Characterization of m6A methylation modifications and tumor microenvironment infiltration in thyroid cancer

Background Thyroid cancer (TC) is the most common endocrine malignancy worldwide, and immunotherapy is a new cancer treatment that stimulates and enhances the natural ability of the immune system to fight cancer cells. The role of RNA N6-methyladenosine (m6A) related genes in these challenges has recently become a research hotspot, but he potential role of m6A modifications in tumor microenvironment (TME) cell infiltration remains unknown. Purpose There is growing evidence that m6A plays a critical role in the regulation of gene expression by participating in important biological processes. A comprehensive analysis of the m6A regulator-mediated infiltration characteristics of the TME will help advance the understanding of immune regulation in thyroid tumors. Methods This study assessed m6A modification modes in 510 thyroid cancer samples from the Cancer Genome Atlas (TCGA) databases according to a comprehensive set of 24 m6A regulators. In this study, we analyzed the biological characteristics and m6A methylation modification patterns. Based on this, we constructed m6A signatures and analyzed m6A modification features in tumor somatic mutations and TCGA molecular subtypes. Results These modification modes were systematically linked to TME cell infiltration signatures. m6A modification patterns were comprehensively assessed and correlated with immune cell infiltration features in the TME. An unsupervised clustering approach was applied and three distinct m6A modification subtypes and three m6A-associated gene subtypes were identified. Additionally, three distinct m6A methylation modification modes were identified in the thyroid cancer samples. The TME profiles of the identified genetic subtypes were strongly congruent with the immuno-heat and immuno-cold phenotypes... (AU)

Characterization of m6A methylation modifications and tumor microenvironment infiltration in thyroid cancer.

BACKGROUND: Thyroid cancer (TC) is the most common endocrine malignancy worldwide, and immunotherapy is a new cancer treatment that stimulates and enhances the natural ability of the immune system to fight cancer cells. The role of RNA N6-methyladenosine (m6A) related genes in these challenges has recently become a research hotspot, but he potential role of m6A modifications in tumor microenvironment (TME) cell infiltration remains unknown. PURPOSE: There is growing evidence that m6A plays a critical role in the regulation of gene expression by participating in important biological processes. A comprehensive analysis of the m6A regulator-mediated infiltration characteristics of the TME will help advance the understanding of immune regulation in thyroid tumors. METHODS: This study assessed m6A modification modes in 510 thyroid cancer samples from the Cancer Genome Atlas (TCGA) databases according to a comprehensive set of 24 m6A regulators. In this study, we analyzed the biological characteristics and m6A methylation modification patterns. Based on this, we constructed m6A signatures and analyzed m6A modification features in tumor somatic mutations and TCGA molecular subtypes. RESULTS: These modification modes were systematically linked to TME cell infiltration signatures. m6A modification patterns were comprehensively assessed and correlated with immune cell infiltration features in the TME. An unsupervised clustering approach was applied and three distinct m6A modification subtypes and three m6A-associated gene subtypes were identified. Additionally, three distinct m6A methylation modification modes were identified in the thyroid cancer samples. The TME profiles of the identified genetic subtypes were strongly congruent with the immuno-heat and immuno-cold phenotypes. CONCLUSIONS: The results revealed that m6A modifications play an integral role in the diversity and complexity of thyroid carcinomas. Evaluating the m6A modification patterns of individual tumors will create more efficient immunotherapeutic strategies. A comprehensive analysis of the role of TME in thyroid cancer provides a research idea for studying the effect of m6A epigenetics on thyroid tumors and their immune microenvironment.

THBS1, a fatty acid-related metabolic gene, can promote the development of laryngeal cancer.

