Acetylcytidine modification of DDX41 and ZNF746 by N-acetyltransferase 10 contributes to chemoresistance of melanoma.

Background: Rapidly developed chemoresistance to dacarbazine (DTIC) is a major obstacle in the clinical management of melanoma; however, the roles and mechanisms of epi-transcriptomic RNA modification in this process have not been investigated. Method: DTIC-resistant (DR) melanoma cells were established for bulk RNA sequencing. The expressions of mRNAs were detected using qRT-PCR, and protein levels were determined using Western blotting and immunohistochemistry. Acetylated RNAs were detected by dot blotting and immunoprecipitation sequencing (acRIP-seq). A lung metastasis mouse model of melanoma was established to evaluate the anti-melanoma effects in vivo. Results: We identified that the expression of N-acetyltransferase 10 (NAT10), a catalytic enzyme for the N 4-acetylcytidine (ac4C) modification of RNA, was significantly upregulated in the DR cells. Clinically, NAT10 expression was elevated in disease progression samples and predicted a poor outcome. Using ac4C RNA immunoprecipitation (ac4C-RIP), we found that the mRNAs of two C2H2 zinc finger transcriptional factors, DDX41 and ZNF746, were targets of NAT10-mediated ac4C modification. Gain- and loss-of-function experiments in NAT10, or in DDX41 and ZNF746, altered the chemosensitivity of melanoma accordingly, and the two target genes also negatively correlated with clinical outcomes. Finally, pharmacological inhibition of NAT10 with Remodelin sensitized melanoma cells to DTIC treatment in vitro and in a mouse xenograft model. Conclusion: Our study elucidates the previously unrecognized role of NAT10-mediated ac4C modification in the chemoresistance of melanoma and provides a rationale for developing new strategies to overcome chemoresistance in melanoma patients.

Eczema as a protective factor for brain cancer: a meta-analysis.

BACKGROUND: Brain cancer is one of the most aggressive cancer types owing to poor treatment effects. Epidemiological studies have demonstrated that allergies may increase the disease risk. Therefore, this study evaluated the association between eczema and the risk of various brain cancers. METHODS: We systematically searched the PubMed and Embase databases from their inception until June 23, 2022. Two reviewers independently reviewed and screened the articles, extracted data, assessed the study quality, and pooled the results. Stata software was used to generate pooled odds ratios and 95% confidence intervals (CIs). RESULTS: We included 20 studies comprising 5,117,222 patients that investigated the relationship between eczema and brain cancer. Eczema was significantly inversely associated with the risk of brain cancer (odds ratio [OR], 0.82; 95% CI, 0.77-0.87), glioma (OR, 0.53; 95% CI, 0.14-2.02), meningioma (OR, 0.74; 95% CI, 0.66-0.84), and acoustic neuroma (OR, 0.60; 95% CI, 0.41-0.88). Interesting, The strong correlation between eczema and the reduced risk of brain cancer was observed in people over 16 years old (OR, 0.79; 95% CI, 0.71-0.88), but not in those under 16 years old (OR, 0.94; 95% CI, 0.79-1.11). In addition, subgroup analyses found that eczema significantly decreased the glioma risk in Europeans (OR, 0.73; 95% CI, 0.65-0.82) but not Australians (OR, 0.53; 95% CI, 0.14-2.02) or Americans (OR, 1.01; 95% CI, 0.69-1.46). CONCLUSION: Eczema may be considered as a potential protective factor of brain cancer in population aged over 16 years. However, this relationship requires verification using large-scale clinical data.

Potential Correlation Between Eczema and Hematological Malignancies Risk: A Systematic Review and Meta-Analysis.

