Overexpression of LIMA1 Indicates Poor Prognosis and Promotes Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma
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ABSTRACT: Background:
LIMA1 encodes LIM domain and actin binding 1, a
SUBMITTER: Ma W
PROVIDER: S-EPMC9274436 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:Deregulated Hippo signaling has been uncovered to be intricately involved in tumorigenesis. Transcriptional factor TEADs serve as key mediators of Hippo signaling and have been increasingly appreciated as putative oncogenes driving cancer initiation and progression. However, its expression pattern and oncogenic role of TEAD4 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Methods:TEAD4 mRNA expression in HNSCC was determined by data mining and analyses from TCGA dataset and four independent cohorts with transcriptional profiling data publically available. The protein abundance of TEAD4 was measured by immunohistochemistry in 105 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The oncogenic roles of TEAD4 was further determined by 4-nitroquinoline 1-oxide (4NQO)-induced animal model, both knockdown/overexpression assay and TGF-?1-induced epithelia-mesenchymal transition (EMT) in vitro. Results:Both mRNA and protein abundance of TEAD4 were significantly increased in HNSCC as compared to its non-tumor counterparts. Overexpression of TEAD4 significantly associated with high pathological grade, cervical node metastasis, advanced clinical stage and reduced overall and disease-free survival. In the 4NQO-induced HNSCC mouse model, increased TEAD4 immunostaining was found associated with disease progression. TEAD4 knockdown significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in HNSCC cells, while its overexpression resulted in opposite effects and EMT. Moreover, TEAD4 was critically involved in TGF-?1-induced EMT in HNSCC cells. Conclusions:Our findings reveal that TEAD4 serves as a novel prognostic biomarker and putative oncogene for HNSCC by promoting cell proliferation, migration and invasion, and EMT.
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Project description:Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of tumors with variable presentation and clinical behavior. Despite improvements in surgical and radiation therapy techniques, the 5-year survival rate has not improved significantly over the past decades. Thus, there is an urgent need to identify novel markers that may allow for the development of personalized therapeutic approaches. In the present study we evaluated the prognostic role of the expression of genes related to the induction of epithelial mesenchymal transition (EMT). To this aim, a consecutive series of 69 HNSCC were analyzed for the expression of TWIST1, TWIST2, SNAI1, SNAI2, E-Cadherin, N-Cadherin and Vimentin.TWIST1, TWIST2, SNAI1 and SNAI2 were significantly overexpressed in HNSCC, with TWIST2, SNAI1 and SNAI2 being more markedly increased in tumors compared to normal mucosae. The expression of TWIST1 and SNAI2 was associated with upregulation of mesenchymal markers, but failed to correlate with pathological parameters or clinical behaviour. In contrast, we found that upregulation of TWIST2, which was independent of the activation of a mesenchymal differentiation program, correlated with poor differentiation grade (p=0.016) and shorter survival (p=0.025), and identifies a subset of node-positive oral cavity/pharynx cancer patients with very poor prognosis (p less than 0.001). Overall our study suggests that the assessment of TWIST2 expression might help to stratify HNSCC patients for risk of disease progression, pointing to TWIST2 as a potential prognostic marker.
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Project description:Globally, hepatocellular carcinoma (HCC) is one of the most common causes of cancer-associated mortalities. It has a high rate of metastasis and recurrence, which predict a poor prognosis. G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multifunctional scaffold protein that mediates the progression of various tumors. Studies have correlated GIT1 with HCC, however, these correlations have not been fully elucidated. Therefore, we aimed at evaluating the expression of GIT1 in HCC tissues and cells, and to investigate its role and potential mechanisms in HCC progression. The expression levels of GIT1 in HCC tissues and other cancers was determined by using the Oncomine and TCGA databases. Functional analysis of GIT1 in HCC was evaluated through in vitro and in vivo experiments, whereby, HCC cells were transfected with synthetically overexpressed and short hairpin RNA (shRNA) lentivirus-mediated plasmids. Kaplan-Meier and Cox regression methods were used to establish the associations between GIT1 and clinical outcomes of 158 HCC patients. GIT1 was found to be elevated in HCC tissues where it promoted the invasion, migration, and proliferation of HCC cells. Moreover, the overexpression of GIT1 prompted epithelial-mesenchymal transition (EMT) by activating extracellular regulated kinase 1/2 (ERK1/2) pathway, which was shown to be reversed by SCH772984, a specific ERK1/2 inhibitor. GIT1 was also found to be associated with malignant features of HCC, leading to a poorer prognosis. In conclusion, GIT1 promotes HCC progression by inducing EMT and may reflect the course of HCC patients.
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Project description:Head and neck squamous cell carcinomas (HNSCCs) are aggressive, recurrent, and metastatic neoplasms with a high occurrence around the world and can lead to death when not treated appropriately. Several molecules and signaling pathways are involved in the malignant conversion process. Epithelial-mesenchymal transition (EMT) has been described in HNSCCs, a major type of aggressive carcinoma. EMT describes the development of epithelial cells into mesenchymal cells, which depends on several molecular interactions and signaling pathways that facilitate mesenchymal conversion. This is related to interactions with the microenvironment of the tumor, hypoxia, growth factors, matrix metalloproteinases, and the presence of viral infections. In this review, we focus on the main molecules related to EMT, their interactions with the tumor microenvironment, plasticity phenomena, epigenetic regulation, hypoxia, inflammation, their relationship with immune cells, and the inhibition of EMT in the context of HNSCCs.
