Snail is a master inducer of epithelial-mesenchymal transition (EMT) and metastasis, however, Snail protein is labile and is quickly degraded through the predominate ubiquitination-mediated proteasome Show more
Snail is a master inducer of epithelial-mesenchymal transition (EMT) and metastasis, however, Snail protein is labile and is quickly degraded through the predominate ubiquitination-mediated proteasome pathway. Deubiquitinases (DUBs) can counteract the Snail degradation process to maintain high level of Snail protein in cancer cells. In this study, we screened a cDNA library containing 79 DUBs, and discovered that a panel of DUBs consisting of USP13, USP28, USP29, USP37, OTUD6A, and DUB3 can markedly stabilize Snail protein, with USP29 displaying the strongest activity to prevent Snail degradation. Mechanistically, USP29 enhances the interaction of Snail and SCP1, resulting in simultaneous dephosphorylation and deubiquitination of Snail and thereafter cooperative prevention of Snail degradation. Biologically, ectopic expression of USP29 promotes gastric cancer cell migration, and depletion of Snail abolishes USP29-mediated cell migration; and USP29 can be induced by major EMT and metastatic inducing factors such as TGFβ, TNFα, and hypoxia. More importantly, high expression levels of Snail, USP29, and SCP1 are associated with poor survival and prognosis. Collectively, these data indicate that Snail is a crucial substrate for USP29 to promote cell migration and USP29/SCP1 complex may be new therapeutic targets to treat metastatic cancer. Show less
Breast cancer (BC) is one of the most lethal malignant tumors and the leading cause of cancer-related death worldwide. Although early diagnostic techniques for BC have been well developed, 40% of case Show more
Breast cancer (BC) is one of the most lethal malignant tumors and the leading cause of cancer-related death worldwide. Although early diagnostic techniques for BC have been well developed, 40% of cases are still diagnosed at the advanced stage, while for BC patients with distant metastases, the 5-year survival rate is usually lower than 30%. The Snail family, generally regarded as transcriptional repressors, has been indicated to be an essential prognostic factor in malignant tumors. However, limited data exist on public databases concerning the prognostic value of individual Snail family members in BC, especially SNAI3. Data from public databases including cBioPortal for Cancer Genomics, Gene Expression Omnibus, UCSC Xena Browser, and Human Protein Atlas (HPA) were downloaded. Based on the Kaplan¬-Meier plotter platform, correlation of the three members of the Snail family and prognosis in BC were analyzed. Individual Snail family members and their co-expressed genes were respectively enriched on different pathways and biological processes via the functional enrichment analysis (FunRich) tool. High SNAI1 mRNA expression was associated with shorter distant metastasis-free survival (DMFS) in all BC patients regardless of PAM50 subtype. Conversely, high SNAI3 mRNA expression was associated with longer DMFS. Although the presence of SNAI2 expression was significantly associated with DMFS in the whole cohort, no significant correlation was found in patients with luminal A or HER2 subtype. For patients with the most diverse clinicopathological features, high SNAI1 expression was associated with poor survival, with the converse being true for SNAI3. However, the impact on prognosis of patients with different clinicopathological features produced by SNAI2 expression was inconclusive. Furthermore, we discovered that SNAI1 or SNAI2 and their co-expressed genes frequently enriched receptor tyrosine kinase (RTK) signaling and integrin-related pathways which mainly functioned on epithelial-mesenchymal transition and were further involved in several processes of signal transduction and cell communication. Furthermore, as SNAI3, along with its co-expressed genes, enriched immune-related pathways, it may thus play a role in mediating the immune system. Our analysis revealed that SNAI1 mRNA expression may potentially be a negative prognostic factor, whereas SNAI3 mRNA was associated with positive prognosis in BC. Therefore, the assessment of SNAI1 and SNAI3 expression may be valuable for predicting prognosis in BC patients. Show less
Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer in China, and the prognosis of patients remains poor mainly due to the occurrence of lymph node and distant metastasi Show more
Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer in China, and the prognosis of patients remains poor mainly due to the occurrence of lymph node and distant metastasis. The long non‑coding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been shown to have tumor‑suppressive properties and to play an important role in epithelial‑to‑mesenchymal transition (EMT) in some solid tumors. However, whether MEG3 is involved in EMT in ESCC remains unclear. In the present study, the MEG3 expression level and its association with tumorigenesis were determined in 43 tumor tissues of patients with ESCC and in ESCC cells using reverse transcription‑quantitative PCR analysis. Gene microarray analysis was performed to detect differentially expressed genes (DEGs). Based on the functional annotation results, the effects of ectopic expression of MEG3 on cell growth, migration, invasion and EMT were assessed. MEG3 expression level was found to be markedly lower in tumor tissues and cells. Statistical analysis revealed that MEG3 expression was significantly negatively associated with lymph node metastasis and TNM stage in ESCC. Fluorescence in situ hybridization assay demonstrated that MEG3 was expressed mainly in the nucleus. Ectopic expression of MEG3 inhibited cell proliferation, migration, invasion and cell cycle progression in EC109 cells. Gene microarray results demonstrated that 177 genes were differentially expressed ≥2.0 fold in MEG3‑overexpressing cells, including 23 upregulated and 154 downregulated genes. Functional annotation revealed that the DEGs were mainly involved in amino acid biosynthetic process, mitogen‑activated protein kinase signaling, and serine and glycine metabolism. Further experiments indicated that the ectopic expression of MEG3 significantly suppressed cell proliferation, migration, invasion and EMT by downregulating phosphoserine aminotransferase 1 (PSAT1). In pathological tissues, PSAT1 and MEG3 were significantly negatively correlated, and high expression of PSAT1 predicted poor survival. Taken together, these results suggest that MEG3 may be a useful prognostic biomarker and may suppress EMT by inhibiting the PSAT1‑dependent glycogen synthase kinase‑3β/Snail signaling pathway in ESCC. Show less
Ji-Min Li, Fang Yang, Juan Li+3 more · 2020 · Medical science monitor : international medical journal of experimental and clinical research · added 2026-04-24
BACKGROUND Emerging evidence suggests the involvement of Reelin in chemoresistance in various cancers. However, its function in cisplatin (DDP) sensitivity of non-small cell lung cancer (NSCLC) needs Show more
BACKGROUND Emerging evidence suggests the involvement of Reelin in chemoresistance in various cancers. However, its function in cisplatin (DDP) sensitivity of non-small cell lung cancer (NSCLC) needs to be investigated. MATERIAL AND METHODS Reelin expression in cisplatin-sensitive A549 cells and cisplatin-resistant NSCLC (A549/DDP) cells was analyzed by western blot analysis. qRT-PCR, western blotting, immunofluorescence, CCK-8 assays, Annexin V/propidium iodide apoptosis assay, and Transwell migration assays were carried out to determine the function of Reelin on DDP resistance. RESULTS Reelin was markedly increased in A549/DDP cells relative to A549 cells. Knockdown of Reelin enhanced DDP chemosensitivity of A549/DDP cells, whereas overexpression of Reelin enhanced DDP resistance of A549, H1299, and H460 cells. Reelin induced DDP resistance in NSCLC cells via facilitating epithelial-mesenchymal transition (EMT). Furthermore, Reelin modulated p38/GSK3Ăź signal transduction and promoted Snail (EMT-associated transcription factor) expression. Suppression of p38/Snail reversed Reelin-induced EMT and resistance of NSCLC cells to DDP. CONCLUSIONS These data indicated that Reelin induces DDP resistance of NSCLC by regulation of the p38/GSK3Ăź/Snail/EMT signaling pathway and provide evidence that Reelin suppression can be an effective strategy to suppress DDP resistance in NSCLC. Show less
Esophageal cancer is one of the most common cancers worldwide with poor prognosis and high mortality. The transcription factor Expression of Cumulatively, these results establish an important mechanis Show more
Esophageal cancer is one of the most common cancers worldwide with poor prognosis and high mortality. The transcription factor Expression of Cumulatively, these results establish an important mechanism by which decrease in miR-203 expression potentiates metastatic progression in EC via USP26-mediated stabilization of Snail1. Hence, miR-203 can serve as a biomarker of metastasis in EC and is a potential target for therapeutic intervention in EC. Show less
RNF8 (ring finger protein 8), a RING finger E3 ligase best characterized for its role in DNA repair and sperm formation via ubiquitination, has been found to promote tumor metastasis in breast cancer Show more
