Journal of Cellular and Molecular Medicine最新文献

Usher syndrome encompasses a group of genetically and clinically heterogeneous autosomal recessive disorders with hearing deficiencies and retinitis pigmentosa. The mechanisms underlying the Usher syndrome are highly variable. In the present study, a Chinese family with Usher syndrome was recruited. Whole exome sequencing (WES), Sanger sequencing, homozygosity mapping, short tandem repeat (STR) analysis and segregation analysis were performed. Functional domains of the pathogenic variant for USH2A were analysed. We identified a homozygous frameshift variant c.99_100insT (p.Arg34Serfs*41) in the USH2A gene in the proband that showed discordant segregation in the father. Further homozygosity mapping and STR analysis identified an unusual homozygous variant of proband that originated from maternal uniparental disomy (UPD). The p.Arg34Serfs*41 variant produced a predicted truncated protein that removes all functional domains of USH2A. The variant was not included in the 1000 Human Genomes Project database, ExAC database, HGMD or gnomAD database, but was included in the ClinVar databases as pathogenic. Although USH2A is an autosomal recessive disease, the effects of UPD should be informed in genetic counselling since the recurrence risk of an affected child is greatly reduced when the disease is due to the UPD mechanism. To test potential patients, WES, combined with STR analysis and homozygosity mapping, provides an accurate and useful strategy for genetic diagnosis. In summary, our discoveries can help further the understanding of the molecular pathogenesis of Usher syndrome type IIA to advance the prevention, diagnosis and therapy for this disorder.

Tumour-derived exosomes have been shown to induce pre-metastatic niche formation, favoring metastatic colonization of tumour cells, but the underlying molecular mechanism is still not fully understood. In this study, we showed that exosomes derived from the LLC cells could indeed significantly enhance their intrapulmonary colonization. Circulating LLC-derived exosomes were mainly engulfed by lung fibroblasts and led to the NF-κB signalling activation. Further studies indicated that the exosomal miR-3473b was responsible for that by hindering the NFKB inhibitor delta's (NFKBID) function. Blocking miR-3473b could reverse the exosome-mediated NF-κB activation of fibroblasts and decrease intrapulmonary colonization of lung tumour cells. Together, this study demonstrated that the miR-3473b in exosomes could mediate the interaction of lung tumour cells and local fibroblasts in metastatic sites and, therefore, enhance the metastasis of lung tumour cells.

The glycoprotein stanniocalcin-1 functions as a regulatory endocrine hormone that maintains the balance of calcium and phosphorus in bony fish and as a paracrine/autocrine factor involved in many physiological/pathological processes in humans, including carcinogenesis. In this review, we provide an overview of (a) the possible mechanisms through which STC1 affects the malignant properties of cancer, (b) transcriptional and post-transcriptional regulation pathways of STC1 and (c) the potential clinical relevance of STC1 as a cancer biomarker and even a therapeutic target in the future. Exploring the role of STC1 in cancer development may provide a better understanding of the tumorigenesis process in humans and may facilitate finding an effective therapeutic method against cancer.

To explore the relationship between autophagy and cell function, we investigated how PLAC8-mediated autophagy influences proliferation, apoptosis and epithelial-mesenchymal transition (EMT) in NPC. Colony formation analyses and CCK8 assays were used to assess the proliferative capacity of NPC cells. Transmission electron microscopy (TEM) was used to identify autophagosomes. Autophagic flux was monitored using the tandem monomeric RFP-GFP-tagged LC3 (tfLC3) assay. The rate of apoptosis in NPC cells was analysed by flow cytometry. Western blot analysis was used to evaluate the activation of autophagy and the signalling status of the AKT/mTOR pathway. Our study reveals that knocking out PLAC8 (koPLAC8) induces autophagy and apoptosis, while suppressing NPC cell proliferation and EMT. However, inhibition of autophagy with 3-methyladenine or by knocking down Beclin-1 reverses the cell proliferation, apoptosis and EMT influenced by koPLAC8. We find that koPLAC8 inhibits the phosphorylation of AKT and its downstream target, mTOR. Moreover, immunofluorescence and co-immunoprecipitation reveal complete PLAC8/AKT colocalization and PLAC8/AKT interaction, respectively. Furthermore, knockout of PLAC8 induced autophagy and inactivated AKT/mTOR signalling pathway of NPC xenografts. Overall, our findings demonstrate that koPLAC8 induces autophagy via the AKT/mTOR pathway, thereby inhibiting cell proliferation and EMT, and promoting apoptosis in NPC cells.

