Long non-coding RNA urothelial carcinoma-associated 1 (UCA1) functions as an oncogene in different human cancers, including melanoma. However, the molecular mechanism of UCA1 underlying melanoma progression still remains largely unknown. In the present study, reverse transcription quantitative polymerase chain reaction and western blot analyses were used to examine the mRNA and protein expression levels, respectively. Cell Counting Kit-8 and wound healing assays were conducted to study cell proliferation and migration, respectively. A luciferase reporter assay was used to confirm the targeting relationship. It was demonstrated that UCA1 expression was increased in melanoma tissues and cell lines. In addition, UCA1 expression was higher in melanoma tissues at stage III-IV than in tissues at stage I-II. Inhibition of UCA1 expression markedly reduced melanoma cell proliferation and migration. Further investigation revealed that UCA1 functioned in melanoma cells through directly binding with microRNA (miR)-28-5p. The expression of miR-28-5p was significantly reduced in melanoma tissues and had an inverse correlation with UCA1 expression. In addition, miR-28-5p expression was higher in melanoma tissues at advanced stages than in stage I-II tissues. Furthermore, homeobox (HOX)B3 was identified as a target gene of miR-28-5p in melanoma cells, and HOXB3 overexpression reversed the suppressive effects of UCA1 downregulation on melanoma cell proliferation and migration. Finally, HOXB3 was upregulated in melanoma tissues compared with its expression in adjacent tissues, and HOXB3 expression was increased in melanoma tissues at advanced stages. Taken together, the regulatory network of the UCA1/miR-28-5p/HOXB3 axis in melanoma was demonstrated for the first time in the present study, expanding the understanding of the molecular mechanism underlying melanoma progression. Future studies may further confirm the function of this signaling pathway in vivo.
Tumorigenic cancer stem cells (CSCs) exist in various tumors including the cutaneous squamous cell carcinoma (cSCC) as a minor subpopulation and are tightly associated with metastasis and therapeutic resistance. Better understanding of CSCs properties is essential for the novel therapeutic strategy targeted toward these cancers. The cSCC stem cells (cSCCSCs) were enriched from a cSCC cell line A431 by repeated sphere culture, and identified via the expression analysis of stemness marker genes and CD44 proteolysis. MiR-199a-5p was previously reported to be related with the proteolysis modulation of CD44, so the specific regulation mechanisms were verified by overexpression in vitro and in vivo. MiR-199a-5p is under-expressed in cSCCSCs and functions as a tumor suppressive molecule. Overexpression of miR-199a-5p reduced the stemness of cSCCSCs and inhibited cell proliferation. By targeting the deacetylase Sirt1, miR-199a-5p inhibited cellular proteolysis of CD44 and reduced the CD44 intracellular domain (CD44ICD) release and nuclear translocation. Overexpression of CD44ICD reversed the effects of miR-199a-5p overexpression or Sirt1 silencing, and increased the transcriptional expression of stemness genes. Our results revealed that the miR-199a-5p/Sirt1/CD44ICD signaling pathway regulates cSCCSCs progression by affecting its migration ability and tumorigenicity, therefore can be utilized to develop a curative approach for cSCC.
Cutaneous melanoma (CM) is an aggressive cancer; given that initial and specific signs are lacking, diagnosis is often late and the prognosis is poor. RNA modification has been widely studied in tumour progression. Nevertheless, little progress has been made in the signature of N1‐methyladenosine (m1A), 5‐methylcytosine (m5C), N6‐methyladenosine (m6A)‐related regulators and the tumour microenvironment (TME) cell infiltration in CM. Our study identified the characteristics of m1A‐, m5C‐ and m6A‐related regulators based on 468 CM samples from the public database. Using univariate, multivariate and LASSO Cox regression analysis, a risk model of regulators was established and validated by a nomogram on independent prognostic factors. The gene set variation analysis (GSVA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) clarified the involved functional pathways. A combined single‐sample gene set enrichment analysis (ssGSEA) and CIBERSORT approach revealed TME of regulator‐related prognostic signature. The nine‐gene signature stratified the patients into distinct risk subgroups for personalized prognostic assessment. Additionally, functional enrichment, immune infiltration and immunotherapy response analysis indicated that the high‐risk group was correlated with T‐cell suppression, while the low‐risk group was more sensitive to immunotherapy. The findings presented here contribute to our understanding of the TME molecular heterogeneity in CM. Nine m1A‐, m5C‐ and m6A‐related regulators may also be promising biomarkers for future research.
