RESUMEN
OBJECTIVE: To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6. DESIGN: We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitroand in vivo. RESULTS: SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a ß2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity. CONCLUSIONS: SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6. ACCESSION NUMBERS: The accession numbers for sequencing data are SRP111763 and SRP111797.
Asunto(s)
Empalme Alternativo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Fosfoproteínas/genética , Factores de Empalme Serina-Arginina/genética , Animales , Antineoplásicos/farmacología , Proliferación Celular , Supervivencia Celular , Neoplasias Colorrectales/tratamiento farmacológico , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoprecipitación , Indanos/farmacología , Ratones , Isoformas de Proteínas , Quinolonas/farmacología , Análisis de Secuencia de ARN , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
BACKGROUND & AIMS: The association between dietary vitamin A, retinol intake and blood retinol level and gastric cancer risk has been investigated by many studies. However, the results of these studies were controversial. The aim of our study was to systematically assess this issue. METHODS: PUBMED and EMBASE were searched, supplemented with manual-screening for relevant publications. Meta-analyses were performed to evaluate the association between vitamin A, retinol dietary intake or blood retinol level and gastric cancer risk. RESULTS: Thirty-one studies were included in this meta-analysis. Comparing the highest with the lowest categories, vitamin A intake significantly reduced gastric cancer risk (pooled RR = 0.66, 95% CI: 0.52-0.84), whereas a marginally inverse association was found between retinol intake (pooled RR = 0.94, 95% CI: 0.87-1.03) or blood retinol level (pooled RR = 0.87, 95% CI: 0.73-1.05) and gastric cancer risk. Interestingly, the results of subgroup analysis indicated that high vitamin A intake and blood retinol level were associated with reduced gastric cancer risk in Western countries, while a marginally inverse association was found between retinol and gastric cancer risk in Western countries. CONCLUSIONS: Vitamin A intake was inversely associated with gastric cancer risk, while no significant association was found with retinol intake or blood retinol level.