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Antisense lncRNA NNT-AS1 promoted esophageal squamous cell carcinoma progression by regulating its sense gene NNT

Xianglong Pan¹, Qi Wang¹, Yue Yu¹

¹Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Cell Death Discovery

|October 21, 2022

Abstract:

Antisense lncRNAs were endogenous productions from the antisense strand of coding genes and were transcribed in the reverse direction of the sense gene. The purpose of this study was to evaluate the roles and functions of antisense lncRNAs in esophageal squamous cell carcinoma (ESCC). Differentially expressed antisense lncRNAs were initially screened based on transcriptome data of 119 paired ESCC samples in GSE53624 and were further validated in 6 paired ESCC samples from our institution. Log-rank test was adopted to identify ESCC prognosis-associated lncRNAs. Finally, functional assays were performed to reveal the functions of our identified antisense lncRNAs. In total, 174 antisense lncRNAs were differentially expressed in both GSE53624 and JSPH databases. Five of them were significantly associated with ESCC prognosis (NNT-AS1, NKILA, CCDC18-AS1, SLCO4A1-AS1, and AC110619.1). Of note, NNT-AS1 showed the most significant association with ESCC prognosis. The upregulation of NNT-AS1 was further confirmed in ESCC cells. Knockdown of NNT-AS1 inhibited ESCC cell proliferation, migration, promoted ESCC cells apoptosis, and induced cell cycle arrest in the G2/M stage. NNT-AS1 expression significantly correlated with its sense gene NNT. As expected, NNT-AS1 knockdown suppressed NNT expression. Inhibition of NNT repressed ESCC cell proliferation and migration, and accelerated ESCC cell apoptosis. Overexpression of NNT could rescue the suppressed proliferation and migration of ESCC cells induced by the silencing of NNT-AS1. In terms of mechanism, NNT-AS1 served as a competing endogenous RNA to sponge the miR-382-5p, which could inhibit NNT expression. Pathway enrichment analysis and western blot assay indicated that NNT-AS1 and NNT could regulate the cell cycle pathway. In conclusion, antisense lncRNA NNT-AS1 facilitated ECSS progression by targeting its sense gene NNT through sponging miR-382-5p. This study provided us with a deeper insight into the roles of antisense lncRNAs in ESCC and identified novel potential therapeutic targets.

Insights

Antisense long non-coding RNA (lncRNA) NNT-AS1 promotes esophageal squamous cell carcinoma (ESCC) progression by regulating its sense gene NNT. This study identifies NNT-AS1 as a potential therapeutic target for ESCC.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Antisense long non-coding RNAs (lncRNAs) are transcribed from the antisense strand of coding genes.
The roles of antisense lncRNAs in esophageal squamous cell carcinoma (ESCC) are not fully understood.
Understanding these roles is crucial for identifying novel therapeutic targets in ESCC.

Purpose of the Study:

To investigate the functions and roles of antisense lncRNAs in esophageal squamous cell carcinoma (ESCC).
To identify specific antisense lncRNAs associated with ESCC prognosis.
To elucidate the molecular mechanisms underlying the function of identified antisense lncRNAs in ESCC.

Main Methods:

Screening of differentially expressed antisense lncRNAs using transcriptome data from ESCC patient samples (GSE53624 and institutional data).
Prognostic analysis using log-rank tests to identify lncRNAs associated with ESCC survival.
Functional assays including cell proliferation, migration, apoptosis, cell cycle analysis, and mechanistic studies (miRNA sponging, pathway analysis).

Main Results:

174 differentially expressed antisense lncRNAs were identified in ESCC.
Five antisense lncRNAs, including NNT-AS1, were significantly associated with ESCC prognosis.
Upregulated NNT-AS1 promotes ESCC cell proliferation and migration, inhibits apoptosis, and induces G2/M cell cycle arrest, partly by regulating its sense gene NNT and sponging miR-382-5p.

Conclusions:

Antisense lncRNA NNT-AS1 acts as an oncogene, facilitating ESCC progression.
NNT-AS1 targets its sense gene NNT through sponging miR-382-5p, influencing cell cycle pathways.
NNT-AS1 represents a promising novel therapeutic target for esophageal squamous cell carcinoma.

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