A dual role for miR-210-3p in hypoxia-driven signaling and mitotic regulation in cancer

Context-dependent effects of MIR100HG on tumorigenic phenotypes and p38/MAPK–AKT signaling in hepatocellular carcinoma

Hypoxia fuels JAK/STAT-LIV1 signaling: A promising therapeutic avenue in triple-negative breast cancer.

Triple-negative breast cancer remains one of the most aggressive and therapeutically challenging breast cancer subtypes because of its high metastatic potential, molecular heterogeneity and limited targeted treatment options. Hypoxia is a hallmark of TNBC tumor microenvironment and activates signaling cascades that promote tumor progression, metastasis, immune evasion, and therapeutic resistance. Although hypoxia, STAT3 signaling, LIV-1 (SLC39A6), and zinc homeostasis have been independently implicated in TNBC progression, the mechanistic crosstalk among these pathways and their integration into a unified, subtype specific model remains insufficiently understood. Emerging evidence suggests that LIV-1 functions not merely as a zinc transporter but as an active regulator of oncogenic signaling. Under hypoxia conditions, stabilization of hypoxia-inducible factor-1α (HIF-1α) promotes cytokine- mediated STAT3 activation, leading to increased LIV-1 expression and consequent intracellular zinc accumulation. Elevated zinc levels, in turn, may sustain STAT3 phosphorylation through inhibition of negative regulatory phosphatases, establishing a self-reinforcing feed-forward loop that enhances epithelial-mesenchymal transition, cancer stemness, immune modulation and treatment resistance. Current TNBC therapies, including chemotherapy and emerging immunotherapies show limited durable efficacy, underscoring the need for mechanistically grounded biomarkers and targets. Based on these observations, we propose the Hypoxia-STAT3-LIV-1-zinc signaling axis as a central regulatory node driving TNBC progression and a promising candidate for biomarker development and therapeutic targeting. This review integrates current evidence supporting this signaling network, identifies critical knowledge gaps, and outlines experimental strategies including hypoxia-mimetic models, LIV-1/STAT3 knockdown systems, and zinc chelation assays needed to validate this proposed mechanism and translate it into clinical application.

HIF-1α-associated transcriptional responses to chemical hypoxia in breast and liver cancer cells.

Hypoxia is a defining feature of the tumor microenvironment and a key driver of malignant progression through transcriptional reprogramming of metabolic, angiogenic, and survival pathways. In this study, hypoxia-induced molecular responses were investigated in human hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cells using cobalt(II) chloride (CoCl2) as a hypoxia mimetic. Cell viability profiling was performed to determine the optimal experimental concentration, followed by quantitative PCR analysis of hypoxia-related genes and miRNA-gene interaction network analysis. Cell viability profiling identified 100 µM CoCl2 as the optimal condition for downstream analyses. Quantitative PCR revealed robust induction of HIF-1α in both cell lines, indicating activation of hypoxic signaling. However, downstream responses differed markedly between cell types. MCF-7 cells exhibited significant upregulation of SLC2A1 and increased VEGFA and NFKB1 expression, consistent with activation of glycolytic and pro-angiogenic pathways. In contrast, HepG2 cells showed limited downstream transcriptional engagement despite elevated HIF1A expression. Furthermore, miRNA-gene interaction analysis revealed a dense regulatory network in MCF-7 cells, whereas HepG2 cells displayed a more restricted, VEGFA-centered miRNA profile. These findings demonstrate that chemical hypoxia induces cell-type-specific transcriptional and post-transcriptional responses in breast and liver cancer cells. The results suggest that miRNA-mediated regulation may contribute to differential tumor adaptation to hypoxic stress and highlight the importance of cellular context in hypoxia-associated signaling pathways.

ERO1A is a hypoxia-ER bridge in NSCLC: from pan-cancer identification to a dual-reporter visualization system.