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Project description:Head and neck squamous cell carcinomas (HNSCC) are common tumors with a poor overall prognosis. Poor survival is resulting from limited response to multi-modal therapy, high incidence of metastasis, and local recurrence. Treatment includes surgery, radio(chemo)therapy, and targeted therapy specific for EGFR and immune checkpoint inhibition. The understanding of the molecular basis for the poor outcome of HNSCC was improved using multi-OMICs approaches, which revealed a strong degree of inter- and intratumor heterogeneity (ITH) at the level of DNA mutations, transcriptome, and (phospho)proteome. Single-cell RNA-sequencing (scRNA-seq) identified RNA-expression signatures related to cell cycle, cell stress, hypoxia, epithelial differentiation, and a partial epithelial-to-mesenchymal transition (pEMT). The latter signature was correlated to nodal involvement and adverse clinical features. Mechanistically, shifts towards a mesenchymal phenotype equips tumor cells with migratory and invasive capacities and with an enhanced resistance to standard therapy. Hence, gradual variations of EMT as observed in HNSCC represent a potent driver of tumor progression that could open new paths to improve the stratification of patients and to innovate approaches to break therapy resistance. These aspects of molecular heterogeneity will be discussed in the present review.
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Project description:BackgroundDCBLD1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the prognostic value and immune infiltration in head and neck squamous cell carcinoma remain unclear and need further research.Materials and methodsDCBLD1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. The mRNA level in cell lines (SCC25 and CAL27) and gingival fibroblasts were detected using quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of DCBLD1 and clinical data in HNSCC. A nomogram was also established to predict the impact of DCBLD1 on prognosis based on Cox multivariate results. The methylation level of DCBLD1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of DCBLD1 were investigated using gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA).ResultsThe mRNA and protein expression levels of DCBLD1 were highly expressed in HNSCC tissue and cell lines. The Cox analyses demonstrate that highly expressed DCBLD1 is an independent prognosis marker (p < 0.05). ROC curve analysis showed the performance of DCBLD1 (area under the ROC curve: 0.948, sensitivity: 93.2%, specificity: 84.7%). The methylation was increased in HNSCC patients compared with normal subjects (p < 0.05) and was associated with poor prognosis at sites cg27642470 and cg21104965. Additionally, DCBLD1 expression is poorly associated with immune cell infiltration and immunological checkpoints PD-L1 and TIM-3.ConclusionIn head and neck squamous cell carcinoma, DCBLD1 is overexpressed, associated with poor patient prognosis. The detailed underlying mechanism merits further research.
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Project description:Hypoxanthine phosphoribosyltransferase (HPRT1), as a salvage pathway enzyme, plays a crucial role in modulating the cell cycle and has been reported to be overexpressed in multiple cancers. Nevertheless, the relationship between the HPRT1 gene and head and neck squamous cell carcinomas (HNSCCs) has not been investigated so far. In this study, we first evaluated the expression and clinical value of HPRT1 mRNA and protein in tumor and healthy control tissues. Then, we examined mutations of the HPRT1 gene and their association with survival outcomes of patients with HNSCC. We also performed functional analyses of HPRT1 coexpressed genes and examined the association between HPRT1 expression and drug sensitivity. Both HPRT1 mRNA and protein were significantly higher in HNSCC compared with normal tissues, and up-regulation of HPRT1 was also correlated with age, sex, pathological stage and histological grades of patients with HNSCC. Moreover, HPRT1 and its associated genes were observed to be enriched for several cancer-related pathways, including DNA replication and cell cycle. Finally, patients exhibiting overexpression of the HPRT1 gene may be resistant to abiraterone and sensitive to several drugs, including tozasertib and teniposide. This study demonstrated that the elevated expression of HPRT1 gene is correlated with the progression of HNSCC; thus, this gene may serve as a useful indicator for the early detection, risk stratification and targeted therapy of patients with HNSCC.
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Project description:The long noncoding RNAs (lncRNAs) have been increasingly appreciated as key players underlying tumourigenesis and hold great potentials as prognostic biomarkers and therapeutic targets. However, their roles in head neck squamous cell carcinoma (HNSCC) have remained incompletely known. Here, we sought to reveal the oncogenic roles and clinical significance of a tumour-associated lncRNA, zinc finger E-box binding homeobox 2 antisense RNA 1 (ZEB2-AS1), in HNSCC. ZEB2-AS1 was aberrantly overexpressed in a fraction of HNSCC samples. Its overexpression significantly associated with large tumour size, cervical node metastasis and reduced overall and disease-free survival. Antisense oligonucleotides (ASO)-mediated ZEB2-AS1 depletion markedly inhibited cell proliferation, migration and invasion while triggered apoptosis in HNSCC cells in part via modulating ZEB2 mRNA stability. Enforced overexpression of ZEB2 largely attenuated the phenotypic changes resulted from ZEB2-AS1 inhibition except the impaired cell proliferation. In addition, ZEB2-AS1 was required for TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro. Significantly reduced tumour growth and lung metastasis were observed in ZEB2-AS1-depleted cells in HNSCC xenograft animal models. Taken together, our findings reveal that overexpression of ZEB2-AS1 associates with tumour aggressiveness and unfavourable prognosis by serving as a putative oncogenic lncRNA and a novel prognostic biomarker in HNSCC.
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