Dynamin 3: a new candidate tumor suppressor gene in hepatocellular carcinoma detected by triple combination array analysis

Abstract

BackgroundTo identify genes associated with hepatocellular carcinoma (HCC) pathogenesis, we developed a triple combination array strategy comprising methylation, gene expression, and single nucleotide polymorphism (SNP) array analysis.MethodsSurgical specimens obtained from a 68-year-old female HCC patient were analyzed by triple combination array, and identified Dynamin 3 (DNM3) as a candidate tumor suppressor gene in HCC. Subsequently, samples from 48 HCC patients were evaluated for DNM3 methylation and expression status using methylation specific polymerase chain reaction (PCR; MSP) and semi-quantitative reverse transcriptase (RT)-PCR, respectively. The relationship between clinicopathological factors and DNM3 methylation status was also investigated.ResultsDNM3 was shown to be hypermethylated (methylation value 0.879, range 0–1.0) in cancer tissue compared with adjacent normal tissue (0.213) by methylation array in the 68-year-old female patient. Expression arrays revealed decreased expression of DNM3 in cancerous tissue. SNP arrays revealed that the copy number of chromosome 1q24.3, in which DNM3 resides, was normal. MSP revealed hypermethylation of the DNM3 promoter region in 33 of 48 tumor samples. A trend toward decreased DNM3 expression was observed in patients with DNM3 promoter methylation (P = 0.189). Furthermore, patients with reduced expression of DNM3 in tumor tissues exhibited worse prognosis with decreased disease specific survival compared to patients without decreased expression (P = 0.014).ConclusionThe present study indicates that a triple combination array strategy is an effective method to detect novel genes related to HCC. We propose that DNM3 is a tumor suppressor gene in HCC.

The CpG Island Methylator Phenotype in Breast Cancer is Associated with the Lobular Subtype

“…Investigating the relationship between DNA methylation status and gene expression showed an inverse corre lation between DNA methylation and gene expression for DNM3 and TACC1. Interestingly, DNM3 is a postulated tumor suppressor gene in hepatocellular carcinoma, since the DNA methylation-induced downregulation of the gene was associated with poor prognosis [51]. Additionally, DNM3 was identified by the TCGA consortium as one of the 490 highly methylated genes in mainly luminal B breast tumors [14], as well as one of the 86 key CpGs in the study of Dedeurwaerder et al [52].…”

Dynamin Functions and Ligands: Classical Mechanisms Behind

“…Overexpression of DNM2 in PCA and the requirement for DNM2 in endocytosis of focal adhesion kinase and integrin open the gate for a new therapy that can control the expression of DNM2 (Xu et al, 2014). In hepatocellular carcinoma, DNM3 has been a candidate tumor suppressor gene (Inokawa et al, 2013).…”

Molecular alterations in the carcinogenesis and progression of hepatocellular carcinoma: Tumor factors and background liver factors

“…Wong et al (81) detected the downregulation of miRNA-223 expression levels in HCC tissues and investigated stathmin 1 (STMN1) as a downstream target. Methylation array analysis has been used to detect cancer-specific epigenetic alterations in HCC (82)(83)(84)(85)(86)(87)(88)(89)(90)(91). Shen et al (82) analyzed tumor and adjacent non-tumor tissue samples from 62 Taiwanese patients with HCC, using Illumina ® methylation arrays, and identified several genes that were hyper-or hypo-methylated in tumor tissues, as compared with adjacent non-tumor tissues (82).…”

“…The candidate genes were pyrosequenced and the array data was validated; analysis of plasma DNA suggested those genes may be used as biomarkers for early-stage HCC. Okamura et al (83) created a triple-combination array, consisting of an SNP array, gene expression microarray and methylation array analysis (83)(84)(85)(86)(87)(88)(89). The tumor-suppressor gene candidates were efficiently identified by detecting downregulation and methylation in tumor tissues, and without chromosomal deletion of the loci of the targeted genes.…”