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Journal of Translational Medicine Feb 2024Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, but the early diagnosis rate is low. The RNA-binding ubiquitin ligase MEX3C promotes...
Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, but the early diagnosis rate is low. The RNA-binding ubiquitin ligase MEX3C promotes tumorigenesis in several cancers but its mechanism of action in LUAD is unclear. In this study, the biological activity of MEX3C was assessed in LUAD. MEX3C and RUNX3 mRNA levels in the tissues of LUAD patients were determined using reverse transcription‑quantitative PCR. The involvement of MEX3C in the growth and metastasis of LUAD cells was measured by EdU assay, CCK-8, colony formation, Transwell assay, TUNEL, and flow cytometry. Expression of apoptosis and epithelial-mesenchymal transition related proteins were determined using western blotting analysis. LUAD cells transfected with si-MEX3C were administered to mice subcutaneously to monitor tumor progression and metastasis. We found that MEX3C is strongly upregulated in LUAD tissue sections, and involved in proliferation and migration. A549 and H1299 cells had significantly higher levels of MEX3C expression compared to control HBE cells. Knockdown of MEX3C dramatically decreased cell proliferation, migration, and invasion, and accelerated apoptosis. Mechanistically, we demonstrate MEX3C induces ubiquitylation and degradation of tumor suppressor RUNX3. Moreover, RUNX3 transcriptionally represses Suv39H1, as revealed by RNA pull-down and chromatin immunoprecipitation assays. The in vivo mice model demonstrated that knockdown of MEX3C reduced LUAD growth and metastasis significantly. Collectively, we reveal a novel MEX3C-RUNX3-Suv39H1 signaling axis driving LUAD pathogenesis. Targeting MEX3C may represent a promising therapeutic strategy against LUAD.
Topics: Animals; Humans; Mice; Adenocarcinoma of Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Ligases; Lung Neoplasms; MicroRNAs; RNA; RNA-Binding Proteins; Ubiquitin; Ubiquitination
PubMed: 38424632
DOI: 10.1186/s12967-023-04700-8 -
Plant Signaling & Behavior Dec 2023Ammonia (NH), as an intermediate product of nitrogen metabolism, is recognized as a novel gasotransmitter (namely gaseous signaling molecule), its signaling role being...
Ammonia (NH), as an intermediate product of nitrogen metabolism, is recognized as a novel gasotransmitter (namely gaseous signaling molecule), its signaling role being revealed in plants. NH exists in two different chemical forms, namely the weak base (free molecule: NH) and the weak acid (ammonium: NH), which are generally in equilibrium with each other in plants. However, the effect of NH on seed germination, seedling growth, and thermotolerance acquirement in maize remains unclear. Here, maize seeds were imbibed in the different concentrations of NH·HO (NH donor), and then germinated and calculated seed germination rate at the various time points. Also, the 60-h-old seedlings were irrigated in the different concentrations of NH·HO, and then subjected to heat stress and counted survival rate. The data implied that the appropriate concentrations (6, 9, and 12 mM) of NH·HO accelerated seed germination as well as increased seedling height and root length compared with the control without NH treatment. Also, the suitable concentrations (2 and 4 mM) of NH·HO improved tissue vitality, relieved an increase in malondialdehyde content, and enhanced survival rate of maize seedlings under heat stress compared with the control. These results firstly suggest that NH could accelerate seed germination, seedling growth, and thermotolerance acquirement in maize.
Topics: Seedlings; Germination; Gasotransmitters; Zea mays; Ammonia; Thermotolerance; Seeds
PubMed: 36682345
DOI: 10.1080/15592324.2022.2163338 -
Experimental Cell Research Sep 2023Casein kinase 2 alpha 1 (CSNK2A1) is a known oncogene, but its role in the progression of colorectal cancer (CRC) remain undefined. Here, we investigated the effects of...
