Ulcerative colitis (UC) is a chronic inflammatory intestinal disease. Genetic susceptibility, gut microbiota and mucosal immune dysfunction play important roles in the pathogenesis and development of Show more
Ulcerative colitis (UC) is a chronic inflammatory intestinal disease. Genetic susceptibility, gut microbiota and mucosal immune dysfunction play important roles in the pathogenesis and development of UC. We investigate the effect of Mist1 in model of colitis and its underlying mechanism. The expressions of Mist1 in patients with colitis tissue were up-regulated. Meanwhile, Mist1 mRNA and protein expressions in DSS-induced colitis mice model were also induced and Mist1 mRNA and protein expressions of LPS induced THP-1 cell were also up-regulated. we found Mist1 human protein promoted inflammation in DSS-induced colitis mice by NLRP3. So, we up-regulated Mist1 expression and over-expression of Mist1 promoted IL-1β and NLRP3 protein expression levels in vitro model. However, down-regulation of Mist1 suppressed IL-1β and NLRP3 protein expression levels in vitro model. Next, SNAI1 is a shooting point of Mist1 in the effects of Mist1 in colitis. The inhibition of SNAI1 reduced the effects of Mist1 on NLRP3 inflammasome in vitro model. Activation of SNAI1 induced the effects of Mist1 on NLRP3 inflammasome in vitro model. Lastly, anti-SNAI1 human protein lowered the effects of Mist1 human protein on NLRP3 inflammasome in DSS-induced colitis mice. We demonstrated that Mist1 promoted inflammation in colitis model via NLRP3 inflammasome by SNAI1, whereas the absence of these macrophages led to a significant improvement in colitis treatment. Show less
Emerging research indicates that miRNAs can regulate cancer progression by influencing molecular pathways. Here, we studied miR-665, part of the DLK1-DIO3 miRNA cluster, which is downregulated by upst Show more
Emerging research indicates that miRNAs can regulate cancer progression by influencing molecular pathways. Here, we studied miR-665, part of the DLK1-DIO3 miRNA cluster, which is downregulated by upstream methylation in bladder cancer. MiR-665 overexpression significantly downregulated the expression of SMAD3, phospho-SMAD3, and SNAIL, reversed epithelial-mesenchymal transition progression, and inhibited the migration of bladder cancer cells. To predict potential targets of miR-665, we used online databases and subsequently determined that miR-665 binds directly to the 3' untranslated region of SMAD3. Moreover, silencing of SMAD3 with small interfering RNAs phenocopied the effect of miR-665 overexpression, and overexpression of SMAD3 restored miR-665-overexpression-induced metastasis. This study revealed the role of the miR-665/SMAD3/SNAIL axis in bladder cancer, as well as the potential of miR-665 as a promising therapeutic target. Show less
PFKFB3 regulates glycolysis in tumor cells, might function as an oncogene, and is associated with cancer metastasis. However, its role in gastric cancer (GC) remains largely unknown. PFKFB3 expression Show more
PFKFB3 regulates glycolysis in tumor cells, might function as an oncogene, and is associated with cancer metastasis. However, its role in gastric cancer (GC) remains largely unknown. PFKFB3 expression was assessed by immunohistochemistry (IHC) in GC tissues and paired paracancerous histological normal tissues (PCHNTs). The associations of PFKFB3 expression with clinical features and HIF-1α, Ki-67, E-cadherin, Snail, and Vimentin expression levels were assessed. A series of in vivo and in vitro experiments were performed to investigate the effects of PFKFB3 on the growth, migration, and invasion of GC cells. We found that PFKFB3 expression was significantly higher in GC tissues compared with PCHNTs (P = 0.000). PFKFB3 expression was positively correlated with tumor size (P = 0.000), differentiation (P = 0.025), venous invasion (P = 0.084), nerve invasion (P = 0.014), lymphatic invasion (P = 0.000), local invasion (P = 0.000), invasive depth (P = 0.000), nodal metastasis (P = 0.000), tumor-node-metastasis stage (P = 0.000), and patient survival (P = 0.000). Notably, PFKFB3 upregulation was highly correlated with increased epithelial-mesenchymal transition (EMT) in GC samples. PFKFB3 overexpression positively modulated cell proliferation, migration, and EMT in GC cells in vitro, with concomitant activation of NF-κB signaling. Administration of an NF-κB inhibitor attenuated PFKFB3-induced EMT in GC cells. PFKFB3 overexpression promoted tumor development and EMT in nude mice, which were attenuated by PFK-15, a PFKFB3 inhibitor. PFKFB3 could potentiate malignancy in GC cells through NF-κB pathway-mediated EMT, suggesting PFKFB3 represents a potential target for GC therapy. Show less
AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for Show more
AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. REVs targeted with Kim-1-binding LTH peptide (REV A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors Show less
Glioma is the most common type of central nervous system tumor. SWItch/sucrose non‑fermentable (SWI/SNF) is a tumor suppressor that serves an important role in epithelial‑mesenchymal transition (EMT). Show more
