Abstract
Background: The aim of the present study was to identify the potential long non-coding (lnc.)-RNA and its associated molecular mechanisms involved in the regulation of the radiosensitivity of esophageal squamous cell cancer (ESCC) in order to assess whether it could be a biomarker for the prediction of the response to radiotherapy and prognosis in patients with ESCC.Methods: Microarrays and bioinformatics analysis were utilized to screen the potential lncRNAs associated with radiosensitivity in radiosensitive (n = 3) and radioresistant (n = 3) ESCC tumor tissues. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed in 35 ESCC tumor tissues (20 radiosensitive and 15 radioresistant tissues, respectively) to validate the lncRNA that contributed the most to the radiosensitivity of ESCC (named the candidate lncRNA). MTT, flow cytometry, and western blot assays were conducted to assess the effect of the candidate lncRNA on radiosensitivity in vitro in ECA109/ECA109R ESCC cells. A mouse xenograft model was established to confirm the function of the candidate lncRNA in the radiosensitivity of ESCC in vivo. The putative downstream target genes regulated by the candidate lncRNA were predicted using Starbase 2.0 software and the TargetScan database. The interactions between the candidate lncRNA and the putative downstream target genes were examined by Luciferase reporter assay, and were confirmed by PCR.Results: A total of 113 aberrantly expressed lncRNAs were identified by microarray analysis, of which family with sequence similarity 201-member A (FAM201A) was identified as the lncRNA that contributed the most to the radiosensitivity of ESCC. FAM201A was upregulated in radioresistant ESCC tumor tissues and had a poorer short-term response to radiotherapy resulting in inferior overall survival. FAM201A knockdown enhanced the radiosensitivity of ECA109/ECA109R cells by upregulating ataxia telangiectasia mutated (ATM) and mammalian target of rapamycin (mTOR) expression via the negative regulation of miR-101 expression. The mouse xenograft model demonstrated that FAM201A knockdown improved the radiosensitivity of ESCC.Conclusion: The lncRNA FAM201A, which mediated the radiosensitivity of ESCC by regulating ATM and mTOR expression via miR-101 in the present study, may be a potential biomarker for predicting radiosensitivity and patient prognosis, and may be a therapeutic target for enhancing cancer radiosensitivity in ESCC.
Highlights
Esophageal cancer (EC) is one of the most common types of cancer, with the 7th highest incidence rate and 6th greatest rate of cancer-associated death (Bray et al, 2018)
There were no significant differences between radiosensitive (4 complete response (CR) and 19 partial response (PR)) and radioresistant (9 stable disease (SD) and 9 progressive disease (PD)) patients regarding the distributions of gender, age, Eastern Cooperative Oncology Group (ECOG) score, tumor location, and clinical stage (Table 2)
A total of 113 aberrantly expressed long non-coding ribonucleic acid (RNA) (lncRNA) were identified in the microarray analysis using three radiosensitive esophageal squamous cell cancer (ESCC) tumor tissues and three radioresistant ESCC tumor tissues, of which 71 lncRNA transcripts were upregulated and 42 lncRNA transcripts were downregulated in the radiosensitive ESCC tumor tissues when compared with the radioresistant ESCC tumor tissues
Summary
Esophageal cancer (EC) is one of the most common types of cancer, with the 7th highest incidence rate and 6th greatest rate of cancer-associated death (Bray et al, 2018). As the molecular mechanism of radioresistance, which is known to involve DNA repair proteins (Zafar et al, 2010), cell signal pathways (Dumont and Bischoff, 2012), angiogenesis (Francescone et al, 2011), cancer stem cells (Moncharmont et al, 2012), and autophagy (Chaachouay et al, 2011), is intricate and has not been elucidated thoroughly, there are currently no accurate biomarkers to predict radioresistance or therapeutic targets to enhance the radiosensitivity of EC. The aim of the present study was to identify the potential long non-coding (lnc.)-RNA and its associated molecular mechanisms involved in the regulation of the radiosensitivity of esophageal squamous cell cancer (ESCC) in order to assess whether it could be a biomarker for the prediction of the response to radiotherapy and prognosis in patients with ESCC
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