Journal of Cellular and Molecular Medicine最新文献

Recombinant adeno-associated virus (rAAV) is an extremely attractive vector in the in vivo delivery of gene therapy as it is safe and its genome is simple. However, challenges including low permissiveness to specific cells and restricted tissue specificity have hindered its clinical application. Based on the previous studies, epidermal growth factor receptor-protein tyrosine kinase (EGFR-PTK) negatively regulated rAAV transduction, and EGFR-positive cells were hardly permissive to rAAV transduction. We constructed a novel rAAV-miRNA133b vector, which co-expressed miRNA133b and transgene, and investigated its in vivo and in vitro transduction efficiency. Confocal microscopy, live-cell imaging, pharmacological reagents and labelled virion tracking were used to analyse the effect of miRNA133b on rAAV2 transduction and the underlying mechanisms. The results demonstrated that miRNA133b could promote rAAV2 transduction and the effects were limited to EGFR-positive cells. The increased transduction was found to be a direct result of decreased rAAV particles degradation in the cytoplasm and enhanced second-strand synthesis. ss-rAAV2-miRNA133b vector specifically increased rAAV2 transduction in EGFR-positive cells or tissues, while ss-rAAV2-Fluc-miRNA133b exerted an antitumor effect. rAAV-miRNA133b vector might emerge as a promising platform for delivering various transgene to treat EGFR-positive cell-related diseases, such as non-small-cell lung cancer.

In this article by Xi Xiang et al.,¹ there were errors in the images of Figure 4A and Figure 5.

The authors confirmed that all results and conclusions of this article remain unchanged.

We apologise for these errors.

The tumour microenvironment (TME) and immunosuppression play an important role in colon cancer (CC) metastasis, which seriously affects the prognosis of CC. G protein subunit gamma 4 (GNG4) has been shown to participate in tumour progression and the tumour mutation burden (TMB) in colorectal cancer. However, the effect of GNG4 on the CC TME and immunology remains elusive. Weighted gene coexpression network analysis (WGCNA) was employed for screening aberrantly expressed genes associated with the immune score, and GNG4 was then selected through prognostic and immune correlation analysis. Based on RNA sequencing data obtained from the TCGA and GEO databases, the expression pattern and immune characteristics of GNG4 were comprehensively examined using a pan-cancer analysis. Upregulation of GNG4 was linked to an adverse prognosis and immune inhibitory phenotype in CC. Pan-cancer analysis demonstrated higher GNG4 expression in tumours than in paired normal tissue in human cancers. GNG4 expression was closely related to prognosis, TMB, immune checkpoints (ICPs), microsatellite instability (MSI) and neoantigens. GNG4 promoted CC cell proliferation, migration and invasion and participated in immune regulation in the TME. Significantly, GNG4 expression was found to negatively correlate with tumour-infiltrating immune cells, ICP, TMB and MSI in CC. GNG4 expression predicted the immunotherapy response in the IMvigor210 cohort, suggesting that GNG4 could be used as a potential biomarker in CC for prognostication and immunology. Moreover, the expression of GNG4 predicted the immunotherapy response of ICB in CC.

Proteasome 26S subunit ATPase 4 (PSMC4) could regulate cancer progression. However, the function of PSMC4 in prostate carcinoma (PCa) progression requires further clarification. In the study, PSMC4 and chromobox 3 (CBX3) levels were verified by TCGA data and tissue microarrays. Cell counting kit-8, cell apoptosis, cell cycle, wound healing, transwell and xenograft tumour model assays were performed to verify biological functions of PSMC4 in PCa. RNA-seq, PCR, western blotting and co-IP assays were performed to verify the mechanism of PSMC4. Results showed that PSMC4 level was significantly increased in PCa tissues, and patients with PCa with a high PSMC4 level exhibited shorter overall survival. PSMC4 knockdown markedly inhibited cell proliferation, cell cycle and migration in vitro and in vivo, and significantly promoted cell apoptosis. Then further study revealed that CBX3 was a downstream target of PSMC4. PSMC4 knockdown markedly reduced CBX3 level, and inhibited PI3K-AKT-mTOR signalling. CBX3 overexpression markedly promoted epidermal growth factor receptor (EGFR) level. Finally, PSMC4 overexpression showed reverse effect in DU145 cells, and the effects of PSMC4 overexpression on cell proliferation, migration and clonal formation were rescued by the CBX3 knockdown, and regulated EGFR-PI3K-AKT-mTOR signalling. In conclusion, PSMC4 could regulate the PCa progression by mediating the CBX3-EGFR-PI3K-AKT-mTOR pathway. These findings provided a new target for PCa treatment.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin-based chemotherapy. As a plasma membrane adhesion molecule, amphoterin-induced gene and ORF-2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin-induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin-induced activation of (caspase-8 and caspase-9)/caspase-3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME-mediated pyroptosis.

Statistics provided by GLOBOCAN list gastric cancer as the sixth most common, with a mortality ranking of third highest for the year 2020. In China, a herb called Rabdosia rubescens (Hemsl.) H.Hara, has been used by local residents for the treatment of digestive tract cancer for hundreds of years. Oridonin, the main ingredient of the herb, has a curative effect for gastric cancer, but the mechanism has not been previously clarified. This study mainly aimed to investigate the role of TNF-alpha/Androgen receptor/TGF-beta signalling pathway axis in mediating the proliferation inhibition of oridonin on gastric cancer SGC-7901 cells. MTT assay, cell morphology observation assay and fluorescence assay were adopted to study the efficacy of oridonin on cell proliferation. The network pharmacology was used to predict the pathway axis regulated by oridonin. Western blot assay was adopted to verify the TNF-α/Androgen receptor/TGF-β signalling pathway axis regulation on gastric cancer by oridonin. The results showed Oridonin could inhibit the proliferation of gastric cancer cells, change cell morphology and cause cell nuclear fragmentation. A total of 11signaling pathways were annotated by the network pharmacology, among them, Tumour necrosis factor alpha (TNF-α) signalling pathway, androgen receptor (AR) signalling pathway and transforming growth factor (TGF-β) signalling pathway account for the largest proportion. Oridonin can regulate the protein expression of the three signalling pathways, which is consistent with the results predicted by network pharmacology. These findings indicated that oridonin can inhibit the proliferation of gastric cancer SGC-7901 cells by regulating the TNF-α /AR /TGF-β signalling pathway axis.