RNF8 (ring finger protein 8), a RING finger E3 ligase best characterized for its role in DNA repair and sperm formation via ubiquitination, has been found to promote tumor metastasis in breast cancer recently. However, whether RNF8 also plays a role in other types of cancer, especially in lung cancer, remains unknown. We show here that RNF8 expression levels are markedly increased in human lung cancer tissues and negatively correlated with the survival time of patients. Overexpression of RNF8 promotes the EMT process and migration ability of lung cancer cells, while knockdown of RNF8 demonstrates the opposite effects. In addition, overexpression of RNF8 activates the PI3K/Akt signaling pathway, knockdown of RNF8 by siRNA inhibits this activation, and pharmacologic inhibition of PI3K/Akt in RNF8-overexpressing cells also reduces the expression of EMT markers and the ability of migration. Furthermore, RNF8 is found to directly interact with Slug and promoted the K63-Ub of Slug, and knockdown of Slug disrupts RNF8-dependent EMT in A549 cells, whereas overexpression of Slug rescues RNF8-dependent MET in H1299 cells, and depletion of RNF8 expression by shRNA inhibits metastasis of lung cancer cells Show less
Prostate cancer (PCa) is the second leading cause of cancer-associated mortality in men. Speckle-type pox virus and zinc finger protein (SPOP), the most frequently mutated gene in PCa, functions as a Show more
Prostate cancer (PCa) is the second leading cause of cancer-associated mortality in men. Speckle-type pox virus and zinc finger protein (SPOP), the most frequently mutated gene in PCa, functions as a tumor suppressor via degradation of cancer-promoting substrates. However, its upstream regulation in PCa metastasis remains poorly determined. Here, in a Snail-induced metastatic PCa model, we observed an accelerated degradation of SPOP protein in cells, which is crucial for the PCa migration and activation of the AKT signaling pathway. Mechanistically, we demonstrated that binding to Snail promoted SPOP ubiquitination and degradation. Moreover, the bric-a-brac/tramtrack/broad complex (BTB) domain of SPOP is turned out to be essential for Snail-mediated SPOP degradation. Thus, our findings reveal a post-translational level regulation of SPOP expression that facilitates the metastasis of PCa cells. Show less
MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of anaplastic thyroid carcinoma (ATC). miR-199a-5p was previously reported to act as a tumor suppressor Show more
MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of anaplastic thyroid carcinoma (ATC). miR-199a-5p was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in ATC remain unclear. Here, we find that miR-199a-5p is significantly downregulated in ATC tissues compared with adjacent non-cancerous tissues. Overexpression of miR-199a-5p significantly inhibits migration and invasion of ATC cells in vitro, and lung metastasis in vivo. Importantly, miR-199a-5p suppresses epithelial-mesenchymal transition (EMT) both in vitro and in vivo by targeting Snail. Taken together, this study reveals that miR-199a-5p is critical to the EMT progression in ATC cells. Targeting the pathway described here may be a novel approach for inhibiting metastasis of ATC. Show less
Tubulointerstitial fibrosis plays an important role in end-stage renal failure, and there are only limited therapeutic options available to preserve organ function. In the present study, we identified Show more
Tubulointerstitial fibrosis plays an important role in end-stage renal failure, and there are only limited therapeutic options available to preserve organ function. In the present study, we identified that nodakenin, a coumarin isolated from the roots of Angelicae gigas, functions effectively against unilateral ureteral obstruction (UUO)-induced fibrosis via down-regulating Snail1 expression. We established UUO-induced renal fibrosis in mice and then administered with nodakenin orally ata a dose of 1 and 10 mg/kg. The in-vivo results indicated that nodakenin protected obstructive nephropathy through its anti-inflammatory and anti-fibrotic properties. Nodakenin prevented the infiltration of inflammatory cells, alleviated the levels of pro-inflammatory cytokines, reduced the polarization of macrophages and down-regulating the aberrant deposition of extracellular matrix at the site of injury. Of note, nodakenin dramatically impeded Smad3, NF-κB p65 phosphorylation and Snail1 expression. In line with in vivo studies, nodakenin suppressed the expression of Snail1, Smad3 phosphorylation and fibrogenesis in TGF-β1-treated renal epithelial cells in-vitro. Furthermore, we found that the effect of nodaknin against fibrosis was reversed in Snail1 overexpressing cells, whereas nodakenin could not further reduce expression of fibrogenesis in Snail1 silenced cells, suggesting that nodaknein may function through a Snail1-dependent manner. Collectively, this study reveal a critical role of nodakenin in the cure of renal fibrosis. Show less
