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Identification of a novel intracellular function of the secreted ribonuclease RNASE1 in inhibiting gene expression

ABSTRACT: RNASE1 is a ribonuclease secreted by cells and degrades extracellular RNAs. Here, we unexpectedly found that endogenous RNASE1, in addition to being secreted, is predominantly localized to the nucleus and primarily functions to inhibit gene expression in human colorectal cancer (CRC) cells. In CRC cells, RNASE1 expression is highly cell type-specific and is restricted to well-differentiated cells where its transcription is activated by the pioneer transcription factor FOXA1. Using CRISPR interference (CRISPRi) utilizing three independent sgRNAs targeting the RNASE1 locus followed by RNA-seq, we found that upon depletion of RNASE1, most of the differentially expressed RNAs are modestly but significantly upregulated suggesting that RNASE1 may predominantly function to inhibit gene expression. In CRC patients, RNASE1 is significantly downregulated and high RNASE1 expression is associated with better patient survival indicating a potential tumor suppressive function. Consistent with this, RNASE1 depletion results in increased proliferation and clonogenicity indicating that RNASE1 inhibits the growth of CRC cells. Finally, a promising RNASE1 target amongst the most significantly upregulated mRNAs upon RNASE1 depletion is DKK1 (Dickkopf inhibitor 1) which is upregulated in CRC and negatively regulated by RNASE1. Collectively, these data uncover an intracellular function of RNASE1 in inhibiting gene expression and CRC cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288583 | GEO | 2025/05/07

REPOSITORIES: GEO

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Project description:Colorectal cancer (CRC) is a genetically heterogeneous disease with several distinct morphological growth patterns. This study was aimed to investigate genes differentially expressed between ulcerative and polypoid colorectal CRC. cDNA microarray was first employed to compare the gene expression profiling of ulcerative and polypoid CRC with paired normal mucosa. Potential candidates identified by data filtering were further validated using quantitative real-time polymerase chain reaction, western blot and immunohistochemistry. Epigenetic regulation of gene expression was investigated using methylation-specific PCR (MSP). cDNA microarray identified 11 up-regulated and 14 down-regulated genes differentially expressed in both types of tumor compared to matched normal mucosa. Among them, S100P was the only upregulated gene preferentially associated with polypoid CRC (p = 0.032), whereas no genes demonstrated significantly differential association with ulcerative CRC. S100P protein and mRNA expression level of polypoid CRC was significantly higher than that of ulcerative CRC (p < 0.05, respectively). Immunoreactivity of S100P protein was localized predominantly in the nuclei and to a less extent in the cytoplasm. Overexpression of S100P occurred early in the adenoma stage. 80% (24/30) and 20% (6/30) polypoid CRC showed diffusely strong and moderate overexpression, respectively. In contrast, S100P was diffusely and strongly expressed in 15% (6/40) ulcerative CRC, with 52.5% (21/40) and 32.5% (13/40) tumors having moderate and weak overexpression, respectively. S100P overexpression was preferentially associated with polypoid CRC (p < 0.001). The relative methylation level determined by MSP was not statistically different between polypoid and ulcerative CRC (43.36% vs. 49.10%, p = 0.168), indicating that promoter hypomethylation was directly related to upregulation of S100P mRNA. The gene expression profiling of ulcerative and polypoid CRC with paired normal mucosa were compared. Dye swapping experiments with ulcerative CRC vs normal mucosa or polypoid CRC vs normal mucosa were performed and we averaged the log ratios of the duplicated spots on each slide.

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Identification of a novel intracellular function of the secreted ribonuclease RNASE1 in inhibiting gene expression

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