Background: Eczema characterized by itch, sleeplessness, and adverse effects on quality of life is associated with a risk of hematological malignancies. However, there is a controversy pertaining to whether this association implies a greater or lesser risk of hematological cancers. We aimed to explore the link between eczema and hematological malignancies risk. Methods: We systematically searched PubMed and Embase databases from their inception to February 17, 2022. Two reviewers independently screened articles, extracted data and assessed study quality, respectively. The odds ratios and 95% confidence intervals (CIs) were pooled by using fixed or random-effects models. Results: 29 studies involving 2,521,574 participants examined the contribution of eczema to hematological malignancies. We found that eczema significantly increased the risk of Hodgkin's lymphoma (1.44; 95% CI, 1.07-1.95), myeloma (1.15; 95% CI, 1.04-1.28), and significantly decreased the risk of lymphocytic leukemia (0.91; 95% CI, 0.84-0.99); however, it is not significantly associated with Non-Hodgkin's lymphoma, and myelocytic leukemia. Conclusion: Eczema has been shown to be associated with the risk of hematological cancer, this association still needs to be verified in large randomized controlled trials. Systematic Review Registration: https://inplasy.com/, INPLASY202260097.

CircSRSF4 Enhances Proliferation, Invasion, and Migration to Promote the Progression of Osteosarcoma via Rac1.

(1) Background: At present, cancer cell metastasis is the main cause of death in patients with malignant tumors, and up to 23% of osteosarcoma patients have died due to lung and lymph node metastasis. Therefore, finding new molecules involved in tumor development can provide new strategies for the diagnosis and treatment of osteosarcoma patients. Circular RNAs (circRNAs) are a type of RNA molecule that are connected head-to-tail to form a closed ring. There is increasing evidence that circRNAs are RNA molecules with many biological functions in various diseases. However, the role and mechanism of circRNAs in osteosarcoma have rarely been reported. (2) Methods: The expression of circSRSF4 in osteosarcoma tissues and cell lines was detected by quantitative real-time PCR (RT-qPCR), and the result of high-throughput sequencing was verified. In order to explore the effect of circSRSF4 on tumor proliferation, invasion, and migration, a dual-luciferase reporter assay, RNA binding protein immunoprecipitation assay, cell counting kit-8 (CCK-8), transwell assay, scratch wound healing assay, Western blot analysis, and other experiments were carried out in vitro. Rescue experiments and a xenograft model confirmed that circSRSF4 directly acted on miR-224 to regulate Rac1 expression. (3) Results: The expression of circSRSF4 was significantly higher in osteosarcoma tissues and cell lines. Down-regulating the expression of circSRSF4 in vitro significantly inhibited the proliferation, invasion, and migration of cells, and also reduced the expression of Rac1, while the overexpression of Rac1 and miR-224 inhibition could reverse these effects. The inhibition of circSRSF4 expression in vivo also attenuated tumor growth. A mechanistic study showed that circSRSF4 can be used as an miR-224 sponge to up-regulate the expression of Rac1, thereby promoting the development of osteosarcoma. (4) Conclusions: CircSRSF4 acting as a ceRNA promotes the malignant behavior of osteosarcoma through the circSRSF4/miR-224/Rac1 axis, which provides a new theoretical basis for the clinical prevention and treatment of osteosarcoma and the study of related markers and intervention targets.

Decreased miR-4512 Levels in Monocytes and Macrophages of Individuals With Systemic Lupus Erythematosus Contribute to Innate Immune Activation and Neutrsophil NETosis by Targeting TLR4 and CXCL2.

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease with complex etiology that is not yet entirely understood. We aimed to elucidate the mechanisms and therapeutic potential of microRNAs (miRNAs) in SLE in a Tibetan population. Methods: Peripheral blood mononuclear cells from SLE patients (n = 5) and healthy controls (n = 5) were used for miRNA-mRNA co-sequencing to detect miRNAs related to immune abnormalities associated with SLE. Luciferase reporter assay was used to identify potential targets of candidate miRNA. The target genes were verified in miRNA-agomir/antagomir transfection assays with multiple cells lines and by expression analysis. The effects of candidate miRNA on monocyte and macrophage activation were evaluated by multiple cytokine profiling. Neutrophil extracellular traps (NETs) formation was analyzed in vitro by cell stimulation with supernatants of monocytes and macrophages transfected with candidate miRNA. The rodent MRL/lpr lupus model was used to evaluate the therapeutic effect of CXCL2Ab on SLE and the regulation effect of immune disorders. Results: Integrated miRNA and mRNA expression profiling identified miRNA-4512 as a candidate miRNA involved in the regulation of neutrophil activation and chemokine-related pathways. MiR-4512 expression was significantly reduced in monocytes and macrophages from SLE patients. MiR-4512 suppressed the TLR4 pathway by targeting TLR4 and CXCL2. Decreased monocyte and macrophage miR-4512 levels led to the expression of multiple proinflammatory cytokines in vitro. Supernatants of miR-4512 antagomir-transfected monocytes and macrophages significantly promoted NETs formation (P < 0.05). Blocking of CXCL2 alleviated various pathogenic manifestations in MRL/lpr mice, including kidney damage and expression of immunological markers of SLE. Conclusions: We here demonstrated the role of miR-4512 in innate immunity regulation in SLE. The effect of miR-4512 involves the regulation of monocytes, macrophages, and NETs formation by direct targeting of TLR4 and CXCL2, indicating the miR-4512-TLR4-CXCL2 axis as a potential novel therapeutic target in SLE.

