Objective This study aimed to investigate the molecular mechanisms of rectal cancer (RC) progression and provide new insights for itstreatment. Methods The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource(TIMER) databases, and the UALCAN platform were used to predict gene expression and correlations. The JASPAR database wasused to predict transcription factors. Quantitative polymerase chain reaction (qPCR) and western blot (WB) were performedto detect gene and protein expression. Cell viability was measured using the cell counting kit-8 (CCK-8). Transcription factor-promoterinteractions were examined through chromatin immunoprecipitation (ChIP) and the dual-luciferase reporter assay (DLR assay).Transcription factor-gene interactions were validated in vivo. The stats and ggplot2 packages in R were used for analysis and visualization. Results Regenerating islet-derived protein 1 alpha (REG1A) was significantly associated with RC malignant progression and was the most markedly upregulated. REG1A expression was elevated in RC patient tissues and cells. REG1A knockdown reduced RC cell survival and increased phosphorylated H2A histone family member X (γH2AX) levels under X-ray or 5-Fluorouracil (5FU). Nuclear transcription factor Y subunit alpha (NFYA) was correlated withREG1A, and NFYA knockdown decreased REG1A expression and cell survival while increasing γH2AX; REG1A reversed these effects. In vivo, NFYA knockdown reduced tumor volume, weight, and REG1A levels. Conclusion NFYA promoted REG1A expression, and the NFYA-REG1A axis enhanced RC resistance to RT and CT and malignant progression.
Approximately 51 non-small-cell lung cancer (NSCLC) risk loci have been identified by genome-wide association studies (GWASs). We conducted a high throughput RNA-interference (RNAi) screening to identify the candidate causal genes in NSCLC risk loci. KIAA0391 at 14q13.1 had the highest score and could promote proliferation and metastasis of NSCLC in vitro and in vivo . We next prioritized rs3783313 as a causal variant at 14q13.1, by integrating a large-scale population study consisting of 27,120 lung cancer cases and 27,355 controls, functional annotation, and expression quantitative trait locus (eQTL) analysis. Then we found that rs3783313 could facilitate a promoter-enhancer interaction to upregulate KIAA0391 expression by affecting the affinity of transcription factor NFYA. Mechanistically, KIAA0391 knockdown dramatically influenced pyroptosis-related pathways and increased the expression of CASP1. And KIAA0391 transcriptionally repressed CASP1 by binding to SMAD2 and induced an anti-pyroptosis phenotype, promoting tumorigenesis of NSCLC, which provides new insights and potential target for NSCLC.
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