ABSTRACT
BACKGROUND: Long non-coding RNAs (lncRNAs) are increasingly investigated in numerous carcinomas containing gastric cancer (GC). The aim of our research is to inquire about the expression profile and role of LBX2-AS1 in GC. METHODS: The expressions of LBX2-AS1, miR-219a-2-3p, FUS and LBX2 were measured by qRT-PCR. Western blot evaluated FUS and LBX2 protein levels. Cell proliferation and apoptosis were, respectively, evaluated by CCK-8, colony formation, EdU, flow cytometry and TUNEL assays. FISH and subcellular fractionation assays examined the position of LBX2-AS1. The binding between genes were certified by RIP, RNA pull-down, ChIP and luciferase reporter assays. Pearson correlation analysis analyzed the association of genes. Kaplan-Meier method detected the relationship of LBX2-AS1 expression with overall survival. RESULTS: The up-regulation of LBX2-AS1 in GC tissues and cells was verified. Function assays proved that LBX2-AS1 down-regulation restricted the proliferation ability. Then, we unveiled the LBX2-AS1/miR-219a-2-3p/FUS axis. Additionally, LBX2-AS1 positively regulated LBX2 mRNA stability via FUS. LBX2 transcriptionally modulated LBX2-AS1. In the end, rescue and in vivo experiments validated the whole regulatory mechanism. CONCLUSION: LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop mainly affected the proliferation and apoptosis abilities of GC cells, offering novel therapeutic targets for the treatment of patients with GC.
Subject(s)
Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/metabolism , MicroRNAs/genetics , RNA, Long Noncoding/genetics , RNA-Binding Protein FUS/metabolism , Stomach Neoplasms/pathology , Animals , Apoptosis , Biomarkers, Tumor/genetics , Cell Proliferation , Feedback, Physiological , Homeodomain Proteins/genetics , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Prognosis , RNA, Antisense/genetics , RNA-Binding Protein FUS/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
There has been an increasing number of studies about microRNAs as key regulators in the development of hepatic fibrosis. Here, we demonstrate that miR-542-3p can promote hepatic fibrosis by downregulating the expression of bone morphogenetic protein 7 (BMP-7), which is known to antagonize transforming growth factor ß1 (TGFß1)-mediated fibrogenesis effect. The expression of miR-542-3p is increased in activated hepatic stellate cells (HSCs). Downregulation of MiR-542-3p by antisense inhibitors can inhibit HSCs activation markers, including α-smooth muscle actin (α-SMA) and collagen as well as TGFß signaling pathways. MiR-542-3p was significantly upregulated in carbon tetrachloride (CCl4 )-induced hepatic fibrosis in mice, and downregulation of miR-542-3p by lentivirus could prevent the development of hepatic fibrosis. In addition, miR-542-3p can directly bind to the 3'-untranslated region of BMP-7 mRNA, indicating that its profibrotic effect appears to be caused by its inhibition of BMP-7. Our results suggest that downregulation of miR-542-3p prevents liver fibrosis both in vitro and in vivo, highlighting its potential as a novel biomarker or therapeutic target for hepatic fibrosis.
Subject(s)
Bone Morphogenetic Protein 7/metabolism , Down-Regulation , Hepatic Stellate Cells/metabolism , Liver Cirrhosis/metabolism , MicroRNAs/biosynthesis , Animals , Cell Line , Hepatic Stellate Cells/pathology , Humans , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Liver Cirrhosis/prevention & control , Male , Mice , MicroRNAs/geneticsABSTRACT
Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.
