCC. IntroductionEsophageal cancer is the eighth most common cancer and ranks sixth in cancer mortality worldwide (1). It is generally diagnosed at a late stage and has a poor prognosis, with a 5-year survival rate of <10% (2). Esophageal squamous cell carcinoma (ESCC) comprises a majority of esophageal cancer in Japan (1). Despite improved multimodal treatment, prognosis remains unsatisfactory, as effective systemic therapy has not been established for patients with advanced ESCC (3). Therefore, investigations that clarify the mechanisms of carcinogenesis and tumor progression in ESCC are urgently required to develop targets for therapy and prognostic biomarkers.It is well known that carcinogenesis of ESCC can be induced by external factors such as alcohol and smoking. Genetically, aberrant expression of tumor suppressor genes and oncogenes coordinately contribute to carcinogenesis and progression of ESCC. Epigenetic alterations, including promoter hypermethylation, play an important ...

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“…PTCs in several tumour suppressor genes (BRCA1, p53, WT1) have been reported to result in reduced abundance of their mRNAs due to NMD [33][34][35][36]. Indeed, a strategy referred to as ''gene identification by NMD inhibition'' (GINI) has been successfully used to identify tumour suppressor genes [37,38], pointing to a crucial role of NMD in eliminating faulty tumour suppressor transcripts and thus protecting cells from malignant growth.…”

Section: Nmd Targets Both Aberrant and Physiological Transcriptsmentioning

confidence: 99%

Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors

Nicholson

Yepiskoposyan

Metze

et al. 2009

Cell. Mol. Life Sci.

287

321

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Nonsense-mediated decay is well known by the lucid definition of being a RNA surveillance mechanism that ensures the speedy degradation of mRNAs containing premature translation termination codons. However, as we review here, NMD is far from being a simple quality control mechanism; it also regulates the stability of many wild-type transcripts. We summarise the abundance of research that has characterised each of the NMD factors and present a unified model for the recognition of NMD substrates. The contentious issue of how and where NMD occurs is also discussed, particularly with regard to P-bodies and SMG6-driven endonucleolytic degradation. In recent years, the discovery of additional functions played by several of the NMD factors has further complicated the picture. Therefore, we also review the reported roles of UPF1, SMG1 and SMG6 in other cellular processes.

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Identification of ARHGEF17, DENND2D, FGFR3, and RB1 mutations in melanoma by inhibition of nonsense‐mediated mRNA decay

Cited by 22 publications

References 39 publications

Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer

Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer

Reduced expression of DENND2D through promoter hypermethylation is an adverse prognostic factor in squamous cell carcinoma of the esophagus

Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors

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