Abstract
Lung adenocarcinoma (LUAD) is the main histological type of lung cancer, which is the leading cause of cancer-related deaths. Long non-coding RNAs (lncRNAs) were recently revealed to be involved in various cancers. However, the clinical relevance and potential biological roles of most lncRNAs in LUAD remain unclear. Here, we identified a prognosis-related lncRNA ITGB1-DT in LUAD. ITGB1-DT was upregulated in LUAD and high expression of ITGB1-DT was correlated with advanced clinical stages and poor overall survival and disease-free survival. Enhanced expression of ITGB1-DT facilitated LUAD cellular proliferation, migration, and invasion, and also lung metastasis in vivo. Knockdown of ITGB1-DT repressed LUAD cellular proliferation, migration, and invasion. ITGB1-DT interacted with EZH2, repressed the binding of EZH2 to ITGB1 promoter, reduced H3K27me3 levels at ITGB1 promoter region, and therefore activated ITGB1 expression. Through upregulating ITGB1, ITGB1-DT activated Wnt/β-catenin pathway and its downstream target MYC in LUAD. The expressions of ITGB1-DT, ITGB1, and MYC were positively correlated with each other in LUAD tissues. Intriguingly, ITGB1-DT was found as a transcriptional target of MYC. MYC directly transcriptionally activated ITGB1-DT expression. Thus, ITGB1-DT formed a positive feedback loop with ITGB1/Wnt/β-catenin/MYC. The oncogenic roles of ITGB1-DT were reversed by depletion of ITGB1 or inhibition of Wnt/β-catenin pathway. In summary, these findings revealed ITGB1-DT as a prognosis-related and oncogenic lncRNA in LUAD via activating the ITGB1-DT/ITGB1/Wnt/β-catenin/MYC positive feedback loop. These results implicated ITGB1-DT as a potential prognostic biomarker and therapeutic target for LUAD.
Highlights
Lung cancer is still the most frequently diagnosed malignancy and the leading cause of mortality among all malignancies, accounting for 11.6% of the total cancer cases and 18.4% of the total cancer deaths worldwide (Bray et al, 2018)
To identify the Long non-coding RNAs (lncRNAs) associated with overall survival in Lung adenocarcinoma (LUAD), we analyzed The Cancer Genome Atlas (TCGA) LUAD dataset using the online tool Gene Expression Profiling Interactive Analysis (GEPIA)1
Through analyzing TCGA LUAD dataset using GEPIA, we found that high expression of RP11-462L8.1 (ITGB1-DT) was correlated with poor overall survival, and correlated with poor disease-free survival in LUAD (Figures 1A,B)
Summary
Lung cancer is still the most frequently diagnosed malignancy and the leading cause of mortality among all malignancies, accounting for 11.6% of the total cancer cases and 18.4% of the total cancer deaths worldwide (Bray et al, 2018). The histological types of lung cancer include lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large cell lung cancer, and small cell lung cancer. LUAD is the most common type, which accounts for 40%–50% of all lung cancers (Liang et al, 2020; Cooke et al, 2020). Most early-stage LUAD could be effectively treated by surgical resection, the prognoses of unresectable LUAD are still very poor with 5-year survival rates less than 20% (Devarakonda et al, 2020).
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