The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor. High-throughput sequencing data have laid a solid foundation for identifying genes related to cancer prognosis, but a gene marker is needed to predict clinical outcomes in HNSCC. In our study, we downloaded RNA Seq, single nucleotide polymorphism, copy number variation, and clinical follow-up data from TCGA. The samples were randomly divided into training and test. In the training set, we screened genes and used random forests for feature selection. Gene-related prognostic models were established and validated in a test set and GEO verification set. Six genes (PEX11A, NLRP2, SERPINE1, UPK, CTTN, D2HGDH) were ultimately obtained through random forest feature selection. Cox regression analysis confirmed the 6-gene signature is an independent prognostic factor in HNSCC patients. This signature effectively stratified samples in the training, test, and external verification sets (P < 0.01). The 5-year survival AUC in the training and verification sets was greater than 0.74. Thus, we have constructed a 6-gene signature as a new prognostic marker for predicting survival of HNSCC patients.
BackgroundAlternatively activated macrophages in tumor microenvironment is defined as M2 tumor-associated macrophages (M2 TAMs) that promote cancer progression. However, communicative mechanisms between M2 TAMs and cancer cells in squamous cell carcinoma of head and neck (SCCHN) remain largely unknown.MethodsQuantitative real-time PCR, western blotting, enzyme-linked immunosorbent assay and flow cytometry were applied to quantify mRNA and protein expression of genes related to M2 TAMs, epithelial–mesenchymal transition (EMT) and stemness. Wounding-healing and Transwell invasion assays were performed to detect the invasion and migration. Sphere formation assay was used to detect the stemness of SCCHN cells. RNA-sequencing and following bioinformatics analysis were used to determine the alterations of transcriptome.ResultsTHP-1 monocytes were successfully polarized into M2-like TAMs, which was manifested by increased mRNA and protein expression of CCL18, IL-10 and CD206. Conditioned medium from M2-like TAMs promoted the migration and invasion of SCCHN cells, which was accompanied by the occurrence of EMT and enhanced stemness. Importantly, CCL18 neutralizing antibody partially abrogated these effects that caused by conditional medium from M2-like TAMs. In addition, recombinant human CCL18 (rhCCL18) correspondingly promoted the malignant biological behaviors of SCCHN in vitro. Finally, RNA-sequencing analysis identified 331 up-regulated and 363 down-regulated genes stimulated by rhCCL18, which were statistically enriched in 10 cancer associated signaling pathways.ConclusionThese findings indicate that CCL18 derived from M2-like TAMs promotes metastasis via inducing EMT and cancer stemness in SCCHN in vitro.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0620-1) contains supplementary material, which is available to authorized users.
Metastasis is one of the primary causes for high mortality in patients with squamous cell carcinoma of the head and neck (SCCHN). Our previous study showed that chemokine (C‐C motif) ligand 18 (CCL18), derived from tumour‐associated macrophages (TAMs), regulates SCCHN metastasis by promoting epithelial‐mesenchymal transition (EMT) and preserving stemness. However, the underlying mechanism needs to be further investigation. Interestingly, metadherin (MTDH) expression was induced when SCCHN cells were stimulated with recombinant CCL18 protein in this study. Suppressing MTDH expression reversed CCL18‐induced migration, invasion and EMT in SCCHN cells. Furthermore, the NF‐κB signalling pathway was involved in the MTDH knock‐down cells with CCL18 stimulation. We performed ELISA to evaluate the CCL18 levels in the serums of 132 treatment‐naive SCCHN patients, 25 patients with precancerous lesion and 32 healthy donors. Our results demonstrated that serum CCL18 levels were significantly higher in SCCHN patients than patients with precancerous lesion and healthy individuals. CCL18 levels were found to be significantly correlated with tumour classification, clinical stage, lymph node metastasis and histological grade in SCCHN patients. Thus, our findings suggest that CCL18 may serve as a potential biomarker for diagnosis of SCCHN and promote SCCHN invasion, migration and EMT by MTDH‐NF‐κB signalling pathway.
The canonical Wnt/β‐catenin signalling pathway and autophagy play critical roles in cancer progression. However, the role of Wnt‐mediated autophagy in cancer radioresistance remains unclear. In this study, we found that irradiation activated the Wnt/β‐catenin and autophagic signalling pathways in squamous cell carcinoma of the head and neck (SCCHN). Wnt3a is a classical ligand that activated the Wnt/β‐catenin signalling pathway, induced autophagy and decreased the sensitivity of SCCHN to irradiation both in vitro and in vivo. Further mechanistic analysis revealed that Wnt3a promoted SCCHN radioresistance via protective autophagy. Finally, expression of the Wnt3a protein was elevated in both SCCHN tissues and patients' serum. Patients showing high expression of Wnt3a displayed a worse prognosis. Taken together, our study indicates that both the canonical Wnt and autophagic signalling pathways are valuable targets for sensitizing SCCHN to irradiation.
