Effect and mechanism of downregulating the long-chain noncoding RNA TM4SF1-AS1 on the proliferation, apoptosis and invasion of gastric cancer cells

He, Chengzhi; Qi, Wenjing; Wang, Zhihui

doi:10.1186/s12957-021-02334-y

Cited by 11 publications

(5 citation statements)

References 31 publications

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“…Recent studies have shown the upregulation of TM4SF1-AS1 and its oncogenicity in several types of cancer, including GC, hepatocellular carcinoma, and lung cancer, but the underlying molecular mechanism is not fully understood [27,28,29]. In the present study, we found that TM4SF1-AS1 is transcriptionally activated in the non-tumorous gastric mucosa of GC patients, suggesting its involvement in the early onset of GC development.…”

Section: Discussionsupporting

confidence: 51%

TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

Kitajima

Maruyama

Niinuma

et al. 2023

Preprint

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Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development; however, little is known about their involvement in the early stages of tumorigenesis. To identify dysregulated lncRNAs in precancerous lesions, we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with gastric cancer (GC) and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell proliferation in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

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Section: Discussionsupporting

confidence: 51%

TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

Kitajima

Maruyama

Niinuma

et al. 2023

Preprint

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“…High TM4SF1-AS1 expression resulted in the activation of the TM4SF1 and PI3K-AKT pathways in gastric cancer cells, thereby enhancing proliferation, invasion, and EMT 46 . Subsequently, TM4SF1 promoted pancreatic cancer metastasis by regulating DDR1 expression 47 .…”

Section: Discussionmentioning

confidence: 99%

Identification of m6A/m5C/m1A-associated LncRNAs for prognostic assessment and immunotherapy in pancreatic cancer

Huang

Zhang

et al. 2023

Sci Rep

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Methylation of RNA plays an important role in cancer. Classical forms of such modifications include N6-methyladenine (m6A), 5-methylcytosine (m5C), and N1-methyladenine (m1A). Methylation-regulated long non-coding (lnc) RNAs are involved in various biological processes, such as tumor proliferation, apoptosis, immune escape, invasion, and metastasis. Therefore, we performed an analysis of transcriptomic and clinical data of pancreatic cancer samples in The Cancer Genome Atlas (TCGA). Using the co-expression method, we summarized 44 m6A/m5C/m1A-related genes and obtained 218 methylation-associated lncRNAs. Next, with COX regression, we screened 39 lncRNAs that are strongly associated with prognosis and found that their expression differed significantly between normal tissues and pancreatic cancer samples (P < 0.001). We then used the least absolute shrinkage and selection operator (LASSO) to construct a risk model comprising seven lncRNAs. In validation set, the nomogram generated by combining clinical characteristics accurately predicted the survival probability of pancreatic cancer patients at 1, 2, and 3 years after diagnosis (AUC = 0.652, 0.686, and 0.740, respectively). Tumor microenvironment analysis showed that the high-risk group had significantly more resting memory CD4 T cells, M0 macrophages, and activated dendritic cells and fewer naïve B cells, plasma cells, and CD8 T cells than the low-risk group (both P < 0.05). Most immune-checkpoint genes were significantly different between the high- and low-risk groups (P < 0.05). The Tumor Immune Dysfunction and Exclusion score showed that high-risk patients benefited more from treatment with immune checkpoint inhibitors (P < 0.001). Overall survival was also lower in high-risk patients with more tumor mutations than in low-risk patients with fewer mutations (P < 0.001). Finally, we explored the sensitivity of the high- and low-risk groups to seven candidate drugs. Our findings indicated that m6A/m5C/m1A-associated lncRNAs are potentially useful biomarkers for the early diagnosis and estimating the prognosis of, and ascertaining the responses to immunotherapy in, patients with pancreatic cancer.

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“…T cells are the main cells involved in tumor immunotherapy and are responsible for defense against pathogen infection. It has been reported that TM4SF1-AS1 can exacerbate the progression of lung cancer ( 31 ), hepatocellular carcinoma ( 32 ) and gastric cancer ( 33 ). TM4SF1-AS1, a representative SE-associated lncRNA, was found to be involved in T cell immunity for the first time in the present study.…”

Section: Discussionmentioning

confidence: 99%

Immune Infiltration and Clinical Outcome of Super-Enhancer-Associated lncRNAs in Stomach Adenocarcinoma

Peng

Cai

et al. 2022

Front. Oncol.

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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.

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Effect and mechanism of downregulating the long-chain noncoding RNA TM4SF1-AS1 on the proliferation, apoptosis and invasion of gastric cancer cells

Cited by 11 publications

References 31 publications

TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

Identification of m6A/m5C/m1A-associated LncRNAs for prognostic assessment and immunotherapy in pancreatic cancer

Immune Infiltration and Clinical Outcome of Super-Enhancer-Associated lncRNAs in Stomach Adenocarcinoma

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