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  • Hub microRNAs as Master Regulators in a Saffron-Targeted Breast Cancer Network

  • Fatemeh Shams,1,* Elina Khannehzar,2 Amirsajad jafari,3
    1. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    2. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    3. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


  • Introduction: MicroRNAs (miRNAs) coordinate broad gene programs that drive cancer survival, invasion, and therapy response. Because each miRNA can control dozens of targets, identifying high-degree “hub” miRNAs in disease-relevant networks can reveal master regulators suitable for intervention. Saffron (Crocus sativus) bioactives act on multiple cancer pathways. We integrated saffron’s target space with breast-cancer miRNA regulation to pinpoint hub miRNAs, quantify their control, and define the processes they govern.
  • Methods: Targets of major saffron constituents were curated and unified. Breast-cancer-associated miRNAs were compiled and intersected with miRNAs known to regulate the curated targets, yielding an 18-miRNA panel. Validated human miRNA→gene interactions were retrieved, restricted to the saffron target union, and imported into Cytoscape. Degree centrality nominated hub miRNAs. Over-representation analysis on the miRNAs (performed over their validated targets) produced Gene Ontology (GO) and pathway enrichments. Target-level results were summarized with observed-vs-expected counts to highlight key regulated genes.
  • Results: The filtered regulatory network contained 68 genes, 10 miRNAs, and 401 validated miRNA-gene edges. Ten miRNAs formed the control core, led by miR-16-5p (degree 48), miR-18a-5p (47), miR-15a-5p (46), miR-424-5p (43), miR-15b-5p (40), miR-195-5p (36), miR-155-5p (33), miR-9-5p (24), miR-146b-5p (20), and miR-497-5p (17). Six of these hubs belong to the miR-15/16 family, consistent with a strong apoptotic-checkpoint signal across the network. GO terms derived over validated interactions highlighted biologically coherent axes with strong significance and high miRNA coverage: G-protein–coupled adenosine receptor activity (Q ≈ 1.1×10⁻¹⁰; 8 contributing miRNAs), pointing to adenosine signaling control. BAD–BCL2 complex (Q ≈ 3.1×10⁻¹⁰; 11 miRNAs), indicating convergent pressure on intrinsic apoptosis. Engulfment of target by autophagosome (Q ≈ 4.2×10⁻⁹; 6 miRNAs), consistent with stress-response crosstalk. Channel inhibitor activity and negative regulation of cellular pH reduction (each Q ≈ 5.1×10⁻⁹; 10 miRNAs), aligning with ion-transport and carbonic-anhydrase-linked pH control. At the target-gene level, ADORA3 (adenosine A3 receptor) was markedly enriched, being regulated by 8 of the 10 network hubs against a very low expected frequency, reinforcing the adenosine/immune-inflammatory axis. Collectively, the network concentrates control over apoptosis (BCL2/BCL-xL axis), inflammation/adenosine signaling, autophagy, ion transport, and pH homeostasis,pathways already engaged by saffron bioactives in experimental systems. Discussion/Impact The architecture supports two complementary strategies. First, restoring or mimicking tumor-suppressive hubs (the miR-15/16/195/497 cluster) should reinforce intrinsic apoptosis by convergent repression of anti-apoptotic nodes (BCL-2/BCL-xL) and checkpoint kinases, naturally dovetailing with BH3-mimetics and DNA-damage therapies. Second, inhibiting oncogenic hubs (miR-18a-5p, miR-155-5p, miR-9-5p) could dampen Wnt/β-catenin, NF-κB/STAT survival programs, epithelial–mesenchymal transition, and metastatic spread. Because saffron compounds are reported to suppress inflammatory signaling and promote pro-apoptotic shifts, they are well-positioned as adjuvants that bias these hub circuits toward tumor cell death. A practical translation emerges: pair standard therapies that act on the same nodes (e.g., BCL2 inhibitors or DNA-damage agents) with saffron bioactives to amplify network-level effects, while exploring miRNA-directed interventions (mimics for the miR-15/16 family; antisense inhibitors for miR-18a/miR-155/miR-9). The convergence on ADORA3 suggests additional synergy with agents that modulate adenosine signaling and the tumor microenvironment. The network’s compactness (10 hubs orchestrating 68 genes across 401 edges) and the strong, multi-axis enrichment profile make this story highly amenable to an oral presentation: a single, interpretable figure can convey hubs, edges, and the prioritized pathways.
  • Conclusion: Integrating saffron target genes with breast-cancer miRNA regulation reveals a compact hub-miRNA architecture concentrating control over apoptosis, adenosine/inflammatory signaling, pH regulation, autophagy, and extracellular-matrix assembly. miR-16-5p, miR-15a/15b-5p, miR-195-5p, and miR-497-5p emerge as actionable tumor-suppressive levers, whereas miR-18a-5p, miR-155-5p, and miR-9-5p represent oncogenic switches. These data motivate kaempferol/crocin-anchored adjuvant strategies and miRNA-targeted combinations that jointly collapse survival and metastatic circuits in breast cancer.
  • Keywords: microRNA networks; hub regulators; breast cancer; saffron; apoptosis regulation

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