Glioma is the most common type of central nervous system tumor. SWItch/sucrose non‑fermentable (SWI/SNF) is a tumor suppressor that serves an important role in epithelial‑mesenchymal transition (EMT). The present study aimed to identify key molecules involved in the EMT process. SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 (SMARCC2) is mutated in and its expression is low in multiple types of cancer. SMARCC2 is the core subunit of the chromatin‑remodeling complex, SWI/SNF. Relative mRNA SMARCC2 expression levels in human glioma tissue were analyzed via reverse transcription‑quantitative PCR, whereas the protein expression levels were determined via immunohistochemistry staining. SMARCC2 expression was knocked down in glioma cells using small interfering RNA (si) and overexpressed by infection with adenovirus vectors carrying SMARCC2 cDNA. Wound healing and Transwell assays were performed to assess cell migration and invasion, respectively. Subsequently, immunofluorescence and western blotting were performed to analyze the expression levels of the oncogene c‑Myc, which is associated with SMARCC2. SMARCC2 combines with C‑MYC to downregulate its expression. Consistent with the results of the bioinformatics analysis, which revealed that the upregulated expression levels of SMARCC2 were associated with a more favorable prognosis in patients with glioma, the mRNA and protein expression levels of SMARCC2 were significantly upregulated in low‑grade glioma tissues compared with high‑grade glioma tissues. The results of the wound healing assay demonstrated that cell migration was significantly increased in the siSMARCC2‑1/3 groups compared with the negative control (NC) group. By contrast, the migratory ability of cells was significantly reduced following transduction with adenovirus overexpressing SMARCC2, which upregulated the expression of SMARCC2, compared with the lentiviral vector‑non‑specific control (LVS‑NC) group. The Transwell assay results further showed that SMARCC2 overexpression significantly inhibited the migratory and invasive abilities of U87MG and LN229 cells compared with the LVS‑NC group. Co‑immunoprecipitation assays were subsequently conducted to validate the binding of SMARCC2 and c‑Myc; the results demonstrated that the expression of c‑Myc was downregulated in adenovirus‑transfected cells compared with LVS‑NC‑transfected cells. The results of the western blotting experiments demonstrated that the expression levels of N‑cadherin, vimentin, snail family transcriptional repressor 1 and β‑catenin were notably downregulated, whereas the expression levels of T‑cadherin were markedly upregulated in cell lines stably overexpressing SMARCC2 compared with the LVS‑NC group. In conclusion, the results of the present study suggested that SMARCC2 may inhibit Wnt/β‑catenin signaling by regulating c‑Myc expression in glioma. SMARCC2 regulates the EMT status of the glioblastoma cell line by mediating the expression of the oncogene C‑MYC to inhibit its migration and invasion ability. Thus, SMARCC2 may function as a tumor suppressor or oncogene by regulating associated oncogenes or tumor suppressor genes. Show less
Therapeutic elevation of high-density lipoprotein (HDL) is thought to minimize atherogenesis in subjects with dyslipidemia. However, this is not the case in clinical practice. The function of HDL is n Show more
Therapeutic elevation of high-density lipoprotein (HDL) is thought to minimize atherogenesis in subjects with dyslipidemia. However, this is not the case in clinical practice. The function of HDL is not determined by its concentration in the plasma but by its specific structural components. We previously identified an index for the prediction of HDL functionality, relative HDL (rHDL) index, and preliminarily explored that dysfunctional HDL (rHDL index value > 2) failed to rescue the damage to endothelial progenitor cells (EPCs). To confirm the effectiveness of the rHDL index for predicting HDL functions, here we evaluated the effects of HDL from patients with different rHDL index values on the endothelial-mesenchymal transition (EndoMT) of EPCs. We also analyzed the lipid species in HDL with different rHDL index values and investigated the structural differences that affect HDL functions. The results indicate that HDL from healthy adults and subjects with an rHDL index value < 2 protected transforming growth factor (TGF)-β1-stimulated EndoMT by modulating Smad2/3 and Snail activation. HDL from subjects with an rHDL index value > 2 failed to restore the functionality of TGF-β1-treated EPCs. Lipidomic analysis demonstrated that HDL with different rHDL index values may differ in the composition of triglycerides, phosphatidylcholine, and phosphatidylinositol. In conclusion, we confirmed the applicability of the rHDL index value to predict HDL function and found structural differences that may affect the function of HDL, which warrants further in-depth studies. Show less
Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not know Show more
Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV-related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value. We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan-Meier analysis and log-rank test to identify lncRNA CNV with prognostic value. We conducted loss- and gain-of-function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR-seq), quantitative real-time PCR (qRT-PCR), western blot, and dual-luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull-down, RNA immunoprecipitation, qRT-PCR, and western blot analyses. Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR-199a-5p, resulting in enhanced expression of SNAI1, which induced epithelial-to-mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway. LINC01133 promotes HCC progression by sponging miR-199a-5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC. Show less
Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell Show more
Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell carcinoma (LSCC) are few, and hence the mechanism is unclear. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumor progression and metastasis. This study aimed to analyze the relationship between SOX4 and EMT, and their relationship with clinicopathological factors and related prognosis. Immunohistochemical staining was used to detect the positive expression of SOX4 protein, EMT-related transcription factor protein, and related marker protein in 127 LSCC tissue samples. At the same time, data on various parameters of clinical pathology and postoperative survival were collected. The positive expression rate of SOX4 and Slug in LSCC was related to pathological differentiation, Lymph node metastasis (LNM), and pathological TNM of a tumor. The expression rates of ZEB1, E-cadherin, N-cadherin, and β-catenin in LSCC correlated with LNM and pTNM. The expression of SOX4, combined expression of SOX4 and ZEB1, and LNM were independent prognostic factors for the total survival time of patients with LSCC. In summary, SOX4 was vital in the LSCC EMT process, which might be mediated by transcription factor ZEB1. SOX4 and ZEB1 might serve as potential biomarkers of metastasis and prognosis, as well as promising therapeutic targets of LSCC. Show less
Colorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. H Show more
Colorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. However, there is no consensus on the value of autophagy-associated genes in predicting the prognosis of CRC patients. This work screens autophagy-related markers and signaling pathways that may participate in the development of CRC, and establishes a prognostic model of CRC based on autophagy-associated genes. Gene transcripts from the TCGA database and autophagy-associated gene data from the GeneCards database were used to obtain expression levels of autophagy-associated genes, followed by Wilcox tests to screen for autophagy-related differentially expressed genes. Then, 11 key autophagy-associated genes were identified through univariate and multivariate Cox proportional hazard regression analysis and used to establish prognostic models. Additionally, immunohistochemical and CRC cell line data were used to evaluate the results of our three autophagy-associated genes EPHB2, NOL3, and SNAI1 in TCGA. Based on the multivariate Cox analysis, risk scores were calculated and used to classify samples into high-risk and low-risk groups. Kaplan-Meier survival analysis, risk profiling, and independent prognosis analysis were carried out. Receiver operating characteristic analysis was performed to estimate the specificity and sensitivity of the prognostic model. Finally, GSEA, GO, and KEGG analysis were performed to identify the relevant signaling pathways. A total of 301 autophagy-related genes were differentially expressed in CRC. The areas under the 1-year, 3-year, and 5-year receiver operating characteristic curves of the autophagy-based prognostic model for CRC were 0.764, 0.751, and 0.729, respectively. GSEA analysis of the model showed significant enrichment in several tumor-relevant pathways and cellular protective biological processes. The expression of EPHB2, IL-13, MAP2, RPN2, and TRAF5 was correlated with microsatellite instability (MSI), while the expression of IL-13, RPN2, and TRAF5 was related to tumor mutation burden (TMB). GO analysis showed that the 11 target autophagy genes were chiefly enriched in mRNA processing, RNA splicing, and regulation of the mRNA metabolic process. KEGG analysis showed enrichment mainly in spliceosomes. We constructed a prognostic risk assessment model based on 11 autophagy-related genes in CRC. A prognostic risk assessment model based on 11 autophagy-associated genes was constructed in CRC. The new model suggests directions and ideas for evaluating prognosis and provides guidance to choose better treatment strategies for CRC. Show less
Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). D Show more
Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Show less
Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biolo Show more
Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutics development, partly because of the incomplete mechanistic understanding. Here we demonstrate a potentially novel mechanism by which PD-L1 promotes the epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells by suppressing the destruction of the EMT transcription factor Snail. PD-L1 directly binds to and inhibits the tyrosine phosphatase PTP1B, thus preserving p38-MAPK activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β). Via this mechanism, PD-L1 prevents the GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail and consequently promotes the EMT and metastatic potential of TNBC. Significantly, PD-L1 antibodies that confine the tumor-intrinsic PD-L1/Snail pathway restricted TNBC progression in immunodeficient mice. More importantly, targeting both tumor-intrinsic and tumor-extrinsic functions of PD-L1 showed strong synergistic tumor suppression effect in an immunocompetent TNBC mouse model. Our findings support that PD-L1 intrinsically facilitates TNBC progression by promoting the EMT, and this potentially novel PD-L1 signaling pathway could be targeted for better clinical management of PD-L1-overexpressing TNBCs. Show less
Snail family transcriptional repressor 1 (SNAIL1) is a master inducer of the epithelial‑to‑mesenchymal transition (EMT) process, contributing to tumor metastasis and recurrence. Our previous study rep Show more
Snail family transcriptional repressor 1 (SNAIL1) is a master inducer of the epithelial‑to‑mesenchymal transition (EMT) process, contributing to tumor metastasis and recurrence. Our previous study reported that G2 and S phase‑expressed‑1 (GTSE1) served a role in regulating SNAIL1 expression in hepatocellular carcinoma (HCC). However, the underlying mechanism remains unknown. Therefore, the present study aimed to reveal the regulatory mechanism of GTSE1 on SNAIL1 expression using Show less
Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell Show more
Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell carcinoma (LSCC) are few, and hence the mechanism is unclear. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumor progression and metastasis. This study aimed to analyze the relationship between SOX4 and EMT, and their relationship with clinicopathological factors and related prognosis. Immunohistochemical staining was used to detect the positive expression of SOX4 protein, EMT-related transcription factor protein, and related marker protein in 127 LSCC tissue samples. At the same time, data on various parameters of clinical pathology and postoperative survival were collected. The positive expression rate of SOX4 and Slug in LSCC was related to pathological differentiation, lymphatic invasion, and pathological tumor node metastasis (TNM) of a tumor. The expression rates of ZEB1, Twist, E-cadherin, N-cadherin, and β-catenin in LSCC correlated with lymphatic invasion and pathological tumor node metastasis. The expression of SOX4, combined expression of SOX4 and ZEB1, and lymphatic invasion were independent prognostic factors for the total survival time of patients with LSCC. In summary, SOX4 was vital in the LSCC EMT process, which might be mediated by transcription factor ZEB1. SOX4 and ZEB1 might serve as potential biomarkers of metastasis and prognosis, as well as promising therapeutic targets of LSCC. Show less
Epstein-Barr virus (EBV) was the first oncovirus found to encode microRNAs. In EBV-associated gastric cancer (EBVaGC), EBV-encoded BamHI-A rightward transcript microRNAs (BARTs) are highly expressed. Show more
Epstein-Barr virus (EBV) was the first oncovirus found to encode microRNAs. In EBV-associated gastric cancer (EBVaGC), EBV-encoded BamHI-A rightward transcript microRNAs (BARTs) are highly expressed. However, the role of BARTs in EBVaGC remains obscure. In this study, we found that EBV-miR-BART12 (miR-BART12) inhibits cell proliferation and migration. Zinc finger protein SNAI1 (Snail) is an important epithelial-mesenchymal transition (EMT) inducer, and overexpression of Snail is closely associated with cancer metastasis. Here, we report that Snail expression in EBVaGC cells is lower than in EBV-negative gastric cancer (EBVnGC) cells. A dual luciferase reporter assay showed that miR-BART12 targets Snail directly by interacting with its 3'-UTR. A CHX chase assay revealed that miR-BART12 accelerates the degradation of Snail. Furthermore, we found that miR-BART12 can regulate the expression of EMT-related genes. Flow cytometry analysis showed that transfection with miR-BART12 induced G2/M phase arrest and promoted cell apoptosis. In summary, the results of our study have suggested a new mechanism by which BARTs can repress cell proliferation and migration in gastric cancer. Show less
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated wit Show more
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated with GC metastasis. However, the specific molecular mechanisms underlying this relationship remain to be unveiled. In this study, we assessed the impact of gastrin and the Wnt/β-catenin inhibitor XAV939 on the epithelial-mesenchymal transition (EMT) of the SGC-7901 and MKN45 GC cell lines, and we determined that gastrin-17 significantly decreased E-cadherin expression and upregulated the expression of Snail1 and N-cadherin in GC cells. In addition, gastrin 17 also significantly increased the expression of Wnt3α in a dose-dependent manner. Consistent with these results, gastrin-17 promoted GC cell invasion, proliferation, and migration in a dose-dependent fashion, and these effects were inhibited by XAV939. Together, these results indicated that gastrin-17 induced GC cell EMT, migration, and invasion via the Wnt/β-catenin signaling pathway, which suggests that this gastrin/Wnt/β-catenin signaling axis may represent a therapeutic target for the prevention of GC metastasis. Show less
