Background: Current treatment options for glioma are limited, and the prognosis of patients with glioma is poor as the available drugs show low therapeutic efficacy. Furthermore, the molecular mechanisms associated with glioma remain poorly understood. METTL1 mainly catalyzes the formation of N(7)-methylguanine at position 46 of the transfer RNA sequence, thereby regulating the translation process. However, the role of METTL1 in glioma has not been studied to date. The purpose of this study was to analyze the expression and prognosis of METTL1 in glioma, and to explore the potential analysis mechanism. Methods: Data from five publicly available databases were used to analyze METTL1 expression across different tumor types and its differential expression between carcinoma and adjacent normal tissues. The expression of METTL1 in glioma was further validated using real-time polymerase chain reaction and immunohistochemistry. Meanwhile, siRNA was used to knockdown METTL1 in U87 glioma cells, and the resultant effect on glioma proliferation was verified using the Cell Counting Kit 8 (CCK8) assay. Furthermore, a nomogram was constructed to predict the association between METTL1 expression and the survival rate of patients with glioma. Results: METTL1 expression increased with increasing glioma grades and was significantly higher in glioma than in adjacent noncancerous tissues. In addition, high expression of METTL1 promoted cell proliferation. Moreover, METTL1 expression was associated with common clinical risk factors and was significantly associated with the prognosis and survival of patients with glioma. Univariate and multivariate Cox regression analyses revealed that METTL1 expression may be used as an independent prognostic risk factor for glioma. Furthermore, results of functional enrichment and pathway analyses indicate that the mechanism of METTL1 in glioma is potentially related to the MAPK signaling pathway. Conclusions: High METTL1 expression is significantly associated with poor prognosis of patients with glioma and may represent a valuable independent risk factor. In addition, high expression of METTL1 promotes glioma proliferation and may regulate mitogen-activated protein kinase (MAPK) signaling pathway. Thus, METTL1 may be a potential biomarker for glioma. Further investigations are warranted to explore its clinical use.

Background: Protein arginine methyltransferase 6 (PRMT6) plays a crucial role in various pathophysiological processes and diseases. Glioblastoma (GBM; WHO Grade 4 glioma) is the most common and lethal primary brain tumor in adults, with a prognosis that is extremely poor, despite being less common than other systemic malignancies. Our current research finds PRMT6 upregulated in GBM, enhancing tumor malignancy. Yet, the specifics of PRMT6’s regulatory processes and potential molecular mechanisms in GBM remain largely unexplored. Methods: PRMT6’s expression and prognostic significance in GBM were assessed using glioma public databases, immunohistochemistry (IHC), and immunoblotting. Scratch and Transwell assays examined GBM cell migration and invasion. Immunoblotting evaluated the expression of epithelial-mesenchymal transition (EMT) and Wnt-β-catenin pathway-related proteins. Dual-luciferase reporter assays and ChIP-qPCR assessed the regulatory relationship between PRMT6 and YTHDF2. An in situ tumor model in nude mice evaluated in vivo conditions. Results: Bioinformatics analysis indicates high expression of PRMT6 and YTHDF2 in GBM, correlating with poor prognosis. Functional experiments show PRMT6 and YTHDF2 promote GBM migration, invasion, and EMT. Mechanistic experiments reveal PRMT6 and CDK9 co-regulate YTHDF2 expression. YTHDF2 binds and promotes the degradation of negative regulators APC and GSK3β mRNA of the Wnt-β-catenin pathway, activating it and consequently enhancing GBM malignancy. Conclusions: Our results demonstrate the PRMT6-YTHDF2-Wnt-β-Catenin axis promotes GBM migration, invasion, and EMT in vitro and in vivo, potentially serving as a therapeutic target for GBM.