(1) Background: Many co-infections of Mycobacterium tuberculosis (MTB) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have emerged since the occurrence of the SARS-CoV-2 pandemic. This study aims to design an effective preventive multi-epitope vaccine against the co-infection of MTB and SARS-CoV-2. (2) Methods: The three selected proteins (spike protein, diacylglycerol acyltransferase, and low molecular weight T-cell antigen TB8.4) were predicted using bioinformatics, and 16 epitopes with the highest ranks (10 helper T lymphocyte epitopes, 2 CD8+ T lymphocytes epitopes, and 4 B-cell epitopes) were selected and assembled into the candidate vaccine referred to as S7D5L4. The toxicity, sensitization, stability, solubility, antigenicity, and immunogenicity of the S7D5L4 vaccine were evaluated using bioinformatics tools. Subsequently, toll-like receptor 4 docking simulation and discontinuous B-cell epitope prediction were performed. Immune simulation and codon optimization were carried out using immunoinformatics and molecular biology tools. (3) Results: The S7D5L4 vaccine showed good physical properties, such as solubility, stability, non-sensitization, and non-toxicity. This vaccine had excellent antigenicity and immunogenicity and could successfully simulate immune responses in silico. Furthermore, the normal mode analysis of the S7D5L4 vaccine and toll-like receptor 4 docking simulation demonstrated that the vaccine had docking potential and a stable reaction. (4) Conclusions: The S7D5L4 vaccine designed to fight against the co-infection of MTB and SARS-CoV-2 may be safe and effective. The protective efficacy of this promising vaccine should be further verified using in vitro and in vivo experiments.
Background: BRAF gene mutation causes melanoma patients to develop drug resistance after 8-9 months BRAF inhibitors treatment. Therefore, overcoming BRAF inhibitor resistance has important implications for improving patient survival. Sorafenib directly inhibits tumor cell proliferation by blocking the RAF/MEK/ERKmediated cell signaling pathway. It remains unknown that whether the combination of sorafenib with vemurafenib could sensitize melanoma cells to vemurafenib, and the underlying mechanism needs to be clarified.Methods: Vemurafenib resistant melanoma cells A375/Vem and SK-Mel-28/Vem were established by exposing to a series of concentration of vemurafenib. Cell viability was measured when A375 and SK-Mel-28 cells treated with vemurafenib or combined with sorafenib. Meanwhile the levels of Iron, GSH, MDA and reactive oxygen species (ROS) were detected. Finally we examined that whether sorafenib sensitizes melanoma cells to vemurafenib through ferroptosis.Results: We found that sorafenib sensitized melanoma cells to vemurafenib. Sorafenib treatment did not significantly alter the production of ROS and the content of iron, GSH and MDA in vemurafenib resistant cells, but cotreatment of sorafenib and vemurafenib dramatically upregulated ROS production, MDA and iron, but decreased GSH concentration. Interestingly, sorafenib strongly promoted vemurafenibinduced cell death, which was blocked by lipid peroxidation inhibitors ferrostatin-1 but not ZVAD-FMK or necrosulfonamid.Conclusions: Sorafenib sensitized melanoma cells to vemurafenib by increasing ROS production through ferroptosis. Our study reveals that the combination of sorafenib may provide a novel strategy of vemurafenib resistant melanoma therapy.
Introduction: Patients with primary aldosteronism (PA) have increased cardiovascular risk and studies have found that medical therapy fails to ameliorate this. This may be due to side effects and limited efficacy of medications at tolerable doses. Methods: We conducted a retrospective study on 201 patients with PA treated with medical therapy (spironolactone, eplerenone or amiloride) for PA from 2000–2020 at two tertiary centres. Patients were assessed for efficacy to achieve clinical and biochemical control, and for side effects. Results: 53.7% of patients achieved blood pressure <140/90mmHg, 44.6% achieved serum potassium ≥4.3mmol/L, and 63.2% achieved renin levels >1ng/ml/hr. Concordance between biochemical control as assessed by potassium and renin levels was 49%. 45.3% of patients experienced side effects, with 8.5% switching to another medication, 18.9% decreasing dose, and 10.0% stopping medications altogether. Risk factors for side effects were spironolactone use, dose ≥50mg, duration of treatment ≥1 year, male gender and unilateral PA. Patients with unilateral PA, compared to bilateral PA, used higher median doses of spironolactone, 75mg vs 50mg, P<0.001, but more had persistent hypokalemia, 20.5% versus 6.4%, P=0.007. 44 patients with unilateral PA underwent surgery after initial medical therapy, which further improved systolic and diastolic BP, from 142 to 134mmHg, P<0.001, and from 85 to 79mmHg, P<0.001, respectively. Conclusion: Dose-dependent side effects limit the efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. In patients with unilateral PA, surgery remains a better option compared to life-long medications.
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