Glioma is one of the most common and aggressive malignant primary brain tumors with high recurrence rate and mortality rate and heavily depends on the angiogenesis. LncRNA H19 has many diverse biological functions, including the regulation of cell proliferation, differentiation and metabolism. Here, we aimed to investigate the molecular mechanism of lncRNA H19 affecting angiogenesis in glioma, which could help to uncover potential target for glioma therapy. RT-qPCR analysis was performed to detect the expression of lncRNA H19 and miR-138 in HEB, U87, A172 and U373 cell lines. MTT assay was used to evaluate the cell viability. To evaluate the migration and invasion after lncRNA H19 knockdown, Transwell and wound healing assay were employed. After lncRNA H19 knockdown, protein expression of HIF-1α and VEGF was detected by western blot and tube formation was assessed. For the prediction and validation of the interaction between lncRNA H19 and miR-138, bioinformatics and luciferase assay were performed. We investigated the regulatory roles and downstream molecular mechanisms of lncRNA H19 in glioma by H19 knockdown, which inhibited the proliferation, migration and angiogenesis of glioma cells. Moreover, miR-138 acted as a target of H19 as detected by luciferase reporter assays. Meanwhile, HIF-1α was also a target of miR-138 and miR-138 could also regulate the proliferation, migration and angiogenesis of glioma cells by targeting HIF-1α and affecting the expression of VEGF in turn. Our findings identified an upregulated lncRNA H19 in glioma cells, which could promote proliferation, migration, invasion and angiogenesis via miR-138/HIF-1α axis as a ceRNA. This study provided a new opportunity to advance our understanding in the potential mechanism of lncRNA in glioma angiogenesis.
The positive correlation between the number of M2 phenotype TAMs (M2-TAMs) and tumour development suggests a supportive role of M2-TAMs in glioma progression. In the present study, the molecular link between glioma cells and M2-TAMs was investigated and it was demonstrated that transforming growth factor-β1 (TGF-β1) secreted by M2-TAMs is key in facilitating the stemness and migration of glioma cells. Cluster of differentiation (CD)133 and CD44, markers for the M2 phenotype, were assessed by western blotting. A sphere formation assay and trans-well assay were applied to test the stemness and migration abilities of glioma cells following co-cultured with M2-TAMs. Stemness markers CD133 and CD44, epithelial-mesenchymal transition-associated markers and mothers against decapentaplegic homolog (SMAD)2/3 and sex determining region Y-box 4/2 (SOX4/2) levels were also evaluated by western blotting. A xenograft tumor mouse model was used to demonstrate the tumor forming ability of glioma cells. The results showed that the U251 glioma cells co-cultured with M2-TAMs exhibited high level of sphere formation, stemness and migration ability. Recombinant TGF-β1 protein treatment was able to achieve the same effects on U251 cells, whereas a TGF-β pathway inhibitor reversed the stemness and migration abilities of the glioma cells induced by M2-TAMs. It was also demonstrated that TGF-β1 secreted by M2-TAMs upregulated the phosphorylation of SMAD2/3 and the expression of SOX4/2 in glioma cells. In a mouse xenograft model, solid tumours formed by U251 cells co-cultured with M2-TAMs or pre-treated with TGF-β1 were larger in size and had a higher growth rate. Taken together, results of the present study demonstrated that M2-TAMs promoted the stemness and migration abilities of glioma cells by secreting TGF-β1, which activated the SMAD2/3 pathway and induced the expression of SOX4 and SOX2. These results highlight the mechanism by which M2-TAMs and glioma interact and demonstrate potential therapeutic strategies for glioma treatment.
SummaryRadiotherapy is the first-line treatment for all stages of cervical cancer, whether it is used for radical or palliative therapy. However, radioresistance of cervical cancer remains a major therapeutic problem. Consequently, we explored if E-cadherin (a marker of epithelial-mesenchymal transition) and osteopontin could predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). Patients were retrospectively reviewed and 111 patients divided into two groups (radiation-resistant and radiation-sensitive groups) according to progression-free survival (PFS). In pretreated paraffin-embedded tissues, we evaluated E-cadherin and osteopontin expression using immunohistochemical staining. The percentage of patients with high osteopontin but low E-cadherin expression in the radiation-resistant group was significantly higher than those in the radiation-sensitive group (p<0.001). These patients also had a lower 5-year PFS rate (p<0.001). Our research suggests that high osteopontin but low E-cadherin expression can be considered as a negative, independent prognostic factor in patients with LACSCC ([Hazard ratios (95% CI) 6.766 (2.940, 15.572)], p<0.001). (J Histochem Cytochem 63:88-98, 2015)
To evaluate the rationality and limitations of the seventh edition of the American Joint Committee on Cancer (the 7th AJCC edition) T-staging system for locally advanced nasopharyngeal carcinoma (NPC). The prognosis of 358 patients with stage T3/T4 NPC treated with intensity-modulated radiotherapy (IMRT) was analyzed with the Kaplan–Meier method or the log-rank test. The 7th AJCC staging system of NPC has some limitations in that the T category is neither the significant factor in OS/LRFS nor the independent prognostic factor in OS/LRFS/DMFS/DFS (P > 0.05). After adjustment by anatomic structures, univariate analysis has shown that the adjusted-T category has statistical significance between T3 and T4 for OS (86.4% and 71.3%, P = 0.002), LRFS (97% and 90.9%, P = 0.048), DMFS (90.9% and 77.2%, P = 0.001), and DFS (86.2% and 67.5%, P = 0.000), and multivariate analysis has shown that the adjusted-T category is an independent prognostic factor for OS/DMFS/DFS (with the exception of LRFS). Then, GTV-P was taken into consideration. Multivariate analysis showed that these nT categories serve as suitable independent prognostic factors for OS/DMFS/DFS (P < 0.001) and LRFS (HR = 3.131; 95% CI, 1.090–8.990; P = 0.043). The 7th AJCC staging system has limitations and should be improved by including the modifications suggested, such as anatomic structures and tumor volume adjustment.
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