It is known that Müllerian ducts develop into the upper two-thirds of the vagina, uterus and Fallopian tubes ( Varner et al., 1985 x Varner et al., 1985 Varner, R.E., Younger, J.B., and Blackwell, R.E. Mullerian dysgenesis. J. Reprod. Med. 1985; 30: 443–450 PubMed | Google Scholar See all References Varner et al., 1985 ) and any alteration in the developmental sequence would lead to a wide spectrum of female reproductive tract abnormalities, called Müllerian duct abnormalities (MDA). The clinical presentation of MDA varies including congenital vagina and uterus defect (Mayer-Rokitansky–Küster–Hauser (MRKH) syndrome; Griffin et al., 1976 x Griffin et al., 1976 Griffin, J.E., Edwards, C., Madden, J.D., Harrod, M.J., and Wilson, J.D. Congenital absence of the vagina: The Mayer–Rokitansky–Kuster–Hauser syndrome. Ann. Intern. Med. 1976; 85: 224–236 Crossref | PubMed | Scopus (253) | Google Scholar See all References Griffin et al., 1976 ), uterine agenesis, unicornuate uterus, didelphic uterus, bicornuate uterus, septate uterus and vaginal septum ( Creatsas et al., 2010 x Creatsas et al., 2010 Creatsas, G., Deligeoroglou, E., and Christopoulos, P. Creation of a neovagina after Creatsas modification of Williams vaginoplasty for the treatment of 200 patients with Mayer–Rokitansky–Kuster-Hauser syndrome. Fertil. Steril. 2010; 94: 1848–1852 Abstract | Full Text | Full Text PDF | PubMed | Scopus (29) | Google Scholar See all References , Parelkar et al., 2009 x Parelkar et al., 2009 Parelkar, S.V., Gupta, R.K., Oak, S., Sanghvi, B., Kaltari, D., Patil, R.S., Prakash, A., and Shimoga, P. Laparoscopic management of persistent mullerian duct syndrome. J. Pediatr. Surg. 2009; 44: e1–e3 Abstract | Full Text | Full Text PDF | PubMed | Scopus (14) | Google Scholar See all References , Tiker et al., 2000 x Tiker et al., 2000 Tiker, F., Yildirim, S.V., Barutcu, O., and Bagis, T. Familial mullerian agenesis. Turk. J. Pediatr. 2000; 42: 322–324 PubMed | Google Scholar See all References ). It is often accompanied with other somatic malformations, such as renal agenesis (25%), skeletal anomalies (10–12%) and, more rarely, cardiac or middle ear anomalies ( Morcel et al., 2007 x Morcel et al., 2007 Morcel, K., Camborieux, L., and Guerrier, D. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. Orp. J. Rare Dise. 2007; 2: 13 Crossref | PubMed | Scopus (186) | Google Scholar See all References Morcel et al., 2007 ). Patients with MDA are asymptomatic before preadolescence and would not be diagnosed with a uterine defect until the child-bearing period because of infertility, recurrent spontaneous abortion, premature birth, abnormal fetal presentation or cyclic pain ( Bernardini et al., 2009 x Bernardini et al., 2009 Bernardini, L., Gimelli, S., Gervasini, C., Carella, M., Baban, A., Frontino, G., Barbano, G., Divizia, T.M., Fedele, L., Novelli, A., Bena, F., Lalatta, F., Miozzo, M., and Dallapiccola, B. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky–Kuster-Hauser (MRKH) syndrome: two case reports. Orphanet J. Rare Dis. 2009; 4: 25 Crossref | PubMed | Scopus (71) | Google Scholar See all References , Biason et al., 2007 x Biason et al., 2007 Biason, L.A., De Filippo, G., Konrad, D., Scarano, G., Nazzaro, A., and Schoenle, E.J. WNT4 deficiency-a clinical phenotype distinct from the classic Mayer-Rokitansky–Kuster-Hauser syndrome: a case report. Hum. Reprod. 2007; 22: 224–229 Crossref | PubMed | Scopus (103) | Google Scholar See all References , Sadic et al., 2002 x Sadic et al., 2002 Sadic, S., Taskin, O., Sehirali, S., Mendilcioglu, I., önoglu, A.S., Kursun, S., and Wheeler, M.J. Complex mullerian malformation: report of a case with a hypoplartic non-carvitated uterus and two rudimentary horns. Hum. Reprod. 2002; 17: 1343–1344 Crossref | PubMed | Google Scholar See all References ). The incidence of MDA in infertile women is about 5% ( Nik-Zainal et al., 2011 x Nik-Zainal et al., 2011 Nik-Zainal, S., Strick, R., Storer, M., Huang, N., Rad, R., Willatt, L., Fitzgerald, T., Martin, V., Sandford, R., Carter, N.P., Janecke, A.R., Renner, S.P., Oppelt, P.G., Oppelt, P., Schulze, C., Brucker, S., Hurles, M., Beckmann, M.W., Strissel, P.L., and Shaw-Smith, C. High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia. J. Med. Genet. 2011; 48: 197–204 Crossref | PubMed | Scopus (56) | Google Scholar See all References Nik-Zainal et al., 2011 ).