Benign prostatic hyperplasia (BPH) is arguably the most common disease in aging men. Although the etiology is not well understood, chronic prostatic inflammation is thought to play an important role i Show more
Benign prostatic hyperplasia (BPH) is arguably the most common disease in aging men. Although the etiology is not well understood, chronic prostatic inflammation is thought to play an important role in BPH initiation and progression. Our recent studies suggest that the prostatic epithelial barrier is compromised in glandular BPH tissues. The proinflammatory cytokine transforming growth factor beta 1 (TGF-β1) impacts tight junction formation, enhances epithelial barrier permeability, and suppresses claudin-1 messenger RNA expression in prostatic epithelial cells. However, the role of claudin-1 in the prostatic epithelial barrier and its regulation by TGF-β1 in prostatic epithelial cells are not clear. The expression of claudin-1 was analyzed in 22 clinical BPH specimens by immunohistochemistry. Human benign prostate epithelial cell lines BPH-1 and BHPrE1 were treated with TGF-β1 and transfected with small interfering RNAs specific to claudin-1. Epithelial monolayer permeability changes in the treated cells were measured using trans-epithelial electrical resistance (TEER). The expression of claudin-1, E-cadherin, N-cadherin, snail, slug, and activation of mitogen-activated proteins kinases (MAPKs) and AKT was assessed following TGF-β1 treatment using Western blot analysis. Claudin-1 expression was decreased in glandular BPH tissue compared with adjacent normal prostatic tissue in patient specimens. TGF-β1 treatment or claudin-1 knockdown in prostatic epithelial cell lines increased monolayer permeability. TGF-β1 decreased levels of claudin-1 and increased levels of snail and slug as well as increased phosphorylation of the MAPK extracellular signal-regulated kinase-1/2 (ERK-1/2) in both BPH-1 and BHPrE1 cells. Overexpression of snail or slug had no effect on claudin-1 expression. In contrast, PD98059 and U0126, inhibitors of the upstream activator of ERK-1/2 (ie, MEK-1/2) restored claudin-1 expression level as well as the epithelial barrier. Our findings suggest that downregulation of claudin-1 by TGF-β1 acting through the noncanonical MEK-1/2/ERK-1/2 pathway triggers increased prostatic epithelial monolayer permeability in vitro. These findings also suggest that elevated TGF-β1 may contribute to claudin-1 downregulation and compromised epithelial barrier in clinical BPH specimens. Show less
Mesenchymal stem cell (MSC)-derived exosomes (MSCs-exos) regulate biological functions in different diseases, such as liver fibrosis, diabetes, and ischaemic heart injury. However, the function of MSC Show more
Mesenchymal stem cell (MSC)-derived exosomes (MSCs-exos) regulate biological functions in different diseases, such as liver fibrosis, diabetes, and ischaemic heart injury. However, the function of MSC-derived exosomes on the intestinal barrier and the underlying mechanisms are poorly characterized. The expression of miR-34a/c-5p, miR-29b-3p and Claudin-3 in human normal intestinal tissues and damaged intestinal tissues was evaluated by RT-qPCR. The effect of MSC-secreted exosomes on Claudins in Caco-2 cells was measured by using confocal microscopy, RT-qPCR and Western blot. Dual luciferase reporter assays and RNA immunoprecipitation (RIP) assays were performed to study the interaction between miR-34a/c-5p, miR-29b-3p and Snail. I/R-induced intestinal damage in rats was used to determine the in vivo effect of MSC-exos on intestinal barrier function. In this study, we found that miR-34a/c-5p, miR-29b-3p and Claudin-3 were downregulated in damaged human intestinal tissues. MSC-exos increased the expression of Claudin-3, Claudin-2 and ZO-1 in Caco-2 cells. Further studies demonstrated that MSC-exos promoted Claudin-3, Claudin-2 and ZO-1 expression in Caco-2 cells by Snail, which was targeted by miR-34a/c-5p and miR-29b-3p. In vivo experiments showed that MSC-derived exosomes could improve I/R-induced intestinal damage through the Snail/Claudins signaling pathway. The findings here suggest a novel molecular basis for the therapy of intestinal barrier dysfunction. Show less
Epithelial homeostasis plays an essential role in maintaining endometrial function. But the epithelial role in endometrial fibrosis has been less studied. Previously, we showed that ectopic expression Show more
