Multi-omics Analysis of Ferroptosis Regulation Patterns and Characterization of Tumor Microenvironment in Patients with Oral Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Gu W
PROVIDER: S-EPMC8416738 | biostudies-literature |
REPOSITORIES: biostudies-literature
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2022-10-31 | GSE186775 | GEO
Project description:BackgroundFerroptosis, a recently discovered form of cell death, whose role in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) has not been well disclosed. To improve our understanding of the differences in tumor progression and therapeutic effects between BCC and SCC, and to find potential therapeutic targets, this study systematically analyzed ferroptosis-related genes (FRGs) and their associated local immune cytolytic activity (LICA) and tumor microenvironment (TME) metabolic function differences.MethodsTwo bulk RNA-seq datasets, GSE7553 and GSE125285, from the Gene Expression Omnibus database were compared within and between groups to screen for common differentially expressed genes (DEGs) for enrichment analysis. The currently recognized FRGs in DEGs gene set were selected as the targets to analyze their correlation and difference in LICA and TME metabolic functions. And validated using immune cell populations from another single-cell RNA-seq (scRNA-seq) dataset (GSE123813) to accurately understand the difference in LICA. All of the gene sets for functional enrichment analysis comes from published results and MSigDB database.ResultsTen FRGs were used to further analyze the differences in LICA and TME metabolic functions between BCC and SCC. In the SCC samples, LICA (e.g. Treg, CCR, Cytolytic activity, etc.) and TME metabolic functions (e.g. lipid and energy, etc.) were significantly related to ferroptosis genes (e.g. SLC1A5, CD44, NQO1, HMOX1 and STEAP3), and the ferroptosis potential index were also significantly higher than that in the BCC samples. Finally, based on these ten FRGs and related enrichment results, we postulated a model of NQO1 homeostasis regulated by FRGs during induction of ferroptosis in SCC.ConclusionsThe results showed that three FRGs, SLC1A5, CD44 and NQO1, have significant potential in targeted therapies for SCC chemotherapy resistance. And two FRGs, STEAP3 and HMOX1, formed a synergistic effect on the occurrence of ferroptosis in tumor cells. Our findings can be used as the main research materials for metastasis and chemotherapy resistance in SCC patients.
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Project description:BackgroundThe cadherin-4 gene (CDH4), a member of the cadherin family genes, encodes R-cadherin (R-cad); however, the function of this gene in different types of cancer remains controversial. The function of CDH4 in OSCC (oral squamous cell carcinoma) is unknown.Materials and methodsWe use the Cancer Genome Atlas (TCGA) database to find the expression of CDH4 in OSCC is more than normal tissue. Our tissue samples also confirmed that CDH4 gene was highly expressed in OSCC. The related cell function assay detected that CDH4 promotes the ability of cell proliferation, migration, self-renewal and invasion. Cell staining experiment confirmed that the change of CDH4 expression would change the cell mortality. The western blot of GPX4 (glutathione-dependent peroxidase-4), GSH (reduced glutathione) test assay and MDA(Malondialdehyde) test assay show that the expression of CDH4 may resist the sensitivity of ferropotosis in OSCC.ResultsCDH4 was upregulated in OSCC samples and was correlation with poor survival of patients. High expression of CDH4 effectively promotes the proliferation, mobility of OSCC cells and reduce the sensitivity of OSCC cells to ferroptosis. CDH4 is positively correlated with EMT pathway genes, negatively correlated with fatty acid metabolism pathway genes and peroxisome pathway genes, and positively correlated with ferroptosis suppressor genes in OSCC.ConclusionsThese results indicate that CDH4 may play a positive role in tumor progression and resistance ferroptosis and may be a potential therapeutic target for OSCC.
