Correction: Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl
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Long non-coding RNA-MIR181A1HG acts as an oncogene and contributes to invasion and metastasis in gastric cancer
Dysregulation of long non-coding RNAs (lncRNA) plays an essential role in cancer development and progression. However, their functions and mechanisms of action in gastric cancer (GC) remain largely unknown. Gene expression in GC was evaluated using quantitative real-time PCR, western blotting, immunofluorescence, immunohistochemistry, and RNA in situ hybridization. The impact of MIR181A1HG on GC cells was explored in vitro and in vivo using cell proliferation, migration, invasion assays and animal models. Biotinylated RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays were performed to evaluate the molecular interactions. LncRNA-MIR181A1HG was upregulated in GC and associated with malignant progression. MIR181A1HG physically interacts with ELAVL1 to regulate epithelial-mesenchymal transition (EMT) in GC cells. MIR181A1HG intron-derived miR-181a-5p/miR-181b-5p triggers MIR181A1HG transcription through binding to and destabilizing SOCS3 messenger RNA. Specifically, SOCS3 interacts with NFATC2 and downregulated SOCS3 enhances the NFATC2-mediated transcriptional activation of the MIR181A1HG promoter. Collectively, MIR181A1HG, activated by miR-181a-5p/miR-181b-5p-SOCS3-NFATC2 positive feedback loop, contributes to GC progression through stabilizing ELAVL1. MIR181A1HG expression correlates positively with ELAVL1, miR-181a-5p, miR-181b-5p, and NFATC2 and negatively with SOCS3 in fresh GC samples. These data demonstrate that MIR181A1HG plays an important role in tumor progression by promoting invasion, metastasis, and EMT, indicating its potential as a prognostic biomarker in GC.
Proteolysis of TAM receptors in autoimmune diseases and cancer: what does it say to us?
Proteolytic processing of Receptor Tyrosine Kinases (RTKs) leads to the release of ectodomains in the extracellular space. These soluble ectodomains often retain the ligand binding activity and dampen canonical pathways by acting as decoy receptors. On the other hand, shedding the ectodomains may initiate new molecular events and diversification of signalling. Members of the TAM (TYRO3, AXL, MER) family of RTKs undergo proteolytic cleavage, and their soluble forms are present in the extracellular space and biological fluids. TAM receptors are expressed in professional phagocytes, mediating apoptotic cell clearance, and suppressing innate immunity. Enhanced shedding of TAM ectodomains is documented in autoimmune and some inflammatory conditions. Also, soluble TAM receptors are present at high levels in the biological fluids of cancer patients and are associated with poor survival. We outline the biology of TAM receptors and discuss how their proteolytic processing impacts autoimmunity and tumorigenesis. In autoimmune diseases, proteolysis of TAM receptors likely reflects reduced canonical signalling in professional phagocytes. In cancer, TAM receptors are expressed in the immune cells of the tumour microenvironment, where they control pathways facilitating immune evasion. In tumour cells, ectodomain shedding activates non-canonical TAM pathways, leading to epithelial-mesenchymal transition, metastasis, and drug resistance.
Exosomal miR-17-5p derived from epithelial cells is involved in aberrant epithelium-fibroblast crosstalk and induces the development of oral submucosal fibrosis
Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development. The epithelium, which is the first line of defense against the external environment, can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment. However, the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear. In this study, we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes. MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts, where it promoted cell secretion, contraction, migration and fibrogenic marker (α-SMA and collagen type I) expression. The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-β pathway signaling. Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes. Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts. In conclusion, we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.
LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer
Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.
Engineered EVs from LncEEF1G – overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells
Fibrosis is a disease that negatively affects liver regeneration, resulting in severe complications after liver surgery. However, there is still no clinically effective treatment for promoting fibrotic liver regeneration because the underlying hepatocellular mechanism remains poorly understood. Through microRNA microarrays combined with the application of AAV6, we found that high expression of miR-181a-5p in activated hepatic stellate cells (HSCs) suppressed the expression of hepatic growth factor (HGF) and partially contributed to impaired regeneration potential in mice with hepatic fibrosis that had undergone two-thirds partial hepatectomy. As nanotherapeutics, mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) have been verified as effective treatments for liver regeneration. Here we observe that MSC-EVs can also promote fibrotic liver regeneration via enriched lncEEF1G, which acts as a competing endogenous RNA to directly sponge miR-181a-5p, leading to the upregulated expression of HGF in HSCs. Finally, engineered MSC-EVs with high expression of lncEEF1G (lncEEF1GOE-EVs) were constructed, suggesting greater potential for this model. In summary, our findings indicate that lncEEF1GOE-EVs have a nanotherapeutic effect on promoting regeneration of fibrotic livers by modulating the miR-181a-5p/HGF pathway in HSCs, which highlights the potential of extracellular vesicle engineering technology for patients with hepatic fibrosis who have undergone hepatic surgery.
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