Biology subjects

Slack, F.

Publications and source records attributed to Slack, F..

5 recordsLinked to original sources

bioRxiv2026

miR-425-5p Regulates Cellular Senescence Through Modulation of Retinoblastoma Protein Phosphorylation

MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating cellular senescence and aging. Our recent studies identified a conserved C. elegans miRNA cluster (miR-229/64/65/66) that is required for normal adult lifespan, with overexpression significantly extending longevity. Notably, cel-miR-229 is evolutionarily conserved in humans, with hsa-miR-425 sharing an identical seed sequence. Here, we investigated the role of miR-425 in mammalian cellular senescence. We found that miR-425 expression is markedly reduced in pharmacologically induced senescence in human lung cancer cells. Restoration of miR-425 expression attenuates senescence and suppresses the expression of senescence-associated secretory phenotype (SASP) cytokines following senescence induction. We further observed that miR-425 levels decline during replicative senescence, whereas stable overexpression in WI-38 fibroblasts delays senescence accumulation and preserves proliferative capacity. Mechanistically, miR-425 suppresses TGF-{beta} signaling, leading to reduced expression of the cyclin-dependent kinase inhibitor p21/CDKN1A and increased phosphorylation of the retinoblastoma (RB) protein, thereby promoting cell-cycle progression. We further identify PPP2CB, the catalytic subunit of protein phosphatase 2A (PP2A), as a direct target of miR-425. PPP2CB expression is downregulated in miR-425-5p overexpressing cells, even under senescence induction. Knockdown of PPP2CB using siRNA phenocopies the effects of miR-425 overexpression, reducing senescence, enhancing proliferative potential, and increasing RB phosphorylation. Collectively, our findings identify miR-425 as a conserved regulator of cellular senescence that acts through upregulation of RB phosphorylation. These results establish a novel miR-425-PPP2CB-RB regulatory axis controlling proliferation and senescence and suggest miR-425 as a potential therapeutic target for mitigating senescence to promote extended health span.

Cell Biology↗

bioRxiv2026

Aging-related Transcriptomic Changes with Spatial Resolution in the Human Prefrontal Cortex

The human prefrontal cortex (PFC), whose laminar organization is essential for cognitive function, is among the first regions to show age-related functional decline1,2. Single-cell sequencing studies revealed cell type-dependent aging effects but lacked spatial specificity3-6. Spatial transcriptomics (ST) advanced our molecular understanding of the human PFC7, yet whether aging-driven changes differ across PFC layers remains unclear. Here, we performed whole-transcriptome ST on postmortem PFC from 37 individuals across the adult lifespan. We mapped cortical layers and revealed aging mechanisms across layers. This represents one of the largest and most comprehensive lifespan ST analysis of the human PFC brain, offering crucial insight into how the brain ages and identifying potential molecular targets to mitigate cognitive aging and extend healthspan.

neuroscience↗

bioRxiv2026

MicroRNA spatial profiling for assessing drug efficacy in BRCA1-related triple-negative breast tumors

BRCA1/2-mutated breast cancers exhibit homologous recombination deficiency (HRD) and are initially sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors, but 40-70% of patients develop resistance, creating a need for predictive biomarkers that capture treatment-associated spatial heterogeneity. Using the K14-Cre Brca1f/fTrp53f/fmodel with tumors that acquired PARP inhibitor resistance, we evaluated PARP inhibitor combinations with either PI3K inhibition or Poly(I:C) in vivo. To determine how treatment altered tumor spatial microRNA (miRNA) profiles, we applied our hydrogel-based, nanoliter well array in situ miRNA assay to quantify and spatially profile miRNAs on FFPE sections from tumors treated for 10 days and developed spatial miRNA analysis frameworks integrating latent Dirichlet allocation (LDA) and principal component analysis (PCA). We also incorporated immune architecture using Structural Similarity Index Measure (SSIM) maps to assess co-localization of immune infiltration and miRNA topics. Both combinations improved antitumor activity compared to PARP inhibition alone. The resulting spatial miRNA topics stratified early tumors according to subsequent PARP inhibitor sensitivity or resistance and distinguished their treatment regimens, while SSIM analysis revealed co-localization of immune infiltration and miRNA topics. This integrative spatial miRNA assay and analysis identified a let-7a-dominant topic associated with PARP inhibitor resistance, indicating that spatial miRNA profiling may inform therapeutic stratification in BRCA1/2-related breast cancers.

biochemistry↗

bioRxiv2024

miR-21: A therapeutic target for delaying severe liver disease and hepatocellular carcinoma in high-fat-diet-fed mice

Liver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and HCC within the context of a Western high-fat diet, without additional choline (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. MiR-21 directly targets Transforming growth factor beta-induced (Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis, Tgfbi expression and tumor burden in HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments. SignificanceOur study demonstrates in vivo that miR-21 has protective functions in the broad spectrum of high-fat diet-based, progressive liver disease and cancer, and we show potential therapeutic value of a microRNA-21 mimic. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/613915v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1915cd8org.highwire.dtl.DTLVardef@66887corg.highwire.dtl.DTLVardef@18a8e54org.highwire.dtl.DTLVardef@18631b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Is evolutionary conservation a useful predictor for cancer long noncoding RNAs? Insights from the Cancer lncRNA Census 3

Evolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census, we observed an inverse relationship between year of discovery and evolutionary conservation. This observation is specific to cancer over other diseases, implying a sampling bias in selection of lncRNA candidates and casting doubt on the value of evolutionary metrics for prioritisation of cancer-related lncRNAs.

cancer biology↗