Patients with non-small cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating mutations in the EGFR and additional lesser Show more
Patients with non-small cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating mutations in the EGFR and additional lesser investigated mechanisms such as the participation of the tumor microenvironment (TME). Here, we examined the potential for MET inhibitor capmatinib for the treatment of osimertinib-resistant NSCLCs and normalizing the TME. We first established that HCC827 and H1975 cells showed increased resistance against osimertinib when co-cultured with CAFs isolated from osimertinib-resistant patients. Additionally, we showed that CAFs promoted epithelial-mesenchymal transition (EMT) and self-renewal ability in both HCC827 and H1975 cells. We subsequently found that both CAF-cultured HCC827 and H1975 showed a significantly higher expression of MET, Akt, Snail and IL-1β, which were associated with survival and inflammatory responses. These cells in turn, promoted the generation of CAFs from normal lung fibroblasts. Subsequently, we observed that the treatment of capmatinib resulted in the re-sensitization of CAF-co-cultured H1975 and HCC827 to osimertinib, in association with reduced EMT and self-renewal ability. MET-silencing experiment using siRNA supported the observations made with capmatinib while with a greater magnitude. MET-silenced cell exhibited a severely hindered expression of inflammatory markers, IL-1β and NF-κB; EMT markers, Snail and Vimentin, while increased E-cadherin. Finally, we demonstrated that the combination of capmatinib and osimertinib led to an increased tumor inhibition and significantly lower number of CAFs within the patient derived xenograft (PDX) model. Taken together, our findings suggested that an increased MET/Akt/Snail signaling was induced between the NSCLC cells and their TME (CAFs), resulting in osimertinib resistance. Suppression of this pathway by capmatinib may bypass the EGFR activating mutation and overcomes osimertinib resistance by targeting both tumor cells and CAFs. Show less
One hallmark of renal cell carcinoma (RCC) is metabolic reprogramming, which involves elevation of glycolysis and upregulation of lipid metabolism. However, the mechanism of metabolic reprogramming is Show more
One hallmark of renal cell carcinoma (RCC) is metabolic reprogramming, which involves elevation of glycolysis and upregulation of lipid metabolism. However, the mechanism of metabolic reprogramming is incompletely understood. Monocarboxylate transporter 1 (MCT1) promotes transport for lactate and pyruvate, which are crucial for cell metabolism. The aim of present study was to investigate the function of MCT1 on RCC development and its mechanism on metabolic reprogramming. The results showed that MCT1 messenger RNA and protein levels significantly increased in cancer tissues of ccRCC compared to normal tissue. MCT1 was further found to mainly located in the cell membrane of RCC. The knockdown of MCT1 by RNAi significantly inhibited proliferation and migration of 786-O and ACHN cells. MCT1 also induced the expressions of proliferation marker Ki-67 and invasion marker SNAI1. Moreover, we also showed that acetate treatment could upregulate the expression of MCT1, but not other MCT isoforms. On the other hand, MCT1 was involved in acetate transport and intracellular histone acetylation. In summary, this study revealed that MCT1 is abnormally high in ccRCC and promotes cancer development. The regulatory effect of MCT1 on cell proliferation and invasion maybe mediated by acetate transport. Show less
Despite the remarkable clinical response in ovarian cancer therapy, the distinctively high metastasis rate is still a barrier to achieve satisfying prognosis. Our study aimed to decipher the role of b Show more
Despite the remarkable clinical response in ovarian cancer therapy, the distinctively high metastasis rate is still a barrier to achieve satisfying prognosis. Our study aimed to decipher the role of berberine in inhibiting chemotherapy-exacerbated ovarian cancer metastasis. We found that chemotherapy exacerbated the migration and cancer stem cell (CSC)-like characteristics through transcriptional factor GLI1, which regulated the pluripotency-associated gene BMI1 and the epithelial-mesenchymal transition (EMT) markers Vimentin and Snail. Berberine could not only down-regulate CSC-like characteristics but also reverse EMT and migration through inhibiting chemotherapy-activated GLI1/BMI1 signaling pathway. Together, our study revealed the pivotal role of berberine in overcoming chemotherapy-exacerbated ovarian cancer metastasis, thereby provided a potential adjuvant therapeutic agent in combination with chemotherapeutics to prevent metastasis during ovarian cancer chemotherapy. Show less