Schistosomiasis is a tropical parasitic disease that damages the liver and poses a serious threat to human health. Macrophages play a key role in the development of liver granulomas and fibrosis by undergoing polarization from M1 to M2 type during schistosomiasis. Therefore, regulating macrophage polarization is important for controlling pathological changes that occur during this disease. Triggering receptor expressed on myeloid cells 2 (TREM2) expressed on the surface of macrophages, dendritic cells and other immune cells has been shown to play a role in inhibiting inflammatory responses and regulating M2 macrophage polarization, however its role in macrophage polarization in schistosomiasis has not been investigated. In this study, we confirmed that TREM2 expression was upregulated in the livers and peritoneal macrophages of mice infected with Schistosoma japonicum. Moreover, the TREM2 expression trend correlated with the expression of M2 macrophage polarization-related molecules in the liver tissues of S. japonicum-infected mice. Using Trem2^−/− mice, we also showed that Trem2 deletion inhibited Arg1 and Ym1 expression in liver tissues. Trem2 deletion also increased the number of F4/80 + CD86+ cells in peritoneal macrophages of infected mice. In summary, our study suggests that TREM2 may be involved in M2 macrophage polarization during schistosomiasis.

Around the world, tuberculosis (TB) remains one of the most common causes of morbidity and mortality. The molecular mechanism of Mycobacterium tuberculosis (Mtb) infection is still unclear. Extracellular vesicles (EVs) play a key role in the onset and progression of many disease states and can serve as effective biomarkers or therapeutic targets for the identification and treatment of TB patients. We analysed the expression profile to better clarify the EVs characteristics of TB and explored potential diagnostic markers to distinguish TB from healthy control (HC). Twenty EVs-related differentially expressed genes (DEGs) were identified, and 17 EVs-related DEGs were up-regulated and three DEGs were down-regulated in TB samples, which were related to immune cells. Using machine learning, a nine EVs-related gene signature was identified and two EVs-related subclusters were defined. The single-cell RNA sequence (scRNA-seq) analysis further confirmed that these hub genes might play important roles in TB pathogenesis. The nine EVs-related hub genes had excellent diagnostic values and accurately estimated TB progression. TB's high-risk group had significantly enriched immune-related pathways, and there were substantial variations in immunity across different groups. Furthermore, five potential drugs were predicted for TB using CMap database. Based on the EVs-related gene signature, the TB risk model was established through a comprehensive analysis of different EV patterns, which can accurately predict TB. These genes could be used as novel biomarkers to distinguish TB from HC. These findings lay the foundation for further research and design of new therapeutic interventions aimed at treating this deadly infectious disease.

Down syndrome is the most common chromosomal abnormality in humans. Patients with Down syndrome have hematologic disorders, including mild to moderate thrombocytopenia. In case of Down syndrome, thrombocytopenia is not associated with bleeding, and it remains poorly characterized regarding molecular mechanisms. We investigated the effects of overexpression of Dyrk1A, an important factor contributing to some major Down syndrome phenotypes, on platelet number and bleeding in mice. Mice overexpressing Dyrk1A have a decrease in platelet number by 20%. However, bleeding time was found to be reduced by 50%. The thrombocytopenia and the decreased bleeding time observed were not associated to an abnormal platelet receptors expression, to a defect of platelet activation by ADP, thrombin or convulxin, to the presence of activated platelets in the circulation or to an abnormal half-life of the platelets. To propose molecular mechanisms explaining this discrepancy, we performed a network analysis of Dyrk1A interactome and demonstrated that Dyrk1A, fibronectin and fibrinogen interact indirectly through two distinct clusters of proteins. Moreover, in mice overexpressing Dyrk1A, increased plasma fibronectin and fibrinogen levels were found, linked to an increase of the hepatic fibrinogen production. Our results indicate that overexpression of Dyrk1A in mice induces decreased bleeding consistent with increased plasma fibronectin and fibrinogen levels, revealing a new role of Dyrk1A depending on its indirect interaction with these two proteins.

Environmental oestrogens (EEs) as environmental pollutants have been paid much attention due to their impact on congenital malformation of male genitourinary system. Exposure to EEs for prolonged time could hinder testicular descent and cause testicular dysgenesis syndrome. Therefore, it is urgent to understand the mechanisms by which EEs exposure disrupt testicular descent. In this review, we summarize recent advances in our understanding of the process of testicular descent, which is regulated by intricate cellular and molecular networks. Increasing numbers of the components of these networks such as CSL and INSL3 are being identified, highlighting that testicular descent is a highly orchestrated process that is essential to human reproduction and survival. The exposure to EEs would lead to the imbalanced regulation of the networks and cause testicular dysgenesis syndrome such as cryptorchidism, hypospadias, hypogonadism, poor semen quality and testicular cancer. Fortunately, the identification of the components of these networks provides us the opportunity to prevent and treat EEs induced male reproductive dysfunction. The pathways that play an important role in the regulation of testicular descent are promising targets for the treatment of testicular dysgenesis syndrome.