Correction: Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts
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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.
Breast cancer: pathogenesis and treatments
Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.
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.
The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma
Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3′ untranslated region (3′UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC.
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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