MIR194-2HG, a miRNA host gene activated by HNF4A, inhibits gastric cancer by regulating microRNA biogenesis

• Published in: Biology direct 2024-10, Vol.19 (1), p.95-15, Article 95
• Main Authors: Cao, Hong, Wang, Zidi, Guo, Qiwei, Qin, Shanshan, Li, Dandan
• Format: Article
• Language: English
• Subjects: Animals; Assaying; Biosynthesis; BTF3L4; Cancer; Care and treatment; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Chromatin; Colon; Correlation analysis; Development and progression; Female; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Gene sequencing; Genetic aspects; Genomes; Health aspects; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Host gene lncRNA; Humans; Immunoprecipitation; In vitro methods and tests; In vivo methods and tests; Male; Medical prognosis; Metastases; Metastasis; Mice; Mice, Nude; MicroRNA; MicroRNA biogenesis; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular modelling; Non-coding RNA; Northern blotting; Oncology, Experimental; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Small intestine; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Survival analysis; Tumor suppressor genes
• ISSN: 1745-6150; 1745-6150
• DOI: 10.1186/s13062-024-00549-z

MicroRNA host gene (MIRHG) lncRNA is a particular lncRNA subclass that can perform both typical and atypical lncRNA functions. The biological function of MIRHG lncRNA MIR194-2HG in cancer is poorly understood. Loss-of-function studies were performed in vivo and in vitro to reveal the biological function of MIR194-2HG in GC. MicroRNA PCR array, northern blotting, RNA sequencing, chromatin immunoprecipitation, and rescue assays were conducted to uncover the molecular mechanism of MIR194-2HG. In this study, we reported an atypical lncRNA function of MIR194-2HG in GC. MIR194-2HG downregulation was clinically associated with malignant progression and poor prognosis in GC. Functional assays confirmed that MIR194-2HG knockdown significantly promoted GC proliferation and metastasis in vitro and in vivo. Mechanismically, MIR194-2HG was required for the biogenesis of miR-194 and miR-192, which were reported to be tumor-suppressor genes in GC. Moreover, hepatocyte nuclear factor HNF4A directly activated the transcription of MIR194-2HG and its derived miR-194 and miR-192. Meanwhile, BTF3L4 was proved to be a common target gene of miR-192 and miR-194. Rescue assay further confirmed that MIR194-2HG knockdown promotes GC progression through maintaining BTF3L4 overexpression in a miR-194/192-dependent manner. The dysregulated MIR194-2HG/BTF3L4 axis is responsible for GC progression. Targeting HNF4A to inhibit miR-192/194 expression may be a promising strategy for overcoming GC.