Casein kinase 2 alpha 1 (CSNK2A1) is a known oncogene, but its role in the progression of colorectal cancer (CRC) remain undefined. Here, we investigated the effects of CSNK2A1 during CRC development. In the current study, CSNK2A1 expression in the colorectal cancer cell lines (HCT116, SW480, HT29, SW620 and Lovo) vs. normal colorectal cell line (CCD841 CoN) were compared via RT-qPCR and western blotting. The role of CSNK2A1 on CRC growth and metastases were investigated through Transwell assay. Immunofluorescence analysis was used to investigate the expression of EMT-related proteins. The association between P300/H3K27ac and CSNK2A1 were analyzed using UCSC bioinformatics and Chromatin-immunoprecipitation (Ch-IP) assays. Results revealed that both the mRNA and protein levels of CSNK2A1 in HCT116, SW480, HT29, SW620 and Lovo cells were upregulated. Additionally, P300-mediated H3K27ac activation at the CSNK2A1 promoter was found to drive the increase in CSNK2A1 expression. Transwell assay showed that CSNK2A1 overexpression increased the migration and invasion of HCT116 and SW480 cells, which decreased following CSNK2A1 silencing. CSNK2A1 was also found to facilitate EMT in HCT116 cells, evidenced by the increases of N-cadherin, Snail and Vimentin expression, and loss of E-cadherin. Importantly, the levels of p-AKT-S473/AKT, p-AKT-T308/AKT, and p-mTOR/mTOR in cells overexpressing CSNK2A1 were high, but significantly decreased following CSNK2A silencing. The PI3K inhibitor BAY-806946 could reverse the increase in p-AKT-S473/AKT, p-AKT-T308/AKT, p-mTOR/mTOR induced by CSNK2A1 overexpression and suppress CRC cell migration and invasion. In conclusion, we report a positive feedback mechanism through which P300 enhances CSNK2A1 expression and accelerates CRC progression through the activation of the PI3K-AKT-mTOR axis.
Topics: Humans; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 37391010
DOI: 10.1016/j.yexcr.2023.113694 -
Biomedicine & Pharmacotherapy =... May 2024Androgenetic alopecia (AGA) is a prevalent disease in worldwide, local application or oral are often used to treat AGA, however, effective treatments for AGA are...
Androgenetic alopecia (AGA) is a prevalent disease in worldwide, local application or oral are often used to treat AGA, however, effective treatments for AGA are currently limited. In this work, we observed the promoting the initial anagen phase effect of pilose antler extract (PAE) on hair regeneration in AGA mice. We found that PAE accelerated hair growth and increased the degree of skin blackness by non-invasive in vivo methods including camera, optical coherence tomography and dermoscopy. Meanwhile, HE staining of sagittal and coronal skin sections revealed that PAE augmented the quantity and length of hair follicles, while also enhancing skin thickness and hair papilla diameter. Furthermore, PAE facilitated the shift of the growth cycle from the telogen to the anagen phase and expedited the proliferation of hair follicle stem cells and matrix cells in mice with AGA. This acceleration enabled the hair follicles to enter the growth phase at an earlier stage. PAE upregulated the expression of the sonic hedgehog (SHH), smoothened receptor, glioma-associated hemolog1 (GLI1), and downregulated the expression of bone morphogenetic protein 4 (BMP4), recombinant mothers against decapentaplegic homolog (Smad) 1 and 5 phosphorylation. This evidence suggests that PAE fosters hair growth and facilitates the transition of the growth cycle from the telogen to the anagen phase in AGA mice. This effect is achieved by enhancing the proliferation of follicle stem cells and matrix cells through the activation of the SHH/GLI pathway and suppression of the BMP/Smad pathway.
Topics: Animals; Antlers; Alopecia; Hair Follicle; Mice; Male; Bone Morphogenetic Protein 4; Hair; Hedgehog Proteins; Zinc Finger Protein GLI1; Cell Proliferation; Signal Transduction; Tissue Extracts; Mice, Inbred C57BL; Disease Models, Animal; Regeneration; Deer; Smad5 Protein
PubMed: 38565060
DOI: 10.1016/j.biopha.2024.116503 -
Clinical Cancer Research : An Official... Jan 2024On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of...
On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients 2 years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiologic response rate at week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiologic response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% [95% confidence interval (CI), 14-44] had a radiologic response at week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Furthermore, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis, and hyperglycemia.
Topics: Adult; Humans; Child; Thiazoles; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases
PubMed: 37624421
DOI: 10.1158/1078-0432.CCR-23-1270 -
BMC Cancer Jan 2024CircRNAs participate in the development of hepatocellular carcinoma (HCC). This work aims to explore the key tumor promoting circRNA as a gene therapy target.
BACKGROUND
CircRNAs participate in the development of hepatocellular carcinoma (HCC). This work aims to explore the key tumor promoting circRNA as a gene therapy target.
METHODS
The differentially expressed gene circRNAs in HCC tumor tissues was identified by mining GSE121714 dataset. EdU staining, wound healing, transwell invasion assay, TUNEL staining and western blotting examined proliferation, migration, invasion, apoptosis and epithelial mesenchymal transition (EMT). Xenograft mouse model and orthotopic transplantation tumor mouse model were constructed to verify the role of hsa_circ_001726 in growth and metastasis of HCC. The relationship among CCT2, E2F6, hsa_circ_001726, miR-671-5p and PRMT9 was identified by RNA-fluorescence in situ hybridization, luciferase reporter assay and RNA Immunoprecipitation.
