Background Breast cancer (BC), a malignant tumor, is characterized by high incidence and poor prognosis among women worldwide. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) can regulate the initiation and progression of BC through competitive endogenous RNA (ceRNA) mechanisms. Despite depression being an important factor affecting patients with BC, the ceRNA regulatory network involving depression‐related genes in BC remains unclear. Methods In this study, we explored the role of the AC104024.2/miR‐30a‐5p axis in BC progression by targeting the depression‐related gene mitogen‐activated protein kinase kinase 3 (MAP2K3). We used depression‐like mouse models to confirm the role of MAP2K3 in modulating depressive behavior. Additionally, gene set enrichment analyses (GSEA) and phenotypic experiments were conducted to verify the effects of the AC104024.2/miR‐30a‐5p/MAP2K3 axis on BC cell proliferation, migration, and apoptosis. Luciferase reporter assays were performed to demonstrate the ceRNA function of AC104024.2 for miR‐30a‐5p. Results Our results showed that the AC104024.2/miR‐30a‐5p axis promotes the malignant progression of BC by regulating MAP2K3. In depression‐like mouse models, MAP2K3 was identified as a key gene modulating depressive behavior. The AC104024.2/miR‐30a‐5p/MAP2K3 axis significantly influenced BC cell proliferation, migration, and apoptosis. Luciferase reporter assays confirmed that AC104024.2 acts as a ceRNA for miR‐30a‐5p, thereby affecting MAP2K3 expression. Rescue experiments suggested that the regulatory effects of AC104024.2 on BC malignancy are at least partly dependent on MAP2K3. Conclusion This study uncovered the role of the depression‐related ceRNA network in BC progression and identified AC104024.2 and MAP2K3 as potential biomarkers for the diagnosis and treatment of BC. These findings provide significant clinical implications and applications for the management of BC.
Objective To investigate the roles of RPARP‐AS1 and miR‐10b‐5p in regulating the prognosis and tumor progression of non‐small cell lung cancer (NSCLC). Methods A total of 138 NSCLC patients were enrolled. Surgical specimens were stored in liquid nitrogen. All patients received 5 years of clinical follow‐up for prognostic assessment. In addition, multivariate Cox regression analysis was conducted to identify independent factors affecting NSCLC prognosis, and gene expression levels were quantified by reverse transcription quantitative polymerase chain reaction (RT‐qPCR). Cell Counting Kit‐8 (CCK‐8) assays were performed to examine cell proliferation, and transwell assays were used to assess cell migration and invasion. Furthermore, nuclear‐cytoplasmic fractionation experiments were conducted to localize RPARP‐AS1 distribution. The interaction between RPARP‐AS1 and miR‐10b‐5p was examined by dual luciferase reporter assays, and downstream targets in NSCLC were predicted using databases. Results RPARP‐AS1 was downregulated, while miR‐10b‐5p was upregulated in both NSCLC patient tissues and cells. Patients with reduced RPARP‐AS1 expression or increased miR‐10b‐5p expression had lower survival rates, accompanied by worsened tumor size, differentiation, and metastasis. oe‐RPARP‐AS1 inhibited tumor cell proliferation, migration, and invasion. However, RPARP‐AS1‐induced functional alterations in NSCLC cells were mediated by miR‐10b‐5p. A total of 47 overlapping genes were identified to potentially mediate downstream signaling pathways of the RPARP‐AS1/miR‐10b‐5p axis in NSCLC cells. Conclusion Silencing RPARP‐AS1 targeted miR‐10b‐5p to induce NSCLC cell proliferation, migration, and invasion, leading to tumor progression and poor prognosis.
Long noncoding RNAs (lncRNAs) are emerging as critical regulators of tumor initiation and progression through transcriptional and posttranscriptional mechanisms. UPK1A antisense RNA 1 (UPK1A-AS1), a cancer-associated lncRNA, has been reported to participate in oncogenic processes; however, its overall landscape across human malignancies and its biological role in therapy resistance remain poorly understood. Given the increasing importance of identifying functional lncRNAs with prognostic and therapeutic potential, this study presents a comprehensive multiomics characterization of UPK1A-AS1 and its experimental validation in hepatocellular carcinoma (HCC). We integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), the cancer immunology data engine (CIDE), and the cBioPortal for cancer genomics (cBioPortal) to systematically assess its expression pattern, genomic alterations, clinical significance, and immunological associations. Our analyses revealed that UPK1A-AS1 is significantly upregulated in multiple tumor types, with copy-number amplification as the predominant genomic alteration driving its overexpression. Elevated UPK1A-AS1 expression was correlated with advanced disease stage, poor differentiation, immune exclusion, and unfavorable prognosis, supporting its potential as a cancer type-dependent biomarker. In parallel, functional studies demonstrated that hypoxia transcriptionally induces UPK1A-AS1 in HCC, where it promotes sorafenib resistance by suppressing apoptosis. Silencing UPK1A-AS1 restored apoptotic and enhanced sorafenib efficacy both in vitro and in vivo. Collectively, our findings suggest that UPK1A-AS1 is a hypoxia-inducible oncogenic lncRNA that plays dual roles in cancer, with cancer type-dependent associations with progression and immune modulation across malignancies and mechanistically mediating hypoxia-associated drug resistance in HCC.