Laryngeal cancer is the second most prevalent head and neck tumor and it is one of the most common malignancies of the upper respiratory tract. Fatty acid metabolism affects cancer cell biology in several ways, and alterations in fatty acid metabolism are characteristic of both tumorigenesis and metastasis. Despite advances in laryngeal cancer diagnosis and treatment over the years, there has been no significant improvement in survival or mortality. Studying the role of fatty acid metabolism-related genes in laryngeal cancer will facilitate our search for valuable biomarkers to guide prognostic management and treatment selection. We constructed a prognostic risk score model for fatty acid metabolism-related genes by downloading and analyzing laryngeal cancers from the TCGA and GEO databases. We predicted survival outcomes of laryngeal cancer patients using a prognostic risk score model of fatty acid metabolism-related genes and analyzed the resistance of laryngeal cancer in different individuals to multiple drugs. In addition, the relationship between the prognostic risk score model and cellular infiltration characteristics of the tumor microenvironment were investigated. Through the prognostic risk scoring model, the genes with risk-prompting effect and related to prognosis were screened out for further research. Through the study of gene expression levels in the TCGA database, we screened out 120 differentially expressed fatty acid metabolism genes. LASSO-Cox and Cox regression analyses identified nine genes associated with prognosis to construct a prognostic risk score model for genes related to fatty acid metabolism. Both TCGA and GEO confirmed that samples in the high-risk score group had a worse prognosis than those in the low-risk score group. We found significant differences between the high-risk and low-risk groups for 22 drugs (P < 0.05). In addition, we found differences in immune cell infiltration between the different risk score groups. Finally, through the risk assessment model, combined with multiple databases, THBS1, a high-risk and prognosis-related gene, was screened. We also found that THBS1 could promote the migration, invasion and proliferation of laryngeal cancer cells by constructing THBS1 knockout cell lines. In our study, we identified key fatty acid-related genes differentially expressed in laryngeal carcinoma that can be used to adequately predict prognosis using a comprehensive bioinformatic experimental approach. It was also found that THBS1, a high-risk and prognosis-related gene, may regulate the occurrence and development of laryngeal cancer through fatty acid metabolism, which has further helped us to explore the role of fatty acid metabolism genes in laryngeal cancer.

FTO Prevents Thyroid Cancer Progression by SLC7A11 m6A Methylation in a Ferroptosis-Dependent Manner.

N6 methyladenosine (m6A) modification serves as a novel epigenetic regulatory mechanism that is heavily implicated in the heredity of tumors. Meanwhile, fat mass and obesity-associated protein (FTO) has the potential to affect the regulation of m6A modification in the mRNA of key oncogenes as well as tumor suppressor genes that facilitate tumor progression. In our study, FTO was downregulated in papillary thyroid carcinoma (PTC) tissues. The role of FTO in PTC was assessed by Cell Counting Kit-8 analysis, cell scratch, migration, invasion experiment, flow cytometry apoptosis analysis, and nude mouse experiment. In addition to RNA-Seq and meRIP-Seq, luciferase reporting and mutation analysis have also identified SLC7A11 as the potential FTO regulatory gene. Moreover, X-ray electron microscopy, glutathione (GSH)/oxidized GSH, GPX, malondialdehyde determination, and western blot helped confirmed that FTO inhibited the development of PTC by downregulating the expression of SLC7A11 through ferroptosis. Finally, a rescue experiment was employed to clarify the relationship between FTO and its specific target gene SLC7A11. FTO is able to inhibit the occurrence of PTC by downregulating SLC7A11 in m6A independently, and it functions as a tumor suppressor gene in PTC. These findings could contribute to our understanding of the tumor malignancy regulated by m6A and might lead to new insights for potential biomarkers and therapeutic targets for the treatment of thyroid papillary carcinoma.

Synthesis and hepatitis†C antiviral activity of 1-aminobenzyl-1H-indazole-3-carboxamide analogues.

FIGHTING HCV: Two potent antiviral analogues were developed from a previously identified lead as novel agents against hepatitis C virus. Their potency and selectivity (5 n: IC50 =0.013 µM and EC50 =0.018 µM; 5 t: IC50 =0.007 µM and EC50 =0.024 µM) make them good candidates for further development as antiviral agents.

WSS45, a sulfated alpha-D-glucan, strongly interferes with Dengue 2 virus infection in vitro.

AIM: To investigate the mode of action of WSS45, one sulfated derivative of an alpha-D-glucan from the Gastrodia elata Bl, on the multiplication cycle of dengue virus serotype 2 (DV2), including initial infection and intracellular replication. METHODS: Virus multiplication in BHK cells were monitored by qRT-PCR, plaque reduction assay, and flow cytometry. Initial virus infection was dissected into adsorption and penetration steps by converting temperature and treating by acid glycine. Surface bound virions were detected by immunofluorescence staining for Evelope protein. RESULTS: WSS45 effectively inhibited DV2 infection in BHK cells with an EC(50) value of 0.68+/-0.17 microg/mL, mainly interfered with virus adsorption, in a very early stage of the virus cycle. However, WSS45 showed no viricidal effect. Moreover, WSS45 could increase the detaching of virus from cell surface in BHK cell line. CONCLUSION: WSS45 exerted potent inhibitory effect on DV2 through interfering with the interaction between viruses and targeted cells. This activity was related to its molecular size.