Background Metastasis is a major event for survival and prognosis in patients with head and neck squamous cell carcinomas (HNSCC). A primary cause of metastasis is the proteolytic degradation of the extracellular matrix (ECM). The plasminogen activator urokinase (PLAU) is involved in the transformation of plasminogen to plasmin leading to hydrolyzation of ECM-related proteins. However, the role of PLAU expression in HNSCC is unclear and the worth being investigated. Methods PLAU expression profiles and clinical parameters from multiple HNSCC datasets were used to investigate the relationship of PLAU expression and HNSCC survival. GO and PPI network were established on PLAU-related downstream molecular. The stroma score was deconvoluted for analysis of PLAU’s association with the immune environment. ROC analysis was applied to show the performance of PLAU in predicting HNSCC prognosis. Results PLAU mRNA was significantly elevated, as opposed to its methylation, in HNSCC tumor samples over normal specimens (all p < 0.01). Univariate and multivariate cox analysis showed PLAU could be an independent indicator for HNSCC prognosis. Combining with neck lymph node status, the AUC of PLAU in predicting 5-years overall survival reached to 0.862. GO enrichment analysis showed the major biological process (extracellular matrix organization and the P13K-Akt signaling pathway) may involve to the possible mechanism of PLAU’s function on HNSCC prognosis. Furthermore, PLAU expression was positively correlated with stroma cell score, M1 type macrophages, and negatively associated with CD4 + T cell, Tregs cell, and follicular helper T cell. Conclusions PLAU might be an independent biomarker for predicting outcomes of HNSCC patients. The elevated expression of PLAU was associated with HPV positivity and neck node status. The PI3K-Akt pathway and aberrant proportions of immune cells might underly the mechanism of PLAU’s oncogene role in HNSCC.
The ubiquitin-proteasome system (UPS) with a capacity of degrading multiple intracellular proteins is an essential regulator in tumor immunosurveillance. Tumor cells that escape from recognition and destruction of immune system have been consistently characterized an important hallmark in the setting of tumor progression. Little know about the exact functions of UPS-related genes (UPSGs) and their relationships with antitumor immunity in head and neck squamous cell carcinoma (HNSCC) patients. In this study, for the first time, we comprehensively identified 114 differentially expressed UPSGs (DEUPSGs) and constructed a prognostic risk model based on the eight DEUPSGs (BRCA1, OSTM1, PCGF2, PSMD2, SOCS1, UCHL1, UHRF1, and USP54) in the TCGA-HNSCC database. This risk model was validated using multiple data sets (all P < 0.05). The high-risk score was found to be an independently prognostic factor in HNSCC patients and was significantly correlated with T cells suppression. Accordingly, our risk model can act as a prognostic signature and provide a novel concept for improving the precise immunotherapy for patients with HNSCC.
Cancer stem cells (CSCs) have been characterized by several exclusive features that include differentiation, self-renew, and homeostatic control, which allows tumor maintenance and spread. Recurrence and therapeutic resistance of head and neck squamous cell carcinomas (HNSCC) have been identified to be attributed to CSCs. However, the biomarkers led to the development of HNSCC stem cells remain less defined. In this study, we quantified cancer stemness by mRNA expression-based stemness index (mRNAsi), and found that mRNAsi indices were higher in HNSCC tissues than that in normal tissue. A significantly higher mRNAsi was observed in HPV positive patients than HPV negative patients, as well as in male patients than in female patients. The 8-mRNAsi signature was identified from the genes in two modules which were mostly related to mRNAsi screened by weighted gene co-expression network analysis. In this prognostic signatures, high expression of RGS16, LYVE1, hnRNPC, ANP32A , and AIMP1 focus in promoting cell proliferation and tumor progression. While ZNF66, PIK3R3 , and MAP2K7 are associated with a low risk of death. The riskscore of eight signatures have a powerful capacity for 1-, 3-, 5-year of overall survival prediction (5-year AUC 0.77, 95% CI 0.69–0.85). These findings based on stemness indices may provide a novel understanding of target therapy for suppressing HNSCC stem cells.
PRAS40 (Prolin-rich Akt substrate of 40 kDa) is a critical protein, which directly connects PI3K/Akt and mTORC1 pathway. It plays an indispensable role in the development of various diseases. However, the relationship between PRAS40 and head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, our study indicated that high expression of PRAS40 mRNA is a favorable prognostic factor in HNSCC patients by analyzing 498 clinical and mRNA data. Moreover, we confirmed that CRISPR/Cas9 induced PRAS40-knockout would promote colony formation, cell migration, and invasion in several HNSCC cell lines. RNA-seq was employed to investigate the further possible mechanisms involving the above regulations by PRAS40 in HNSCC cells. The molecular landscape contributed by 253 differentially expressed mRNA after PRAS40-knockout was enriched in TGF-beta, PI3K-Akt, P53, mTOR, NF-κB signaling pathway. Partial molecular alternations within these pathways were validated by qPCR or Western blotting. Besides, we found that high expression of PRAS40 in HNSC patients would present more CD8+ T and T follicular helper cells, but less Th17 cells than the patients with low expression of PRAS40. The altered molecular pathways and tumor-infiltrating immune cells might associate with the mechanism of PRAS40 being a suppressor in HNSCC cells, which would provide a potential prognostic predictor and therapeutic target in HNSCC patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.