Subject(s)
Brain , Drug Design , Enzyme Inhibitors , Methionine Adenosyltransferase , Methionine Adenosyltransferase/antagonists & inhibitors , Methionine Adenosyltransferase/metabolism , Humans , Animals , Structure-Activity Relationship , Rats , Brain/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Mice , Male , Rats, Sprague-Dawley , Xenograft Model Antitumor AssaysABSTRACT
There is now growing interest in the use of Ultrasound-guided radiofrequency ablation (RFA) to treat hyperparathyroidism. But the efficacy and limitations of this treatment have not been described in sufficient detail. Assessing and contrasting the effectiveness and safety of RFA in treating primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). This retrospective study included 57 HPT patients (48 for PHPT and 9 for SHPT) who underwent RFA between January 2017 and April 2021. The serum intact parathyroid hormone (iPTH) and calcium, hyperplastic parathyroid volume, volume reduction rate (VRR) before and after RFA, clinical success rate, symptoms, and complications were analyzed and compared. In SHPT group, bone pain (7/9, 77.8%), skin pruritus (4/9, 44.4%), and multiple hyperplastic parathyroid glands (4/9, 44.4%) were more common compared to the PHPT group. After 12 months of follow-up, the serum iPTH, calcium, and the volume of PHPT and SHPT groups had decreased by more than 60%, 10%, and 90%, respectively (P < 0.05). In the VRR, 13 glands of SHPT (72.2%) and 42 glands of PHPT (87.5%) had achieved the clinical success. In addition, the preoperative and postoperative serum iPTH were higher in the SHPT group than in the PHPT group (P < 0.05). In terms of the serum iPTH and calcium, the PHPT group had substantially higher rates of clinical success, with 42 patients (87.5%) and 46 patients (95.8%) meeting the criteria, respectively compared to 3 patients (33.3%) and 6 patients (66.7%) of SHPT group (P < 0.05). After RFA, the clinical symptoms improved in both groups. The overall incidence of complications (hoarseness and postoperative hematoma) of RFA in the two groups was 10.5% (6/57), and hoarseness (3/9, 33.3%) of SHPT group was more common than PHPT group. All the complications were resolved spontaneously within 12 months after symptomatic treatments. In the treatment of PHPT and SHPT, ultrasound-guided RFA is both successful and safe. PHPT patients have better results in restoring normal iPTH by RFA, and have no considerable difference with the SHPT patients in terms of serum calcium, the volume of the ablation area, and the VRR.
Subject(s)
Hyperparathyroidism, Secondary , Radiofrequency Ablation , Humans , Retrospective Studies , Calcium , Hoarseness , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/surgery , Parathyroid Hormone , Radiofrequency Ablation/adverse effects , Radiofrequency Ablation/methodsABSTRACT
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.
Subject(s)
Thyroid Neoplasms , Tumor Microenvironment , Humans , Methylation , Tumor Microenvironment/genetics , Thyroid Neoplasms/genetics , RNA , AdenosineABSTRACT
Head and neck squamous cell carcinoma (HNSC) is one of the leading causes of cancer death globally, yet there are few useful biomarkers for early identification and prognostic prediction. Previous studies have confirmed that CCND1 amplification is closely associated with head and neck oncogenesis, and the present study explored the ceRNA network associated with CCND1. Gene expression profiling of the Head and Neck Squamous Cell Carcinoma (HNSC) project of The Cancer Genome Atlas (TCGA) program identified the TPRG1-AS1-hsa-miR-363-3P-MYO1B gene regulatory axis associated with CCND1. Further analysis of the database showed that MYOB was regulated by methylation in head and neck tumors, and functional enrichment analysis showed that MYO1B was involved in "actin filament organization" and "cadherin binding ". Immune infiltration analysis suggested that MYO1B may influence tumorigenesis and prognosis by regulating the immune microenvironment of HNSC. MYO1B enhanced tumor spread through the EMT approach, according to epithelial mesenchymal transition (EMT) characterisation. We analyzed both herbal and GSCALite databases and found that CCND1 and MYO1B have the potential as predictive biomarkers for the treatment of HNSC patients. RT-qPCR validated bioinformatic predictions of gene expression in vitro cell lines. In conclusion, we found a CCND1-related ceRNA network and identified the novel TPRG1-AS1-hsa-miR-363-3p-MYO1B pathway as a possible HNSC diagnostic biomarker and therapeutic target.