Immune-checkpoint therapy has failed to show significant benefit in glioblastoma (GBM) patients. Immunologic subtypes of GBM are necessary to identify patients who might benefit from immune-checkpoint therapy. This study reviewed 152 GBM samples from The Cancer Genome Atlas (TCGA) and 214 GBM samples from Chinese Glioma Genome Atlas (CGGA). Correlation analysis showed that immune checkpoint genes (ICGs) were mainly positively correlated. The prognostic analysis of the overall survival showed that there was a significant correlation between the overall survival (OS) and the prognosis of ICGs, in which the TNFSF14 gene was a significant adverse prognostic factor. Combined with TMB and neoantigens, we found that TNFSF9 and CD27 were significantly negatively correlated with TMB and neoantigens. The association between adaptive immune pathway genes and ICG expression showed that they were positively correlated with ICGs, indicating that adaptive immune pathway genes have a certain regulatory effect on the expression of ICGs. The analysis of clinical features of the samples showed that the higher the expression of ICGs, the more likely to be correlated with mutant isocitrate dehydrogenase (IDH), while the lower the expression level of IDH, the more likely to be significantly correlated with the primary GBM. Survival analysis showed that low expression of PD-L1, IDO1, or CTLA4 with TNFSF14 in the low expression group had the best prognosis, while high expression of IDO1 or CD274 with TNFSF14 in the high expression group and low expression of CTLA4 with TNFSF14 in the high expression group had the worst prognosis. We conclude that TNFSF14 is a biomarker to identify immunologic subtype and prognosis with other ICGs in GBM and may serve as a potential therapeutic target.

Purpose. In our study, we aimed to screen the risk factors that affect overall survival (OS) and cancer‐specific survival (CSS) in adult glioma patients and to develop and evaluate nomograms. Methods. Primary high‐grade gliomas patients being retrieved from the surveillance, epidemiology and end results (SEER) database, between 2004 and 2015, then they randomly assigned to a training group and a validation group. Univariate and multivariate Cox analysis models were used to choose the variables significantly correlated with the prognosis of high‐grade glioma patients. And these variables were used to construct the nomograms. Next, concordance index (C‐index), calibration plot and receiver operating characteristics (ROCs) curve were used to evaluate the accuracy of the nomogram model. In addition, the decision curve analysis (DCA) was used to analyze the benefit of nomogram and prognostic indicators commonly used in clinical practice. Results. A total of 6395 confirmed glioma patients were selected from the SEER database, divided into training set (n =3166) and validation set (n =3229). Age at diagnosis, tumor grade, tumor size, histological type, surgical type, radiotherapy and chemotherapy were screened out by Cox analysis model. For OS nomogram, the C‐index of the training set was 0.741 (95% CI: 0.751‐0.731), and the validation set was 0.738 (95% CI: 0.748‐0.728). For CSS nomogram, the C‐index of the training set was 0.739 (95% CI: 0.749‐0.729), and the validation set was 0.738 (95% CI: 0.748‐0.728). The net benefit and net reduction in inverventions of nomograms in the decision curve analysis (DCA) was higher than histological type. Conclusions. We developed nomograms to predict 3‐ and 5‐year OS rates and 3‐ and 5‐year CSS rates in adult high‐grade glioma patients. Both the training set and the validation set showed good calibration and validation, indicating the clinical applicability of the nomogram and good predictive results.

Background: Gliomas are the most prevalent type of intracranial tumors. NKCC1 is an important regulator in tumor cell volume. We noticed that abnormally high NKCC1 expression resulted in changes in the shape and adhesion of glioma cells. However, little is known about the role of NKCC1 in the epithelial-mesenchymal transition (EMT) of gliomas. This study aims to clarify the biological function of NKCC1 in glioblastoma multiforme (GBM) progression. Methods: Using data from The Cancer Genome Atlas (TCGA), we performed a Kaplan–Meier analysis on NKCC1 expression levels to estimate the rate of survival of mesenchymal GBM patients. The correlation between NKCC1 and EMT-related proteins was analyzed from the Gene Expression Profiling Interactive Analysis (GEPIA) server. We conducted Gene Set Enrichment Analysis (GSEA) to verify molecular signatures and pathways. We then studied the expression of NKCC1 in grade I–IV glioma tissue samples collected from patients using immunohistochemistry (IHC). Finally, we evaluated the effects of NKCC1 migration and invasion on the cellular behaviors of U251 cells using the transwell assay and western blots. Results: High NKCC1 expression was associated with poor prognoses in mesenchymal GBM. Our results suggest a correlation between NKCC1 and EMT-protein markers: CDH2 and VIM. GSEA showed that gliomas, TGF-beta signaling and EMT were enriched in the NKCC1 high expression phenotype. Higher expression levels of NKCC1 in gliomas correlate with higher glioma grades. Transwell assay and western blot results demonstrated that the knockdown of NKCC1 led to a reduction in migration and invasion, while also inhibiting MMP-2 and MMP-9 expression in U251. Conclusion: These results suggest that high expression of NKCC1 regulates EMT in gliomas, providing a new therapeutic strategy for addressing the spread of gliomas by inhibiting the spread of intracranial tumors.