Abstract
Super-enhancers (SEs) comprise large clusters of enhancers that highly enhance gene expression. Long non-coding RNAs (lncRNAs) tend to be dysregulated in cases of stomach adenocarcinoma (STAD) and are vital for balancing tumor immunity. However, whether SE-associated lncRNAs play a role in the immune infiltration of STAD remains unknown. In the present study, we identified SE-associated lncRNAs in the H3K27ac ChIP-seq datasets from 11 tumor tissues and two cell lines. We found that the significantly dysregulated SE-associated lncRNAs were strongly correlated with immune cell infiltration through the application of six algorithms (ImmuncellAI, CIBERSORT, EPIC, quantiSeq, TIMER, and xCELL), as well as immunomodulators and chemokines. We found that the expression of SE-associated lncRNA TM4SF1-AS1 was negatively correlated with the proportion of CD8+ T cells present in STAD. TM4SF1-AS1 suppresses T cell-mediated immune killing function and predicts immune response to anti-PD1 therapy. ChIP-seq, Hi-C and luciferase assay results verified that TM4SF1-AS1 was regulated by its super-enhancer. RNA-seq data showed that TM4SF1-AS1 is involved in immune and cancer-related processes or pathways. In conclusion, SE-associated lncRNAs are involved in the tumor immune microenvironment and act as indicators of clinical outcomes in STAD. This study highlights the importance of SE-associated lncRNAs in the immune regulation of STAD.
Highlights
Stomach cancer is the fifth most common cause of cancer-related morbidity and fourth most common cause of mortality worldwide, accounting for over 1,000,000 new cases and approximately 769,000 deaths in 2020 [1]
LncRNAs, which are transcribed by RNA polymerase II and independent transcriptional elements with lengths >200 bp, were thought to be unable to be translated into proteins [17]
Some Long non-coding RNAs (lncRNAs) are proven prospective markers of diagnosis, prognosis, and potential treatment targets in stomach adenocarcinoma (STAD), including EMT-associated lncRNA induced by TGFb1 (ELIT-1) [20], LINC00346 [21], gastric cancer-associated lncRNA 1 [22] and gastric cancer metastasisassociated long noncoding RNA [23]
Summary
Stomach cancer is the fifth most common cause of cancer-related morbidity and fourth most common cause of mortality worldwide, accounting for over 1,000,000 new cases and approximately 769,000 deaths in 2020 [1]. Infection with Helicobacter pylori, smoking, and diets high in nitrate and nitrite can lead to stomach cancer [2]. With progress in diagnosis and treatment, the quality of life of patients with stomach cancer can be improved. Stomach adenocarcinoma (STAD), aka gastric adenocarcinoma, is the most common histological type of stomach cancer (approximately 95%) [3], and patients still have a poor prognosis [2, 4]. Biomarkers such as PD1 and PDL1 are used increasingly often as immunotherapy for STAD, which benefits patients [2]. Identifying credible biomarkers is important for the early identification of STAD and novel molecular targeting treatments
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