N-nitrosamines-mediated downregulation of LncRNA-UCA1 induces carcinogenesis of esophageal squamous by regulating the alternative splicing of FGFR2

Concerns are raised over the risk to digestive system's tumors from the N-nitrosamines (NAs) exposure in drinking water. Albeit considerable studies are conducted to explore the underlying mechanism responsible for NAs-induced esophageal squamous cell carcinoma (ESCC), the exact molecular mechanisms remain largely unknown, especially at the epigenetic regulation level. In this study, it is revealed that the urinary concentration of N-Nitrosodiethylamine is higher in high incidence area of ESCC, and the lncRNA-UCA1(UCA1) is significantly decreased in ESCC tissues. In vitro and in vivo experiments further show that UCA1 is involved in the malignant transformation of Het-1A cells and precancerous lesions of the rat esophagus induced by N-nitrosomethylbenzylamine (NMBzA). Functional gain and loss experiments verify UCA1 can affect the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Mechanically, through binding to heterogeneous nuclear ribonucleoprotein F (hnRNP F) protein, UCA1 regulates alternative splicing of fibroblast growth factor receptor 2 (FGFR2), which promotes the FGFR2IIIb isoform switching to FGFR2 IIIc isoform, and the latter activates epithelial-mesenchymal transition via PI3K-AKT signaling pathways impacting tumorigenesis. Therefore, NAs-mediated downregulation of UCA1 promotes ESCC progression through targeting hnRNP F/FGFR2/PI3k-AKT axis, which provides a new chemical carcinogenic target and establishes a previously unknown mechanism for NAs-induced ESCC. Schematic representation of NAs-mediated downregulation of UCA1 promotes carcinogenesis of esophageal squamous by regulating the alternative splicing of FGFR2. [Display omitted] •The urine concentration of asymmetric NAs in ESCC patients was higher than that in healthy people.•NAs induces the malignant transformation of Het-1A and precancerous lesions of the rat esophagus.•NAs inhibits the expression of UCA1 in ESCC.•UCA1 acts as a molecular bridge to bind hnRNP F to regulate alternative splicing of FGFR2.•NAs participates in the carcinogenesis process via hnRNP F/FGFR2/PI3k-AKT axis.