Tumor hypoxia is a hallmark of solid tumor progression, in which hypoxia-inducible factor 1α (HIF-1α) and its signaling network play a pivotal role in regulating tumor progression. Here, leveraging TCGA and GEO datasets through pan-cancer analysis, we rapidly identified 21 candidate genes closely associated with cancer progression and hypoxia response in six cancer types exhibiting high HIF-1α expression. Meanwhile, through literature mining and cellular experiments, ERO1A was identified in NSCLC (Non-Small Cell Lung Cancer) as a gene whose expression patterns highly correlated with HIF-1α. ERO1A, an endoplasmic reticulum (ER) oxidoreductase involved in ER protein quality control and stress response, has been linked to various malignant tumor processes. Our bioinformatics analysis and quantitative cellular experiments indicated its strong association with hypoxia-related HIF-1α signaling, although direct binding evidence between HIF-1α and the ERO1A promoter remains to be established in future studies. However, direct and intuitive cell-level tools for visualizing how the hypoxic microenvironment affects ER function remain limited. To address this gap, we constructed a dual-reporter system, ERO1Ap2-miRFP670/5HRE-EGFP, driven by the ERO1A promoter and hypoxia response element (HRE), respectively. This system enables real-time, visual monitoring of the dynamic interplay between ER function and the tumor hypoxic microenvironment by simultaneously tracking ERO1A promoter activity and HIF-1α pathway activation. This novel tool provides a robust platform for in-depth exploration of the HIF-1α signaling pathway and ER protein quality control mechanisms. Furthermore, it also offers new insights and experimental evidence for developing therapeutic strategies targeting the tumor hypoxic microenvironment.

miR-142-3p in cancer: intracellular tumor suppression and extracellular vesicle- mediated microenvironmental signaling

miR-142-3p has emerged as an important regulator of cancer progression and treatment response, exhibiting predominantly tumor-suppressive functions. Intracellularly, miR-142-3p inhibits proliferation, promotes apoptosis, suppresses epithelial–mesenchymal transition (EMT), and enhances chemosensitivity through the downregulation of key pathways, including HMGB1, Wnt/β-catenin, and SIRT1-mediated autophagy. Notably, miR-142-3p is frequently enriched in extracellular vesicles (EVs), indicating selective export from tumor cells. This EV-mediated trafficking introduces functional complexity, as the loss of intracellular miR-142-3p may attenuate its tumor-suppressive effects, while its transfer to recipient cells within the tumor microenvironment (TME) may exert context-dependent roles. Within the TME, miR-142-3p has been associated with the regulation of cancer-associated fibroblast (CAF) activation, angiogenesis, and immune responses. Emerging evidence further suggests a potential role for EV-associated miR-142-3p in systemic processes such as cancer-associated cachexia through modulation of muscle-related pathways, although this remains poorly defined. This review summarizes the dual intracellular and extracellular functions of miR-142-3p in cancer and highlights its contribution to treatment sensitivity and TME interactions. We also discuss current challenges and future directions, including therapeutic strategies aimed at restoring intracellular miR-142-3p levels or modulating its EV-mediated transfer. A deeper understanding of its context-dependent roles will be critical for the development of targeted and clinically relevant therapeutic approaches.

miR-519d-3p inhibits gastric cancer progression by targeting the Beclin-1-dependent autophagy pathway.

Dysregulation of microRNA networks is a hallmark of gastric cancer pathogenesis, but the mechanisms driving early-stage disease remain poorly understood. This study utilized integrative bioinformatics analysis of the Gene Expression Omnibus dataset GSE158315 to identify tumor-suppressive microRNAs in early gastric cancer. We identified hsa-miR-519d-3p as a core downregulated microRNA in early-stage tissues. Functional assays in NUGC-3 and MKN-45 cell lines demonstrated that miR-519d-3p overexpression significantly suppressed cell migration and invasion, whereas its inhibition enhanced these malignant phenotypes. Dual-luciferase reporter assays confirmed that miR-519d-3p directly targets the 3' untranslated region of BECN1 (Beclin-1). Silencing Beclin-1 via siRNA mimicked the effects of miR-519d-3p overexpression, while rescue experiments showed that Beclin-1 knockdown reversed the pro-migratory and pro-invasive effects triggered by miR-519d-3p inhibition. Furthermore, monitoring of autophagic flux using mRFP-GFP-LC3 tandem reporters revealed that miR-519d-3p inhibition enhances autophagy in a Beclin-1-dependent manner. Clinical data analysis from The Cancer Genome Atlas further supported the upregulation of Beclin-1 in gastric cancer and its correlation with aggressive clinicopathological features. In conclusion, our findings establish the miR-519d-3p/Beclin-1 axis as a critical regulator of motility and autophagy in gastric cancer, representing a potential therapeutic target for early intervention.