Yun Feng, Xin Zhao, Zhengda Li+8 more · 2021 · Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada · added 2026-04-24
Somatic cell nuclear transfer (SCNT) holds vast potential in agriculture. However, its applications are still limited by its low efficiency. Histone 3 lysine 9 trimethylation (H3K9me3) was identified Show more
Somatic cell nuclear transfer (SCNT) holds vast potential in agriculture. However, its applications are still limited by its low efficiency. Histone 3 lysine 9 trimethylation (H3K9me3) was identified as an epigenetic barrier for this. Histone demethylase KDM4D could regulate the level of H3K9me3. However, its effects on buffalo SCNT embryos are still unclear. Thus, we performed this study to explore the effects and underlying mechanism of KDM4D on buffalo SCNT embryos. The results revealed that compared with the IVF embryos, the expression level of KDM4D in SCNT embryos was significantly lower at 8- and 16-cell stage, while the level of H3K9me3 in SCNT embryos was significantly higher at 2-cell, 8-cell, and blastocyst stage. Microinjection of KDM4D mRNA could promote the developmental ability of buffalo SCNT embryos. Furthermore, the expression level of ZGA-related genes such as ZSCAN5B, SNAI1, eIF-3a, and TRC at the 8-cell stage was significantly increased. Meanwhile, the pluripotency-related genes like POU5F1, SOX2, and NANOG were also significantly promoted at the blastocyst stage. The results were reversed after KDM4D was inhibited. Altogether, these results revealed that KDM4D could correct the H3K9me3 level, increase the expression level of ZGA and pluripotency-related genes, and finally, promote the developmental competence of buffalo SCNT embryos. Show less
Recent clinical trials with agents targeting immune checkpoint pathway have emerged as an important therapeutic approach for a broad range of cancer types. Resveratrol has been shown to possess cancer Show more
Recent clinical trials with agents targeting immune checkpoint pathway have emerged as an important therapeutic approach for a broad range of cancer types. Resveratrol has been shown to possess cancer preventive and therapeutic effects and has potential to be chemotherapeutic agent/adjuvant. Here, we assessed the effect of resveratrol on immune checkpoint pathways. The expression patterns of Wnt components and PD-L1 were examined by Western blot, Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction, the promoter activity was determined by luciferase reporter assay, apoptosis was analyzed by flow cytometry and the ability of the resveratrol to modulate T cell function was assessed in a co-culture system. Although the dose-, and cell-type dependent effects of resveratrol on PD-L1 expression have been reported, we show here that resveratrol dose-dependently upregulates PD-L1 expression at the range of pharmacologic-achievable concentrations in lung cancer cells and that is essential for suppression of T-cell-mediated immune response. We also found that Wnt pathway is critical for mediating resveratrol-induced PD-L1 upregulation. Mechanistically, resveratrol activates SirT1 deacetylase to deacetylate and stabilize transcriptional factor Snail. Snail in turn inhibits transcription of Axin2, which leads in disassembly of destruction complex and enhanced binding of β-catenin/TCF to PD-L1 promoter. We conclude that resveratrol is capable to suppress anti-tumor immunity by controlling mainly PD-L1 expression. This finding will extend the understanding of resveratrol in regulation of tumor immunity and is relevant to the debate on resveratrol supplements for lung cancer patients. Show less
The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa Show more
The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa_circ₀₀₀₈₅₃₇ (circ₀₀₀₈₅₃₇₎ in liver cancer pathogenesis remain undetermined. In the present study, circ₀₀₀₈₅₃₇ expression was associated with the GLI3 gene and was markedly increased in liver cancer tissue specimens and cells. High expression levels of circ₀₀₀₈₅₃₇ exhibited a poor prognosis. In addition, circ₀₀₀₈₅₃₇ overexpression resulted in an increased proliferation, migration and invasion of liver cancer cells, whereas circ₀₀₀₈₅₃₇ knockdown exhibited opposite effects. circ₀₀₀₈₅₃₇ acted as a sponge of microRNA‑153‑3p (miR‑153‑3p), and a negative correlation was observed between circ₀₀₀₈₅₃₇ and miR‑153‑3p expression in liver cancer. Transfection with miR‑153‑3p further abolished the effects of circ₀₀₀₈₅₃₇ on the malignant behavior of liver cancer cells. Furthermore, circ₀₀₀₈₅₃₇ indirectly affected the expression levels of pro‑survival protein myeloid cell leukemia 1 (MCL1) and snail family zinc finger 1 (Snail1) via miR‑153‑3p in liver cancer cells. In conclusion, the data indicated that circ₀₀₀₈₅₃₇ facilitated liver carcinogenesis by indirectly regulating miR‑153‑3p and leading to the release of MCL1 and Snail1. Show less
Drug resistance is one of the major challenges for treatment of hepatocellular carcinoma (HCC) with sorafenib. Our present study found that sorafenib resistant (SR) HCC cells showed epithelial-mesench Show more