Effect of lncRNA XLOC_005950 knockout by CRISPR/Cas9 gene editing on energy metabolism and proliferation in osteosarcoma MG63 cells mediated by hsa-miR-542-3p.

Cancer cells use glucose via glycolysis to maintain tumor cell proliferation. However, the effect of long non-coding RNAs (lncRNAs) on glycolysis in osteosarcoma (OS) cells remains unclear. The present study aimed to investigate the involvement of the lncRNA XLOC_005950/hsa-microRNA (miR)-542-3p/phosphofructokinase, muscle (PFKM) axis in the regulation of glucose metabolism, cell proliferation and apoptosis in the progression of OS. lncRNA XLOC_005950, hsa-miR-542-3p and PFKM expression in OS tissues and cells was detected via reverse transcription-quantitative PCR analysis. CRISPR/Cas9 gene editing was used to knockout lncRNA XLOC_005950 expression in MG63 cells. Cell Counting Kit-8 assay, flow cytometry, PFKM activity, and glucose and lactic acid content determination were performed to assess the effects of lncRNA XLOC_005950 knockout and overexpression of hsa-miR-542-3p on the phenotypes of OS cells. The dual-luciferase reporter assay was performed to confirm the targeting associations between lncRNA XLOC_005950, hsa-miR-542-3p and PFKM. The results demonstrated that lncRNA XLOC_005950 expression was upregulated in OS tissues and cells. Functional experiments indicated that lncRNA XLOC_005950 knockout decreased PFKM activity, the intracellular glucose and lactic acid content, and cell proliferation, while increasing apoptosis of OS cells. Furthermore, lncRNA XLOC_005950 knockout upregulated hsa-miR-542-3p expression and downregulated PFKM expression. Overexpression of hsa-miR-542-3p suppressed PFKM expression. Furthermore, lncRNA XLOC_005950, as the molecular sponge of miR-542-3p in OS, modulated the downstream target gene, PFKM. Taken together, the results of the present study suggest that lncRNA XLOC_005950 knockout may inhibit the progression of OS via hsa-miR-542-3p-mediated regulation of PFKM expression.

Lymphatic vessel density as a prognostic indicator in Asian NSCLC patients: a meta-analysis.

BACKGROUND: To determine the association of lymphatic vessel density (LVD) with the prognosis of Asian non-small cell lung cancer (NSCLC) patients via a meta-analysis. METHODS: Eligible studies were selected by searching PubMed and EMBASE from inception to July 25, 2017. The reference lists of the retrieved articles were also consulted. The information was independently screened by two authors. When heterogeneity was significant, a random-effects model was used to determine overall pooled risk estimates. RESULTS: A total of 15 studies with 1075 patients were finally included in the meta-analysis. LVD was positively associated with the prognosis of NSCLC in the overall analysis (hazard ratio (HR) 1.14, 95% confidence interval (95% CI): 1.02-1.27, p = 0.000, I2 = 73.2%). Subgroup analyses were performed on 5 VEGFR-3 groups (p = 0.709, I2 = 0.0%), 3 LYVE-1 groups (p = 0.01, I2 = 86.4%), 5 D2-40 groups (p = 0.019, I2 = 66.2%), and 2 podoplanin groups (p = 0.094, I2 = 64.5%). Sensitivity analysis indicated robust results. There was no publication bias. CONCLUSIONS: LVD is an indicator of poor prognosis in Asian NSCLC patients.