Subject(s)
Critical Pathways , Head and Neck Neoplasms , Humans , Carcinogenesis , Cell Transformation, Neoplastic , Cyclin D1/genetics , Head and Neck Neoplasms/genetics , Myosin Type I/genetics , Prognosis , Squamous Cell Carcinoma of Head and Neck/genetics , Tumor Microenvironment , RNA, Long Noncoding/genetics , MicroRNAs/geneticsABSTRACT
Purpose: To evaluate the diagnostic and prognostic utility of E2F transcription factors (E2Fs) in thyroid carcinoma (THCA) and their association with immune infiltration. Methods: The transcription and protein levels of E2Fs in THCA tissues were examined using the R language and the Human Protein Atlas (HPA) database in this research. We utilized the UALCAN and GEPIA2 databases to analyze the association between the level of E2Fs and the clinicopathological features of THCA. The prognostic utility of E2F expression in THCA was studied using the R language and the Gene Set Cancer Analysis (GSCA) database. Over-representation analysis (ORA) and gene set enrichment analysis (GSEA) were employed to analyze the effect of E2F family members. The TISIDB database and Tumor Immune Estimation Resource (TIMER) database were utilized to investigate the relationship between E2F expression and the level of immune infiltration in thyroid cancer. Results: E2Fs are highly conserved in thyroid carcinoma and rarely mutated. E2Fs are strongly expressed in THCA and are highly related with the clinicopathological stage of THCA. Patients with THCA have a poor prognosis when E2Fs are highly expressed. The function of E2Fs in THCA may be closely related to the renin-angiotensin system (Ras) signaling pathway, platelet-derived growth factor (PDGF) signaling pathway, apoptosis, and immune response. With regard to the immune infiltration, E2F expression and tumor-infiltrating lymphocytes exhibited a positive connection. Conclusion: The level of E2Fs is connected with the prognosis and immune infiltration level in THCA, revealing that E2Fs may be a prognostic and immune infiltration cell marker in THCA patients.
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Background: Ectopic thyroid gland (ETG) is an uncommon clinical condition, presenting various challenges and limitations in its regulate diagnosis and treatment currently. This study aims to enhance our understanding of ETG and improve the strategies for its diagnosis and treatment. Methods: The retrospective single-center study was conducted, encompassing clinical data from ETG patients screened at our institution between 2013 and 2022. Patients were categorized based on the location of the disease, and follow-ups were performed on each. Results: This study included a total of 47 patients who were confirmed to hav confirmed to have ETG. Among them, we found 29 cases of accessory thyroid and 18 cases of aberrant thyroid. Furthermore, 42 cases exhibited the single ETG, while 5 cases displayed the double ETG. The distribution of the ETG was as follows: 20 were lingual, 10 were submandibular, 10 were lateral cervical, 4 were thoracic mediastinal, 1 was esophageal, and 7 were ovarian. Of these cases, 22 patients underwent surgery, 18 received thyroid hormone replacement therapy, and 7 were placed under observation. All patients were followed up for 59.4 (12-117) months. No significant abnormalities were detected at the conclusion of the follow-up period. Conclusion: ETG is frequently observed in the head and neck, particularly in lingual. Accessory thyroid glands are commonly reported, with most cases being single ETG. Notably, these glands usually do not manifest specific clinical symptoms. Therefore, the appropriate and comprehensive examinations during the initial diagnosis are crucial to avoid misdiagnosis. Treatment should be individualized, and long-term follow-up is essential for managing ETG effectively.
Subject(s)
Thyroid Dysgenesis , Thyroid Gland , Humans , Follow-Up Studies , Retrospective Studies , Thyroid Dysgenesis/diagnosis , Thyroid Dysgenesis/surgery , Treatment Outcome , Thyroid Gland/diagnostic imaging , Laryngoscopy , Magnetic Resonance Imaging , Tomography, X-Ray ComputedABSTRACT
Thyroid disorders are among the most common endocrinological conditions. As the prevalence of thyroid diseases increases annually, the exploration of thyroid disease mechanisms and the development of treatments are also gradually improving. With the gradual advancement of therapies, non-apoptotic programmed cell death (NAPCD) has immense potential in inflammatory and neoplastic diseases. Autophagy, pyroptosis, ferroptosis, and immunogenic cell death are all classical NAPCD. In this paper, we have compiled the recent mechanistic investigations of thyroid diseases and established the considerable progress by NAPCD in thyroid diseases. Furthermore, we have elucidated the role of various types of NAPCD in different thyroid disorders. This will help us to better understand the pathophysiology of thyroid-related disorders and identify new targets and mechanisms of drug resistance, which may facilitate the development of novel diagnostic and therapeutic strategies for patients with thyroid diseases. Here, we have reviewed the advances in the role of NAPCD in the occurrence, progression, and prognosis of thyroid diseases, and highlighted future research prospects in this area.
ABSTRACT
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.
