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Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) remains one of the most deadly cancer types worldwide. Comprehensively dissecting the molecular characterization of ESCC paves the way for developing more promising therapeutics. Here, we performed RNA-seq and ATAC-seq on three pairs of ESCC tumor tissues and patient-matched adjacent normal tissues.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167488 | GEO | 2021/02/25

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.

Project description:Objective: Globally, esophageal cancer is among the most deadly cancer forms. Long non-coding RNAs (lncRNA) are frequently found to have important regulatory roles. We aim to assess the lncRNA expression profile of esophageal squamous cell carcinoma (ESCC) and identify prognosis related lncRNAs. Design: LncRNA expression profiles were studied by microarray in paired tumor and normal tissues from 119 ESCC patients, and validated by qRT-PCR. The 119 patients were subsequently divided randomly into training (n=60) and test (n=59) groups. A prognostic signature was developed from the training group using a random forest supervised classification algorithm and a nearest shrunken centroid algorithm, and validated in test group and further in an independent cohort (n=60). The independence of the signature in survival prediction was evaluated by Multivariable Cox regression analysis. Results: LncRNAs showed significantly altered expression in ESCC tissues. From the training group, we identified a three-lncRNA signature (including the lncRNAs ENST00000435885•1, XLOC_013014, and ENST00000547963•1) which classified the patients into two groups with significantly different overall survival (median survival 19•2 months vs. not reached, p<0•0001). The signature was applied to the test group (median survival 21•5 months vs. not reached, p=0•0030) and independent cohort (median survival 25•8 months vs. not reached, p=0•0187) and showed similar prognostic values in both. Multivariable Cox regression analysis showed that the signature was an independent prognostic factor for ESCC patients. Stratified analysis suggested that the signature was prognostic within clinical stages. Conclusions: Our results suggest that the three-lncRNA signature can serve as a novel biomarker for the prognosis of ESCC patients. Application of it allows for more accurate survival prediction. The lncRNA expression profiles of cancer and adjacent normal tissues form 119 ESCC patients were studied by microarray and an lncRNA signature that can perdict the survival of ESCC patients was identified.

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Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

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