Drug resistance is one of the major challenges for treatment of hepatocellular carcinoma (HCC) with sorafenib. Our present study found that sorafenib resistant (SR) HCC cells showed epithelial-mesenchymal transition (EMT) characteristics with the downregulation of epithelial marker and upregulation of mesenchymal makers. The expression of Snail, a core factor of EMT, was increased in HCC/SR cells, while knockdown of Snail can restore sorafenib sensitivity and EMT potential of HCC/SR cells. Further, the upregulation of protein stability was responsible for the upregulation of Snail in HCC/SR cells. ATM and CSN2, which can stabilize Snail protein, were increased in HCC/SR cells. Knockdown of ATM and CSN2 can suppress the expression of Snail and increase sorafenib sensitivity of HCC/SR cells. It indicated that targeted inhibition of Snail might be helpful to overcome sorafenib resistance of HCC patients. Show less
Glomerular capillaries are lined with a highly specialized fenestrated endothelium and contribute to the glomerular filtration barrier. The Notch signaling pathway is involved in regulation of glomeru Show more
Glomerular capillaries are lined with a highly specialized fenestrated endothelium and contribute to the glomerular filtration barrier. The Notch signaling pathway is involved in regulation of glomerular filtration barrier, but its role in glomerular endothelium has not been investigated due to the embryonic lethality of animal models with genetic modification of Notch pathway components in the endothelium. To determine the effects of aberrant activation of the Notch signaling in glomerular endothelium and the underlying molecular mechanisms. We established the Our results reveal novel regulatory mechanisms whereby endothelial Notch1 signaling dictates the level of VE-cadherin through the transcription factors SNAI1 and ERG, leading to dysfunction of glomerular filtration barrier and induction of albuminuria. Graphic Abstract: A graphic abstract is available for this article. Show less
MicroRNA-205 (miR-205) is believed to be related to the progress of tumors. HOXD9 has been proved to be expressed abnormally in several kinds of cancers. However, the role of miR-205 and HOXD9 in brea Show more
MicroRNA-205 (miR-205) is believed to be related to the progress of tumors. HOXD9 has been proved to be expressed abnormally in several kinds of cancers. However, the role of miR-205 and HOXD9 in breast cancer remains unclear. The biological role of miR-205 in breast cancer cell proliferation and chemoresistance was investigated. The expression of miR-205 in clinical tissues and breast cancer cell lines were analyzed using quantitative real-time PCR test (qRT-PCR). Overexpression and knockdown models of miR-205 were established to study cell proliferation and chemotherapy-resistant. Moreover, the potential relationships between miR-205 and HOXD9/Snail1 were measured using qRT-PCR, western blot, and chemotherapy-resistant study. miR-205 was lowly expressed in breast cancer tissues and cell lines. Overexpression of miR-205 could inhibit cell proliferation and chemotherapy-resistance. Moreover, we proved that miR-205 could target the HOXD9-Snail1 axis to suppress triple negative breast cancer cell proliferation and chemoresistance. The activation of Snail1 gene by HOXD9 was also proved in this study. The present study may provide a novel insight for the therapeutic strategies of breast cancer through targeting miR-205/HOXD9/Snail1. Show less
Histological risk factors for lymph node metastasis (LNM) in early-stage colorectal cancers (CRC) have been described, although the predictive utility of these factors varies. Improved LNM risk assess Show more
Histological risk factors for lymph node metastasis (LNM) in early-stage colorectal cancers (CRC) have been described, although the predictive utility of these factors varies. Improved LNM risk assessment based on findings in endoscopic colon and rectal excisions is necessary for optimal surgical management of CRC patients with pathologic T1- /T2-staged invasive depth (i.e., tumor not invading beyond the muscularis propria layer); as the current system is overly conservative, and results in many unnecessary radical surgeries. To identify molecular features in early CRC with elevated LNM potential, we carried out proteomic and gene expression profiling to compare T1 lymph node (LN) negative with T1/2 LN positive CRC tumors from formalin-fixed paraffin-embedded (FFPE) specimens. Using a data-independent acquisition mass spectrometry workflow, we detected over 7400 proteins and quantified over 4400 in all 21 specimens. Proteins from tumors with LN metastasis were enriched with effectors of epithelial-mesenchymal transition (EMT) and gene expression profiling confirmed activation of key transcription factors, SNAI1 and ZEB1, as well as a reduction in E-cadherin expression. Toward an implementation pathway, we investigated immunohistochemistry assays targeting four EMT-related proteins. While MS could reliably discern twofold protein abundance changes, we found the semiquantitative nature of IHC scoring limited confirmation of this degree of protein expression difference. This study demonstrated that EMT effectors are associated with locoregional metastasis in T1/T2 CRC and could be used to augment metastatic risk assessment, although further developments are required to enable routine implementation. Show less