Subject(s)
Laryngeal Neoplasms , Humans , Laryngeal Neoplasms/genetics , Laryngeal Neoplasms/pathology , Gene Expression Profiling , Fatty Acids , Prognosis , Computational Biology , Tumor Microenvironment/geneticsABSTRACT
Yin-Yang 1 (YY1) has a crucial function in the development of several malignancies, according to recent research. However, nothing is known about its aberrant expression and prognostic significance in human pan-cancer. We first explored the potential carcinogenic effect of YY1 in 33 cancers using the cancer genome atlas (TCGA) project and gene expression omnibus (GEO) datasets in this research. Then, we contained a variety of elements, for instance, gene expression, the state of survival, gene alterations, protein phosphorylation, immune infiltration, and related cellular pathways, and used a series of bioinformatics methods to investigate the underlying molecular mechanism of YY1 in the etiology or clinical prognosis of various malignancies. In most malignancies, YY1 was expressed at high levels, and the level of YY1 expression was statistically associated with the prognosis of tumor patients. The S118 site of YY1 implied higher phosphorylation expression in breast cancer, colon cancer, uterine corpus endometrial carcinoma (UCEC), and lung adenocarcinoma (LUAD) tumor tissues, but lower phosphorylation levels in ovarian cancer and clear cell carcinoma tumor tissues. For S247, higher phosphorylation levels were found in colon cancer, UCEC, and LUAD tumor tissue, and lower phosphorylation expression was found in clear cell carcinoma tumor tissue. In TCGA database, YY1 expression in BRCA, BRCA-LumA, BRCA-LumB, CESC, CHOL, COAD, ESCA, HNSC, HNSC-HPV-, KIRP, LGG, LIHC, and PAAD tumor tissues was a statistically significant positive connection of the estimated infiltration value of cancer-associated fibroblasts but a negative correlation in TGCT. In addition, the functional mechanism of YY1 also involves viral carcinogenesis and ribonucleic acid (RNA) metabolism related functions. Our first pan-cancer analysis offers a pretty comprehensive knowledge of YY1's oncogenic involvement in various cancers.
Subject(s)
Adenocarcinoma of Lung , Breast Neoplasms , Colonic Neoplasms , Lung Neoplasms , Breast Neoplasms/pathology , Carcinogenesis/genetics , Female , Humans , Tumor Microenvironment/genetics , YY1 Transcription Factor/genetics , YY1 Transcription Factor/metabolismABSTRACT
Microbial inactivation by pulsed electric field (PEF) has been studied widely although with high operational risk, while few studies on the potential of low intensity electric fields for microbial inactivation have been reported. In this study, the feasibility of inactivating microorganisms in milk by low intensity direct current (DC) electric field was investigated. Then a kinetics model was proposed based on the inactivation curves. Finally, the effect of electric field on the microflora and physicochemical properties of milk was analyzed. Results showed that the bacterial reduction >5 log CFU/mL could be achieved at 50-55°C, 0.3 A-0.6 A, and with 5 min starting intensity of 5 V/cm-9 V/cm. The inactivation kinetics consisted of three stages, therein, the middle stage, main part of the inactivation curve, followed 1st-order reaction kinetics, and the effect of temperature on it was consistent with the Arrhenius Law, which implied that the electric field itself can inactivate bacteria without thermal inactivating effect. The microflora analysis showed that naturally occurring bacteria in the milk contained typical potential pathogenic bacteria (e.g., 56.9% of Acinetobacter spp.) and spoilage bacteria (e.g., 27.5% of Pseudomonas spp.), and the electric field can inactivate them. Moreover, the inactivation chemically preserved the milk's fresh-like characteristics (according to indexes of whey protein denaturation rate, furosine content), and physical stability (turbidity, zeta potential, particle size, color and so on). Therefore, a promising approach is provided for microbial inactivation in dairy industry.
