Differentially expressed SE-lncRNAs in lung adenocarcinoma

ABSTRACT: Background: Lung adenocarcinoma (LUAD) is the leading cause of deaths worldwide, and metastasis accounts for the vast majority of cancer-related deaths. Driver mutations play important roles in treatment decision making for LUAD patients, while the complicated metastatic progress cannot be explained by genetic aberrations alone. Epigenomic reprogramming is particularly notable as an important signature of the metastasis transition. However, long noncoding RNAs (lncRNAs) hijacked by super-enhancer (SE), vital regulatory elements in epigenome, remain elusive in the progression of metastasis. Methods: SE associated lncRNAs microarray was utilized to identified the dysregulated lncRNAs related to metastasis. ChIP-seq, Hi-C data analysis and luciferase reporter assay were utilized to confirm LINC01977 was hijacked by SE. In vitro and in vivo assays were applied to elucidate effects of LINC01977 on the malignancy of LUAD. Results: In this study, we identified that LINC01977, a cancer-testis lncRNA, was up-regulated in tumor, which was driven by a …kb-long SE upstream of LINC01977 and sensitive to BRD4 inhibitor. LINC01977-antisense oligonucleotides (ASO) dramatically suppresses proliferation and invasion both in vitro and in vivo. Mechanically, LINC01977 promotes phosphorylation of SMAD3 to facilitate its nuclear retention, and it also act as a scaffold to cooperate the interaction between SMAD3 and CBP/P300, the transcriptional co-activators, to regulate the downstream target gene ZEB1. Interestingly, SMAD3 also positively regulated LINC09177 transcription by binding the promoter and active elements of its SE, which was medicated by canonical TGF-β signaling secreted by M2-like tumor-associated macrophages (TAM2). We also revealed that the expression of LINC01977 was positively correlated with TAM2 infiltration especially in early stage. Additionally, stage I LUAD patients with high LIN01977 expression predicated a shorter progression-free survival (PFS). Conclusions: LINC01977 promotes the malignant progression of LUAD through facilitating the interaction between SMAD3 and CBP/P300. The upregulation of LINC01977 was medicated by super-enhancer and TAM2 infiltration, dependent on canonical TGF-β signaling. LINC01977 could be a valuable therapeutic target especially for early stage patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196584 | GEO | 2022/08/24

REPOSITORIES: GEO