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Identification of a Novel Angiogenesis and Tumor Suppressor Gene Rab25 in Esophageal Squamous Cell Carcinoma

ABSTRACT: Twelve clinical samples from human esophageal squamous cell carcinoma (ESCC) (seven tumors and five non-tumors) were sequenced using Illumina high-throughput sequencing and the RNA-Seq profiling was investigated with 1730 genes significantly differentially expressed. The gene Rab25 was found to be down-regulated in tumors (p-value < 1E-20) and identified as a novel candidate tumor suppressor gene. The down-regulation of Rab25 was examined in a large cohort of ESCC and non-tumor cases by qPCR and immunohistochemistry analyses. Aberrant methylation in the promoter region of Rab25 was studied by demethylation treatment with 5-aza-dC and bisulfite genomic sequencing (BGS). In order to assess the effect of Rab25 on tumor growth and angiogenesis, in vitro and in vivo functional studies in ESCC cell lines using lentiviral-based overexpression or knockdown models were also performed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32424 | GEO | 2012/12/05

SECONDARY ACCESSION(S): PRJNA147913

REPOSITORIES: GEO

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Project description:Esophageal cancers (ECs) are highly aggressive tumors with poor prognosis and few treatment options. This study investigated the possibility of treating esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells by inhibitors of broad and specific histone deacetylases (HDACi; SAHA, MS-275, FK228) and/or of DNMT (Azacytidine, AZA). Drug targets (HDAC1,2,3 and DNMT1) were present in non-neoplastic (HET-1A), ESCC (OE21) and EAC (OE33) cell lines. All cell lines responded to HDACi by reduced HDAC activity and increased histone acetylation as well as to AZA by up-regulation of p21. Expression of drug targets remained largely unaffected by HDACi and AZA treatment. Importantly, cell viability, apoptosis, cell cycle dynamics and DNA damage were only affected by HDACi and/or AZA in ESCC and EAC, but not the non-neoplastic cells. This was specifically seen for the combination of MS-275 and AZA, leading to enhanced cancer cell selectivity and drug efficiency. By transcriptome analyses of MS-275, AZA and MS-275/AZA treated cells, known (e.g. p21) as well as novel regulated genes significantly associated with the cellular effects post HDACi and/or AZA treatment in ESCC and EAC cells were identified. Finally, human EC tissue specimens frequently expressed the actionable drug targets HDAC1/2/3 and DNMT1. In summary, a combined HDACi (MS-275)/AZA treatment is cancer cell selective and efficient in vitro. Since the majority of ECs express the drug targets in situ, this paves the way for further investigations of HDACi/AZA treatment in esophageal cancer cells and their translation into a clinico-pathological setting. To elucidate the transcriptome response to HDAC inhibitors of normal esophageal cells and esophageal tumor cells, total RNA was isolated from non-neoplastic esophageal epithelial cells (Het1A cells) a well as from two esophageal tumor cell lines (OE21 and OE33), respectively. Cells were treated with either MS-275, Azacytidine (AZA) or in combination of both. DMSO treatment was used as control in each case. Total RNA was isolated from cells 24 h after treatment and experiments were performed in biological triplicates.

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Identification of a Novel Angiogenesis and Tumor Suppressor Gene Rab25 in Esophageal Squamous Cell Carcinoma

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