Long noncoding RNA FOXD2 adjacent opposite strand RNA1 (FOXD2-AS1) plays an oncogenic role in various cancers, including gastric cancer (GC). However, the function of FOXD2-AS1 in regulating radiosensitivity of GC cells and its underlying molecular mechanisms have not been elucidated. This study aimed to figure out the potential mechanisms of FOXD2-AS1 in regulating GC cell radiosensitivity. RT-qPCR revealed upregulation of FOXD2-AS1 in GC cells exposed to radiation. Subcellular fractionation assay was used to localize FOXD2-AS1 in GC cells. Colony formation, MTT, EdU, and flow cytometry assays were performed to investigate the role of FOXD2-AS1 in regulating cell proliferation, cell cycle progression, and cell apoptosis. Western blotting was used to assess protein levels of apoptosis-associated markers and SET domain containing 1A (SETD1A). Homologous recombination reporter assay was conducted to explore the effect of FOXD2-AS1 on DNA damage repair. The downstream molecules of FOXD2-AS1 were identified with RNA pulldown, luciferase reporter, and RNA immunoprecipitation assays. The results showed that FOXD2-AS1 knockdown suppressed cell proliferation and cell cycle progression and promoted cell apoptosis and radiosensitivity of GC. FOXD2-AS1 could bind with miR-1913 in GC cells. In addition, miR-1913 targeted SETD1A, which was highly expressed in GC cells. Overexpression of SETD1A reversed FOXD2-AS1 silencing-induced effects on proliferation, apoptosis, and radiosensitivity of GC cells. In conclusion, knocking down FOXD2-AS1 enhances the radiosensitivity of GC cells by sponging miR-1913 to upregulate SETD1A expression.
Background: Lymphoid enhancer-binding factor-1 (LEF1) was previously reported to contribute to a variety of malignancies, including hepatocellular carcinoma (HCC). However, its role in HCC is poorly understood. Objective: To explore the role of LEF1 in HCC, including its prognostic and drug-targeting value. Methods: The LEF1 expression and patient characteristics were investigated. The associations between clinical characteristics and LEF1 were analyzed using both univariate and multivariate logistic regression. Cox regression and Kaplan–Meier curves were used to explore the clinicopathological factors related to overall survival in patients with HCC. A nomogram to predict the survival rate was constructed and validated. The Kyoto Encyclopedia of Genes and Genomes database (KEGG) was used to explore the function of LEF1. Gene Set Enrichment Analysis (GSEA) was also performed using The Cancer Genome Atlas dataset. Furthermore, compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC were identified using the Comparative Toxicogenomics Database (CTD), patents about these drugs in HCC were also reviewed through Worldwide Espacenet® and Patentscope®. Results: Increased expression of LEF1 was significantly associated with high histological grade of HCC (odds ratio (OR) = 2.521 for grade (G)2 vs. G1, OR = 2.550 for G3 vs. G1, OR = 7.081 for G4 vs. G1, all P < 0.05). A Kaplan–Meier survival curve showed that HCC patients with LEF1 overexpression had a poor prognosis compared with those with normal LEF1 expression (P = 0.025). Multivariate Cox regression analysis revealed that LEF1 is an independent prognostic factor for overall survival of patients with HCC (hazard ratio (HR) = 1.095; P = 0.04). The constructed nomogram to predict the survival rate produced a statistically significant prediction (area under the curve (AUC) = 86.68). In addition, Gene Ontology (GO) and KEGG analysis of genes co-expressed with the protein showed that LEF1 was associated with transcriptional regulation. GSEA suggested that the cell cycle, the WNT signaling pathway, and the NOTCH signaling pathway may be the key pathways regulated by LEF1 in HCC. Furthermore, the Comparative Toxicogenomics Database (CTD) identified nine compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC. Patents review suggested that these drugs may show some efficacy in HCC, but whether these drugs interact with LEF1 and improve prognosis for patients with HCC remains to be explored. Conclusion: LEF1 is a latent prognostic molecular biomarker of HCC. The cell cycle, and WNT and NOTCH signaling pathways are regulated by LEF1 in HCC. LEF1 could be a potential drug target for HCC.
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