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Introduction: Currently, there is no consensus on the specific effect of Extrathyroidal Extension (ETE) on prognosis. The purpose of our study was to study the relationship between different states of ETE and its disease-free survival rate and to determine the basic standard of Micro ETE (tumor extends through capsule only) in risk stratification. Material and Methods: We conducted a retrospective and single-center study that included the clinical data of all papillary thyroid carcinoma (PTC) patients with ETE in our hospital from 2013 to 2017 and followed them up after rigorous screening. According to ETE state, it is divided into four groups: Microscopic, Micro, Minimal, Macro. Kaplan-Meier method was used to calculate disease-free survival (DFS). Log-rank test was used to compare the differences between the groups and to polt the survival curves. P<0.05 was considered statistically significant. Micro ETE was included in different risk stratification subgroups and their DFS was compared. Results: A total of 436 patients were included: Microscopic group N=50 (11.47%), Micro group N=74 (16.97%), Minimal group N=135 (30.96%), and Macro group N=177 (40.60%). The frequency of ETE was in strap muscles N=191, trachea N=114, laryngeal recurrent nerve N=92, and capsule N=74, etc. The 5-year DFS rate in Micro group was 95.3%, higher than that in Macro group (P<0.05). The 5-year DFS rate of Micro ETE was 90.0% in the intermediate-risk group and 84.9% in the high-risk group when Micro ETE was included in different risk stratification subgroups. Conclusion: Micro ETE deserves more attention, has a batter prognosis than Macro ETE, and may have little effect on recurrence. It seems more appropriate to treat Micro ETE as the intermediate-risk group in risk stratification.
ABSTRACT
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.
Subject(s)
Adenosine/analogs & derivatives , Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Amino Acid Transport System y+ , Ferroptosis , Thyroid Neoplasms , Adenosine/genetics , Adenosine/metabolism , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism , Amino Acid Transport System y+/genetics , Amino Acid Transport System y+/metabolism , Animals , Epigenesis, Genetic , Ferroptosis/genetics , Methylation , Mice , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/prevention & controlABSTRACT
Background: Circular RNA circ_0004771 (termed circNRIP1) was identified by RNA-Seq previously and was elevated in papillary thyroid carcinoma (PTC) tissues. A series of studies also showed that circNRIP1 was upregulated in some tumors and could promote the malignant progression of tumors. This research intended to focus on the role of circNRIP1 in PTC progression and explore the mechanisms underlying circNRIP1 functions. Methods: RT-PCR or western blot determined circNRIP1, miR-653-5p, and pre-B-cell leukemia homeobox 3 (PBX3) expression. EdU, CCK-8, Tunel, and transwell assays determined cell proliferation, apoptosis, invasion, and migration, respectively. Luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down assays clarified the target relation between miR-653-5p and circNRIP1 or PBX3. Xenograft models were applied to explore the role of circNRIP1 in vivo. Results: circNRIP1 significantly increased in PTC tissues and PTC cell lines than that in normal ones. Higher circNRIP1 expression was associated with the TNM stage and poorer overall survival. circNRIP1 knockdown attenuated the malignant progression of PTC, specifically by inhibiting proliferation and invasion/migration and promoting apoptosis. circNRIP1 was a miR-653-5p sponge; miR-653-5p knockdown reversed the suppressive role of circNRIP1 silence in PTC progression. PBX3, a target of miR-653-5p, was positively medicated through circNRIP1 via competitively sponging miR-653-5p. Knockdown of circNRIP1 attenuated the PTC tumor progression via miR-653-5p/PBX3 axis. Conclusion: Silencing of circNRIP1 suppressed PTC development via miR-653-5p elevation and PBX3 reduction, providing a novel perspective for understanding PTC pathogenesis.
ABSTRACT
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.