AMP-activated protein kinase (AMPK) serves as a "supermetabolic regulator" that helps maintain cellular energy homeostasis. However, the role of AMPK in glucose metabolism reprogramming in lung cancer remains unclear. Here, our study shows that low AMPK expression correlates with metastasis and clinicopathologic parameters of non-small-cell lung cancer. Low AMPK significantly enhances the Warburg effect in HBE and A549 cells, which in turn induces the expression of mesenchymal markers and enhances their invasion and migration. At the mechanistic level, low AMPK up-regulates HK2 expression and glycolysis levels through HDAC4 and HDAC5. Collectively, our findings demonstrate that low AMPK-induced metabolism can promote epithelial-mesenchymal transition progression in normal bronchial epithelial cells and lung cancer cells, and increase the risk for tumour metastasis.

Tumour microenvironment (TME) is crucial to tumorigenesis. This study aimed to uncover the differences in immune phenotypes of TME in endometrial cancer (EC) using Uterine Corpus Endometrial Carcinoma (UCEC) cohort and explore the prognostic significance. We employed GVSA enrichment analysis to cluster The Cancer Genome Atlas (TCGA) EC samples into immune signature cluster modelling, evaluated immune cell profiling in UCEC cohort (n = 538) and defined four immune subtypes of EC. Next, we analysed the correlation between immune subtypes and clinical data including patient prognosis. Furthermore, we analysed the expression of immunomodulators and DNA methylation modification. The profiles of immune infiltration in TCGA UCEC cohort showed significant difference among four immune subtypes of EC. Among each immune subtype, natural killer T cells (NKT), dendritic cells (DCs) and CD8⁺ T cells were significantly associated with EC patients survival. Each immune subtype exhibited specific molecular classification, immune cell characterization and immunomodulators expression. Moreover, the expression immunomodulators were significantly related to DNA methylation level. In conclusion, the identification of immune subtypes in EC tissues could reveal unique immune microenvironments in EC and predict the prognosis of EC patients.

Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF-dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6-week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP-induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa-B (NF-κB) phosphorylation; up-regulated interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) levels in LA and EAT; decreased peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL-6, TNF-α and TGF-β1 expression and decreased PPARγ/APN expression in 3T3-L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL-1 cells with LPS-stimulated 3T3-L1 conditioned medium (CM) significantly increased IL-6, TNF-α and TGF-β1 expression and decreased SERCA2a and p-PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca²⁺ handling dysfunction. MET attenuated the RAP-induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF-dependent EAT remodelling and AF vulnerability by MET.

Radiation-induced myocardial fibrosis (RIMF) is a potentially lethal clinical complication of chest radiotherapy (RT) and a final stage of radiation-induced heart disease (RIHD). RIMF is characterized by decreased ventricular elasticity and distensibility, which can result in decreased ejection fraction, heart failure and even sudden cardiac death. Together, these conditions impair the long-term health of post-RT survivors and limit the dose and intensity of RT required to effectively kill tumour cells. Although the exact mechanisms involving in RIMF are unclear, increasing evidence indicates that the occurrence of RIMF is related to various cells, regulatory molecules and cytokines. However, accurately diagnosing and identifying patients who may progress to RIMF has been challenging. Despite the urgent need for an effective treatment, there is currently no medical therapy for RIMF approved for routine clinical application. In this review, we investigated the underlying pathophysiology involved in the initiation and progression of RIMF before outlining potential preventative and therapeutic strategies to counter this toxicity.

Lung adenocarcinoma (LUAD), as the most common subtype of non-small cell lung cancer, is responsible for more than 500 000 deaths worldwide annually. In this study, we identify a novel microRNA-26b-5p (miR-26b-5p) and elucidated its function on LUAD. The survival rate of parent LUAD cells and radiation-resistant LUAD cells were determined using clonogenic survival assay. We overexpressed or inhibited miR-26b-5p in LUAD, and the correlation between activating transcription factor 2 (ATF2) and miR-26b-5p was determined using integrated bioinformatics analysis and dual-luciferase reporter gene assay. Exosomes derived from A549 cell lines were then detected using Western blot assay, followed by co-transfection with radiation-resistant A549R cells. LUAD tissues and serum were collected, followed by miR-26b-5p relative expression quantification using RT-qPCR. miR-26b-5p was identified as the most differentially expressed miRNA and was down-regulated in LUAD. Radiation-resistant cells were more resistant to X-radiation compared with parent cells. miR-26b-5p overexpression and X-irradiation led to enhanced radiosensitivity of LUAD cells. ATF2 was negatively targeted by miR-26b-5p. Exosomal miR-26b-5p derived from A549 cells could be transported to irradiation-resistant LUAD cells and inhibit ATF2 expression to promote DNA damage, apoptosis and radiosensitivity of LUAD cells, which was verified using serum-based miR-26b-5p. Our results show a regulatory network of miR-26b-5p on radiosensitivity of LUAD cells, which may serve as a non-invasive biomarker for LUAD.