INTRODUCTION:There is no specific therapy for triple-negative breast cancer (TNBC), and the recurrence rate is high. Cancer stem cells (CSCs) play an important role in cancer chemoresistance and metastasis, but there is no consensus marker in this type of cancer. The aim of this study was to identify CSC biomarkers in the plasma secretome of TNBC patients. METHODS:CD44+/CD24- CSCs were isolated from MDA-MB-436 and MDA-MB-231 (ATCC) lines by magnetic immunoselection. The extracellular vesicles (EVs) of CSCs were isolated by size exclusion chromatography (SEC) of conditioned medium (CM) without fetal bovine serum (FBS) and blood plasma from TNBC and healthy women. Tetraspanins CD9 and CD81 identified the EVs, while electron microscopy determined the morphology and tunable resistive pulse sensing (TRPS) established particle size. Luminex technology was used to determine the presence of L1 cell adhesion molecule (L1CAM), carbonic anhydrase IX (CA9), mesothelin, midkine, hepsin, kallikrein-6 (KLK6), transglutaminase 2 (TGM2), aldehyde dehydrogenase 1a1 (ALDH1A1), epithelial cell adhesion molecule (EpCAM), and differentiation cluster 44 (CD44). RESULTS:Particles of 0-200 nm in size were more frequent in CSC-MDA-MB-436, while particles of 201-500 nm were more frequent in CSC-MDA-MB-231. In blood plasma, the particle size was 150-250 nm in TNBC patients and 150-300 nm in healthy individuals. Particle concentrations were 1.3 × 1010 in CSCs of the MDA-MB-231 (CSC-MDA-MB-231) cell line and 3.8 × 107 in the MDA-MB-231 cell line (L-MDA-MB-231). The concentration of CSCs in MDA-MB-436 was 2.7 × 108 compared to 9.4 × 107 in L-MDA-MB-436. Midkine and CA9 were present in the EVs of both CSC lines and in the plasma of women with TNBC but absent in the blood plasma of healthy women. Midkine showed better statistical discrimination. CONCLUSIONS:The size and concentration of EVs are heterogeneous. Midkine and CA9 are produced by CSCs in women with TNBC and may be possible biomarkers of these cells in this tumour type.
Abnormal healing of corneal injury can lead to corneal opacity, a leading cause of blindness. This process is extremely complex and involves precise interactions of multiple signaling pathways. A lack of understanding of these complex interactions provides a major challenge in developing therapeutic strategies. Both sphingosine-1-phosphate (S1P) and transforming growth factor beta (TGFβ) signaling have been associated with tissue fibrosis. The purpose of this study was to understand the interplay between S1P and TGFβ signaling in the process of corneal wound healing and fibrosis. Mice lacking the Sphingosine kinase 1 gene (Sphk1-/-) and their wildtype littermates were subjected to corneal injury by alkali burn. The progress of wound healing and the expression and activation of TGFβ signaling intermediates and profibrotic proteins were measured at different days postinjury (DPI). We observed that reduction of S1P signaling in Sphk1-/- mice induced the closure of corneal epithelial layer at a faster rate than its wildtype littermates following alkali burn. Reduced activation of profibrotic proteins Smad2 and 3, along with reduced expression of Smad4 and higher expression of antifibrotic protein Smad7, was also observed in the Sphk1-/- mice as compared to the wildtype littermates following corneal injury. Inhibition of S1P signaling by exogenous delivery of a small-molecule inhibitor of sphingosine kinase 1 (SphK1) could accelerate corneal wound healing in similarly injured wildtype (Sphk1+/+) mice. These results suggest that S1P signaling positively influences TGFβ signaling pathways that negatively affect corneal wound healing by delaying the process and inducing fibrotic development. Thus, inhibition of S1P signaling could be an effective therapeutic option to accelerate corneal wound healing and thereby prevent corneal fibrosis/scar formation.