RESULTS
Eleven differentially expressed circRNAs were found in HCC tumors. Among them, hsa_circ_001726 was highly expressed in HCC tumors and cells, which was transcribed from CCT2. As a transcription factor of CCT2, E2F6 knockdown inactivated CCT2 promoter and reduced hsa_circ_001726 expression. Moreover, hsa_circ_001726 elevated PRMT9 expression by sponging miR-671-5p, and then activated Notch signaling pathway. Additionally, hsa_circ_001726 deficiency repressed malignant phenotypes of HCC cells, including proliferation, migration, invasion, EMT and apoptosis. In vivo, hsa_circ_001726 deficiency reduced tumor growth and lung metastasis of HCC in xenograft mouse models and orthotopic transplantation tumor mouse models.
CONCLUSION
Hsa_circ_001726 functioned as an oncogene in HCC, which was derived from CCT2 and regulated by E2F6. Hsa_circ_001726 elevated PRMT9 expression by sponging miR-671-5p, and then activated Notch signaling pathway, thereby accelerating malignant phenotypes of HCC. Therefore, targeting hsa_circ_001726 may be a new avenue for HCC treatment.
Topics: Animals; Humans; Mice; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; E2F6 Transcription Factor; Gene Expression Regulation, Neoplastic; In Situ Hybridization, Fluorescence; Liver Neoplasms; MicroRNAs; RNA, Circular
PubMed: 38166853
DOI: 10.1186/s12885-023-11703-7 -
Glia Apr 2024Schwann cells (SCs), the primary glial cells of the peripheral nervous system, which have been identified in many solid tumors, play an important role in cancer...
Schwann cells (SCs), the primary glial cells of the peripheral nervous system, which have been identified in many solid tumors, play an important role in cancer development and progression by shaping the tumor immunoenvironment and supporting the development of metastases. Using different cellular, molecular, and genetic approaches with integrated bioinformatics analysis and functional assays, we revealed the role of human SC-derived exosomal miRNAs in lung cancer progression in vitro and in vivo. We found that exosomal miRNA-21 from SCs up-regulated the proliferation, motility, and invasiveness of human lung cancer cells in vitro, which requires functional Rab small GTPases Rab27A and Rab27B in SCs for exosome release. We also revealed that SC exosomal miRNA-21-5p regulated the functional activation of tumor cells by targeting metalloprotease inhibitor RECK in tumor cells. Integrated bioinformatic analyses showed that hsa-miRNA-21-5p is associated with poor prognosis in patients with lung adenocarcinoma and can promote lung cancer progression through multiple signaling pathways including the MAPK, PI3K/Akt, and TNF signaling. Furthermore, in mouse xenograft models, SC exosomes and SC exosomal hsa-miRNA-21-5p augmented human lung cancer cell growth and lymph node metastasis in vivo. Together our data revealed, for the first time, that SC-secreted exosomes and exosomal miRNA-21-5p promoted the proliferation, motility, and spreading of human lung cancer cells in vitro and in vivo. Thus, exosomal miRNA-21 may play an oncogenic role in SC-accelerated progression of lung cancer and this pathway may serve as a new therapeutic target for further evaluation.
Topics: Humans; Mice; Animals; Lung Neoplasms; Exosomes; Phosphatidylinositol 3-Kinases; MicroRNAs; Schwann Cells; Disease Models, Animal; Cell Proliferation; GPI-Linked Proteins
PubMed: 38192185
DOI: 10.1002/glia.24497 -
Journal of Orthopaedic Surgery and... Jul 2023Osteoporosis remains a significant clinical challenge worldwide. Recent studies have shown that exosomes stimulate bone regeneration. Thus, it is worthwhile to explore...
BACKGROUND
Osteoporosis remains a significant clinical challenge worldwide. Recent studies have shown that exosomes stimulate bone regeneration. Thus, it is worthwhile to explore whether exosomes could be a useful therapeutic strategy for osteoporosis. The purpose of this study was to investigate the effects of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) on osteoblast proliferation and differentiation.
METHODS
Exosomes were isolated from hucMSCs. Bioinformatics analysis was performed to identify the differentially expressed lncRNAs in myeloma-derived mesenchymal stem cells. Plasmids encoding LINC00520 or short hairpin RNA of LINC00520 were transfected into hucMSCs and then exosomes were isolated. After human osteoblasts hFOB1.19 were exposed to the obtained exosomes, cell survival, cell cycle, apoptosis and calcium deposits of hFOB1.19 cell were detected by MTT, 7-aminoactinomycin D, Annexin V-FITC/propidium iodide and Alizarin red staining, respectively.