Subject(s)
Antiviral Agents/therapeutic use , Dengue Virus/drug effects , Dengue/drug therapy , Drugs, Chinese Herbal/therapeutic use , Gastrodia/chemistry , Glucans/therapeutic use , Animals , Antiviral Agents/pharmacology , Cell Line , Cell Survival/drug effects , Drugs, Chinese Herbal/pharmacology , Glucans/pharmacology , Humans , Virus Replication/drug effectsABSTRACT
Colon carcinoma is a recurring type of cancer that affects the intestine epithelial with a poor survival rate. It was already proven the anticancer property of hesperidin in various cancers but the bioavailability hesperidin is poor, which hinders the hesperidin usage. In this investigation we synthesized hesperidin loaded Zn2+@ SA/PCT nanocomposites and assessed its anticancer potential against colon cancer (HCT116) cells. Hesperidin loaded Zn2+@ SA/PCT nanocomposites were characterized using Fourier transform infrared (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis. The drug releasing capacity and cytotoxic property was assessed via drug releasing assay, MTT assay with HCT116 cells. The anticancer potency of hesperidin nanocomposites were evaluated with TUNEL, DAPI staining, reactive oxygen species (ROS) generation assay and it is confirmed with flow cytometry analysis of MMP disruption in colon cancer (HCT116) cell line. Further the immunoblotting analysis of cysteine proteases Caspases 3, 9, PARP, proapoptotic protein Bax and antiapoptotic protein Bcl2 were performed. The results of FTIR, XRD and electroscopic analyses confirmed the synthesized hesperidin nanocomposites accomplish the properties of potent nanodrug and the MTT assay authentically confirmed that the synthesized hesperidin nanocomposite inhibited the HCT116 cell growth, and the results of fluorescent staining proved that the hesperidin nanocomposite induced the apoptotic mediated cell necrosis via promoting the expression of apoptotic proteins thereby induced the apoptosis in colon cancer (HCT116) cells. Hence, it was concluded that the, hesperidin loaded nanocomposites persuasively inhibited proliferation of colon carcinoma cell and induced apoptosis in in vitro condition.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Cell Proliferation/drug effects , Hesperidin/chemistry , Nanocomposites/chemistry , Alginates/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Caspase 3/metabolism , Cell Survival/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Drug Compounding , Drug Liberation , HCT116 Cells , Hesperidin/pharmacology , Humans , Membrane Potential, Mitochondrial/drug effects , Pectins/chemistry , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Reactive Oxygen Species/metabolism , Zinc/chemistryABSTRACT
Liver fibrosis resulting from chronic liver damage constitutes a major health care burden worldwide; however, no antifibrogenic agents are currently available. Our previous study reported that the small molecule NPLC0393 extracted from the herb Gynostemma pentaphyllum exerts efficient antifibrotic effects both in vivo and in vitro. In this study, a TMT-based quantitative proteomic study using a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was performed to identify the potential target of NPLC0393. Combining this study with bioinformatic analysis of differentially expressed proteins between the CCl4 model and NPLC0393 treatment groups, we focused on the function of N-myc downstream-regulated gene 2 (NDRG2) involved in cell differentiation. In vitro studies showed that NPLC0393 prevented the TGF-ß1 stimulation-induced decrease in the NDRG2 level in hepatic stellate cells (HSCs). Functional studies indicated that NDRG2 can inhibit the activation of HSCs by preventing the phosphorylation of ERK and JNK. Furthermore, knockdown of NDRG2 abolished the ability of NPLC0393 to inhibit HSC activation. In conclusion, these results provide information on the mechanism underlying the antifibrotic effect of NPLC0393 and shed new light on the potential therapeutic function of the TGF-ß1/NDRG2/MAPK signaling axis in liver fibrosis.
ABSTRACT
OBJECTIVE: Dipeptidyl peptidase IV (DPP4) has been indicated as a possible prognostic biomarker in papillary thyroid cancer (PTC). However, the mechanism of DPP4 during metastasis of PTC remains unclear. In this study, we investigated whether lysine acetyltransferase 5 (KAT5) and FBJ murine osteosarcoma viral oncogene homolog B (FosB) synergistically regulate high DPP4 expression in PTC. METHODS: PTC tissues and matched paracancerous tissues were harvested, followed by the establishment of IHH-4 and TPC-1 cells with downregulation of DPP4. The relevance of DPP4 on the metastasis of PTC cells was assessed. Subsequently, the effect of KAT5 on the transcription of DPP4 was verified. The binding relationship between FosB and DPP4 was predicted by a bioinformatics website. Functional rescue experiments were performed to evaluate cell activities after overexpression of KAT5 or FosB in cells with DPP4 knockdown. RESULTS: DPP4 was overexpressed in PTC tissues and cell lines, which was correlated with higher risks for metastases and poorer survival. DPP4 downregulation curtailed cell growth and metastasis. Moreover, KAT5 acetylated DPP4 promoter histone, which promoted transcription activation of DPP4. Subsequently, FosB recruited KAT5 at the DPP4 promoter, thereby enhancing DPP4 transcriptional activation. Further overexpression of KAT5 or FosB in cells with low expression of DPP4 promoted cell activity. Finally, DPP4 expedited p62 nuclear translocation to elevate Keap1/Nrf2 expression, thus facilitating the growth and metastasis of PTC cells. CONCLUSION: FosB enhanced the growth and metastasis of PTC cells by recruiting histone acetyltransferases KAT5 to increase DPP4 transcription and activate the p62/Keap1/Nrf2 signaling.