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Project description:The stromal cells in the tumor microenvironment (TME) can influence the progression of multiple types of cancer; however, data on oral squamous cell carcinoma (OSCC) are limited. In the present study, the effects of verrucous squamous cell carcinoma‑associated stromal cells (VSCC‑SCs), squamous cell carcinoma‑associated stromal cells (SCC‑SCs) and human dermal fibroblasts (HDFs) on the tumor nest formation, proliferation, invasion and migration of HSC‑3 cells were examined in vitro using Giemsa staining, MTS, and Transwell (invasion and migration) assays, respectively. The results revealed that both the VSCC‑SCs and SCC‑SCs inhibited the tumor nest formation, and promoted the proliferation, invasion and migration of OSCC cells in vitro. Furthermore, the effects of VSCC‑SCs, SCC‑SCs and HDFs on the differentiation, proliferation, invasion and migration of OSCC cells in vivo were evaluated by hematoxylin and eosin staining, tartrate‑resistant acid phosphatase staining, immunohistochemistry and double‑fluorescent immunohistochemical staining, respectively. The results demonstrated that the VSCC‑SCs promoted the differentiation, proliferation, invasion and migration of OSCC cells, while the SCC‑SCs inhibited the differentiation, and promoted the proliferation, invasion and migration of OSCC cells in vivo. Finally, microarray data were used to predict genes in VSCC‑SCs and SCC‑SCs that may influence the progression of OSCC, and those with potential to influence the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. It was found that C‑X‑C motif chemokine ligand (CXCL)8, mitogen‑activated protein kinase 3 (MAPK3), phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA), C-X-C motif chemokine ligand 1 (CXCL1) and C‑C motif chemokine ligand 2 (CCL2) may be involved in the crosstalk between VSCC‑SCs, SCC‑SCs and OSCC cells, which regulates the progression of OSCC. Intercellular adhesion molecule 1 (ICAM1), interleukin (IL)1B, Fos proto‑oncogene, AP‑1 transcription factor subunit (FOS), bone morphogenetic protein 4 (BMP4), insulin (INS) and nerve growth factor (NGF) may be responsible for the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. On the whole, the present study demonstrates that both VSCC‑SCs and SCC‑SCs may promote the progression of OSCC, and SCC‑SCs were found to exert a more prominent promoting effect; this may represent a potential regulatory mechanism for the progression of OSCC.
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Project description:Heterogeneity and complexity of hepatocellular carcinoma (HCC) have been an impediment to effective diagnosis and treatment of HCC. Mounting evidence suggests that ferroptosis-related genes (FRGs) regulate the development of HCC by affecting the tumor microenvironment (TME). Herein, we explored the role of ferroptosis-related molecular patterns in the HCC microenvironment. The transcriptome and corresponding clinicopathological data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, respectively. Molecular patterns of ferroptosis were explored using consensus clustering analysis and ferroptosis-related molecular patterns in the individual patients were analyzed using principal component analysis (PCA). The ability of ferroptosis-related patterns to predict the biological status and survival outcomes of HCC patients was investigated. Based on the expression of FRGs, three molecular patterns related to ferroptosis were identified. Single sample gene set enrichment analysis (ssGSEA) showed that the molecular patterns associated with the worst prognosis were significantly correlated with high infiltration of immunosuppressive cells in the TME. Besides, we identified three ferroptosis gene clusters underlying the different biological features of the three ferroptosis patterns. Patients in the high-risk group had a worse biological status and survival outcomes than those in the low-risk group. This study demonstrates that ferroptosis-related molecular patterns lead to high heterogeneity in HCC. These molecular patterns can be used to assess the survival of HCC patients and guide the design of immunotherapy strategies for HCC patients.
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Project description:Background: Ferroptosis is a unique iron-dependent form of cell death and bladder cancer (BCa) is one of the top ten most common cancer types in the world. However, the role of ferroptosis in shaping the tumor microenvironment and influencing tumor clinicopathological features remains unknown. Methods: Using the data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we comprehensively evaluated the ferroptosis patterns of 570 BCa samples based on 234 validated ferroptosis genes reported in the FerrDb database and systematically correlated these ferroptosis patterns with tumor microenvironment (TME) cell-infiltrating characteristics. The ferroptosis score was constructed to quantify ferroptosis patterns of individuals using principal component analysis (PCA) algorithms. Results: Four distinct ferroptosis patterns and two gene clusters were finally determined. Significant differences in clinical characteristics and the prognosis of patients were found among different ferroptosis patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system to quantify the ferroptosis pattern of individual patients with BCa named the ferroptosis score, which was discovered to tightly interact with clinical signatures such as the TNM category and tumor grade and could predict the prognosis of patients with BCa. Moreover, tumor mutation burden (TMB) was positively correlated to the ferroptosis score, and the low ferroptosis score was related to a better response to immunotherapy using PD-1 blockade. Finally, we also found there existed a positive correlation between the sensitivity to cisplatin chemotherapy and ferroptosis score. Conclusions: Our work demonstrated and interpreted the complicated regulation mechanisms of ferroptosis on the tumor microenvironment and that better understanding and evaluating ferroptosis patterns could be helpful in guiding the clinical therapeutic strategy and improving the prognosis of patients with BCa.
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