RESULTS
In hFOB1.19 cells, 10 × 10/mL hucMSC-derived exosomes inhibited cell proliferation, arrested cell cycle, and promoted apoptosis, while hucMSCs or 1 × 10/mL exosomes promoted cell proliferation, accelerated cell cycle, and promoted calcium deposits and the expression of OCN, RUNX2, collagen I and ALP. In hFOB1.19 cells, exosomes from hucMSCs with LINC00520 knockdown reduced the survival and calcium deposits, arrested the cell cycle, and enhanced the apoptosis, while exosomes from hucMSCs overexpressing LINC00520 enhance the proliferation and calcium deposits and accelerated the cell cycle.
CONCLUSIONS
LINC00520 functions as a modulator of calcium deposits, and exosomes derived from hucMSCs overexpressing LINC00520 might be a novel therapeutic approach for osteoporosis.
Topics: Humans; Calcium; Exosomes; Cell Cycle; Cell Differentiation; Cell Proliferation
PubMed: 37516879
DOI: 10.1186/s13018-023-04021-y -
Acta Paediatrica (Oslo, Norway : 1992) Aug 2023To assess whether small-for-gestational-age (SGA) - an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors. (Observational Study)
Observational Study
AIM
To assess whether small-for-gestational-age (SGA) - an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors.
METHODS
This was a nested matched (1:2) prospective observational study of 65 SGA (birth weight < 10th percentile) and 130 optimal-for-gestational-age (OGA, birth weight 25th-75th percentiles, control) infants in the 3D birth cohort with subjects recruited in Canada from 1 May 2010 to 31 August 2012. The outcomes included homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β), circulating leptin and adiponectin concentrations at age 2 years.
RESULTS
HOMA-IR, HOMA-β, leptin and adiponectin concentrations were similar in SGA versus OGA infants. Female sex and accelerated growth in length during mid-infancy (3-12 months) were associated with higher HOMA-IR. Caucasian ethnicity and decelerated growth in weight during late infancy (12-24 months) were associated with lower HOMA-IR. Current BMI was positively associated with circulating adiponectin in SGA infants only (+13.4% [4.0%-23.7%] per BMI z score increment).
CONCLUSION
Insulin resistance and secretion, circulating leptin and adiponectin levels were normal in SGA subjects in infancy at age 2 years. The novel observation in SGA-specific positive association between current BMI and circulating adiponectin suggests dysfunctional adiposity-adiponectin negative feedback loop development during infancy in SGA subjects.
Topics: Humans; Infant; Female; Child, Preschool; Insulin Resistance; Adiponectin; Leptin; Insulin; Birth Weight; Fetal Growth Retardation
PubMed: 37151183
DOI: 10.1111/apa.16816 -
Bioengineering (Basel, Switzerland) Oct 2023Macrophages play a pivotal role in the process of healing burns. One of the major risks in the course of burn healing, in the absence of regenerating epidermis, is... (Review)
Review
Macrophages play a pivotal role in the process of healing burns. One of the major risks in the course of burn healing, in the absence of regenerating epidermis, is infections, which greatly contribute to morbidity and mortality in such patients. Therefore, it is widely agreed that accelerating the recruitment of macrophages into burns may contribute to faster regeneration of the epidermis, thus decreasing the risk of infections. This review describes a unique method for the rapid recruitment of macrophages into burns and the activation of these macrophages to mediate accelerated regrowth of the epidermis and healing of burns. The method is based on the application of bio-degradable "α-gal" nanoparticles to burns. These nanoparticles present multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R), which bind the abundant natural anti-Gal antibody that constitutes ~1% of immunoglobulins in humans. Anti-Gal/α-gal nanoparticle interaction activates the complement system, resulting in localized production of the complement cleavage peptides C5a and C3a, which are highly effective chemotactic factors for monocyte-derived macrophages. The macrophages recruited into the α-gal nanoparticle-treated burns are activated following interaction between the Fc portion of anti-Gal coating the nanoparticles and the multiple Fc receptors on macrophage cell membranes. The activated macrophages secrete a variety of cytokines/growth factors that accelerate the regrowth of the epidermis and regeneration of the injured skin, thereby cutting the healing time by half. Studies on the healing of thermal injuries in the skin of anti-Gal-producing mice demonstrated a much faster recruitment of macrophages into burns treated with α-gal nanoparticles than in control burns treated with saline and healing of the burns within 6 days, whereas healing of control burns took ~12 days. α-Gal nanoparticles are non-toxic and do not cause chronic granulomas. These findings suggest that α-gal nanoparticles treatment may harness anti-Gal for inducing similar accelerated burn healing effects also in humans.
PubMed: 37892895
DOI: 10.3390/bioengineering10101165