Gastric Cancer (GC) is the fifth most frequently diagnosed malignancy and the third leading cause of cancer-related mortality worldwide. The aggressive nature of GC, coupled with late clinical presentation and limited therapeutic options, underscores the urgent need for a deeper molecular understanding of its pathogenesis. In the past, microRNAs (miRNAs)-evolutionarily conserved, 19-25-nucleotide, non-protein-coding RNAs-have emerged as pivotal post- transcriptional regulators that simultaneously modulate dozens of messenger RNAs through seed-sequence-mediated binding to 3' untranslated regions. In GC, the most intensively studied axes include Notch, Wnt/β-catenin, Hippo, Hedgehog, TGF-β, MAPK, PI3K-AKT-mTOR, and JAK/STAT. Importantly, these pathways do not operate in isolation; instead, they form interconnected networks wherein a single miRNA can create feed-forward or feedback loops that amplify or attenuate oncogenic signaling. Decoding such miRNA-orchestrated crosstalk is not merely an academic exercise; it offers tangible translational opportunities. Restoration of tumor-suppressive miRNAs using synthetic mimics delivered by lipid nanoparticles, or selective silencing of oncomiRs with antagomirs locked by 2'-O-methoxyethyl modifications, has already shown synergistic efficacy with chemotherapy, HER2-targeted agents, and immune checkpoint blockade in preclinical GC models. Moreover, circulating exosomal miRNA signatures that reflect pathway activation states are being vigorously pursued as minimally invasive biomarkers for early detection, molecular subtyping, and real-time monitoring of therapeutic response. In this comprehensive review, we therefore synthesize current mechanistic insights into miRNA- mediated regulation of the aforementioned signaling highways, highlight context-dependent controversies arising from tumor heterogeneity and microbial influence, and outline rational combinatorial strategies that may accelerate the development of next-generation, highly selective, low-toxicity interventions against gastric cancer.
Liu-Shan Wei, Jia Yu, Yan Hu et al.· Current Cancer Drug Targets· 0 citations
Hypoxia‐inducible factor‐1 α (HIF‐1α) is a key transcription factor for tumor cells to sense and adapt to the hypoxic microenvironment, regulate tumor progression such as tumor glycolysis, and is an important target for the development of anti‐tumor drugs. YC‐1 (1‐benzyl‐3‐(5’‐hydroxymethyl‐2’‐furyl)indazole), as a classic inhibitor of HIF‐1α, has received extensive attention in multiple anti‐tumor studies. Some derivatives that replace YC‐1 indazole with the benzimidazole skeleton have shown certain HIF‐1α inhibitory and anti‐tumor potential. In this study, a series of substituted benzimidazole derivatives were designed and synthesized, and their HIF‐1α inhibitory and anti‐tumor effects were screened and investigated. In vitro anti‐proliferation and dual‐luciferase reports showed that compound 9o had superior in vitro anti‐tumor (IC50 = 33.85 μM) and HIF‐1α transcriptional inhibitory activity (79.59% inhibition rate) compared with the positive control YC‐1. Meanwhile, compound 9o can also significantly inhibit the colony formation and survival rate of HCT‐116 cells. In addition, Western blotting, real‐time PCR and and lactic acid content experiments verified its inhibitory effect on HIF‐1α and downstream glycolysis. In addition, compound 9o was found to reduce platelet aggregation more than YC‐1, and the molecular docking results suggested that compound 9o weakened its interaction with soluble guanylate cyclase (sGC), which is beneficial for avoiding the bleeding risk during tumor treatment. In vivo studies have shown that compound 9o can inhibit tumor growth and reduce the levels of HIF‐1α and glycolysis rate‐limiting enzyme HK2 in HCT‐116 tumor‐bearing mice. The acute toxicity results also demonstrated the safety of compound 9o in vivo. Finally, we also explored its pharmacokinetic properties in rats, suggesting its potential for subsequent intravenous administration. These findings provide a basis for the further discovery of anti‐tumor candidate compounds based on HIF‐1α inhibitors.
Qixian Yang, Jing Zhang, Meijing Liu et al.· Drug development research (P...· 0 citations
Results highlight lncRNA ABCA9-AS1 as a novel and promising prognostic biomarker that promotes gastric cancer progression by acting as a ceRNA to modulate the miR-497-5p/KIF23 axis.
Yiwen Wu, Yiniu Xia, Hanyu Liu et al.· Current Cancer Drug Targets· 0 citations
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