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progre Show more
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progression and worse prognosis. Our previous study found that HES1 was overexpressed and promoted invasion in TNBC. However, the role of HES1 in modulating BCSC stemness of TNBC remains unclear. Here, we found that HES1 upregulates Slug both in transcriptional level and in protein level. HES1 also has a positive correlation with Slug expression in 150 TNBC patient samples. TNBC patients with high HES1 and Slug levels show worse prognosis in both progression-free survival and overall survival analyses. Survival analyses indicate that the effects of HES1 on survival prognosis may depend on Slug. Furthermore, we reveal that HES1 is a novel transcriptional activator for Slug through acting directly on its promoter. Meanwhile, HES1 knockdown reduces BCSC self-renewal, BCSC population, and cancer cell proliferation in TNBC, whereas overexpression of Slug restores the oncogenic function of HES1, both Show less
Parthenolide has been demonstrated to have anticancer effects against various types of cancer. However, the functional role of parthenolid has yet to be clearly reported in renal cell carcinoma (RCC). Show more
Parthenolide has been demonstrated to have anticancer effects against various types of cancer. However, the functional role of parthenolid has yet to be clearly reported in renal cell carcinoma (RCC). The aim of the present study was to investigate the effect of parthenolide in RCC 786‑O and ACHN cells. CCK‑8 and colony‑formation assays were used to observe the proliferation of RCC 786‑O and ACHN cells. Migration and invasion abilities were assessed through Transwell assays. The stem cell‑like properties of RCC cell lines were evaluated by mammosphere formation assay. Western blot analysis was used to investigate the metastasis and epithelial‑mesenchymal transition (EMT) induced by parthenolide on the expression levels of MMP2, MMP9, E‑cadherin, N‑cadherin, vimentin and snail. The results revealed that when the cells were treated with various concentrations of parthenolide, the rate of proliferation and growth was decreased in 786‑O and ACHN cells. The number of invasive cells in a field was approximately 170, 90, 40 and 190, 150, 70 in 786‑O and ACHN cells with 0, 4 and 8 µM of parthenolide treatment. MMP‑2/‑9 expression (P<0.05) was inhibited by parthenolide. The protein levels of E‑cadherin were increased (P<0.05) and N‑cadherin, vimentin and snail were decreased (P<0.05) by parthenolide treatment. In addition, Parthenolide inhibited the expression of cancer stem cell markers and the PI3K/AKT pathway. The present study confirmed that parthenolide inhibited RCC cell proliferation and metastasis and suppressed the stem cell‑like properties of RCC cell lines, which could be a potential strategy to treat RCC. However, further molecular mechanisms of parthenolide in RCC should be observed and reported in the future. Show less
Epithelial ovarian cancer (EOC) is a highly fatal gynecological cancer. A long noncoding RNA (lncRNA) gastric cancer-associated lncRNA1 (GClnc1) has been revealed to play critical roles in metastasis. Show more
Epithelial ovarian cancer (EOC) is a highly fatal gynecological cancer. A long noncoding RNA (lncRNA) gastric cancer-associated lncRNA1 (GClnc1) has been revealed to play critical roles in metastasis. Therefore, the present study aims to explore the correlation between GClnc1 and the metastasis and progression of EOC. First, 57 paired EOC and paracancerous tissues were collected to detect GClnc1 expression by RT-qPCR. Subsequently, OVC1 and SKOV3 cells with GClnc1 silencing/overexpression were developed to detect changes in cell activity, apoptosis, migration and invasion abilities. Then, the subcellular localization of GClnc1 was detected by nuclear/cytoplasmic fractionation, ISH and FISH assays. The binding relationships between GClnc1 and forkhead box protein C2 (FOXC2), and between FOXC2 and NOTCH1 were predicted and verified. GClnc1 was significantly overexpressed in EOC tissues, and knockdown of GClnc1 inhibited cell viability and promoted apoptosis. Moreover, GClnc1 in the nucleus bound to the transcription factor FOXC2, thereby activating the transcription of NOTCH1. NOTCH1 overexpression enhanced the proliferation and epithelial-mesenchymal transition of SKOV3 and OVC1 cells. Moreover, NOTCH1 activated the NF-κB/Snail signaling. Finally, in vivo experiments demonstrated that GClnc1 knockdown suppressed the growth and metastasis of SKOV3 and OVC1 cells in vivo. GClnc1 promoted NOTCH1 transcription by recruiting FOXC2, thereby activating the NF-κB/Snail signaling and promoting EOC cell growth and metastasis. Show less
Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many individuals carrying DDX3 mutations have additional defects in craniofacial struc Show more
Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many individuals carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Show less