Epithelial homeostasis plays an essential role in maintaining endometrial function. But the epithelial role in endometrial fibrosis has been less studied. Previously, we showed that ectopic expression of ΔNp63α is associated with fibrosis process and epithelial dysfunction in endometria of patients with intrauterine adhesions (IUAs). Since ΔNp63α is profoundly involved in maintaining the epithelial homeostasis, we hereby focused on its roles in regulating the function and phenotype of endometrial epithelial cells (EECs) in context of endometrial fibrosis. We identified a typical type 2 epithelial-to-mesenchymal transition (EMT) in EECs from IUA patients and this process was induced by the forced expression of ΔNp63α in EECs. In transcriptomic analysis, we found that diverse signaling pathways regulated by ΔNp63α were involved in pro-EMT. We demonstrated that the DUSP4/GSK-3β/SNAI1 pathway was critical in transducing the pro-EMT signals initiated by ΔNp63α, while bFGF reversed ΔNp63α-induced EMT and endometrial fibrosis both in vitro and in vivo by blocking DUSP4/GSK3β/SNAI1 pathway. Taken together, our findings are important to understand the molecular mechanisms of endometrial fibrosis and to provide potential therapeutic targets. Show less
Osteosarcoma (OS) is the most common type of primary bone tumor that exhibits invasive growth and long-distance organ metastasis. Thus, investigating the specifically targeted therapeutic agents again Show more
Osteosarcoma (OS) is the most common type of primary bone tumor that exhibits invasive growth and long-distance organ metastasis. Thus, investigating the specifically targeted therapeutic agents against metastatic osteosarcoma depends on understanding the molecular mechanisms. The long noncoding RNAs (lncRNA) XIST (X-inactive specific transcript) has been reported to have oncogenic roles in various malignant tumors including OS. However, its molecular mechanisms in OS migration and invasion are still under investigation. In the current study, we demonstrate that XIST is significantly upregulated in 30 pairs of OS tissues compared with their matched adjacent nontumor tissues by the quantitative reverse transcription polymerase chain reaction. Overexpression of XIST significantly induced the invasion, migration, and the epithelial-to-mesenchymal transition (EMT) phenotype. The epithelial marker, E-cadherin was effectively suppressed by XIST overexpression. On the other way, the mesenchymal marker, Fibronectin, Snail, and Vimentin were significantly activated by exogenous XIST overexpression. Furthermore, we observed XIST was upregulated by the oxidative stress-induced EMT. Bioinformatical analysis indicated that miR-153 has multiple biding sites for XIST and miR-153 was inversely suppressed by oxidative stress. XIST was verified to directly downregulate miR-153 via sponging. We identified the mesenchymal marker, SNAI1 was a direct messenger RNA target of miR-153. Importantly, inhibiting XIST successfully blocked the H Show less
Cancer metastasis is the primary cause of death in patients diagnosed with colorectal cancer. Piperine, an active nontoxic ingredient in pepper, has potent anti-inflammatory and anti-cancer properties Show more
Cancer metastasis is the primary cause of death in patients diagnosed with colorectal cancer. Piperine, an active nontoxic ingredient in pepper, has potent anti-inflammatory and anti-cancer properties. However, little is known about the anti-migratory and anti-invasive effects of piperine on colorectal cancer. We demonstrated piperine inhibited the migration and invasion of colorectal cancer cells. Then, we found piperine reversed the biomarker expression of epithelial-to-mesenchymal transition (EMT), and suppressed the EMT regulator Snail. Furthermore, signal transducers and activators of transcription 3 (STAT3) was downregulated by piperine. Finally, STAT3 inhibitors were applied to observe the role of STAT3 in colorectal cancer migration, invasion and EMT. Collectively, piperine inhibits colorectal cancer migratory and invasive capacities through STAT3/Snail mediated EMT. Therefore, piperine could be applied as a possible therapeutic regimen for the prevention of colorectal cancer metastasis. Show less
Metastasis is the main cause of cancer-associated deaths, yet this complex process is still not well understood. Many studies have shown that acetate is involved in cancer metastasis, but the molecula Show more
Metastasis is the main cause of cancer-associated deaths, yet this complex process is still not well understood. Many studies have shown that acetate is involved in cancer metastasis, but the molecular mechanisms remain to be elucidated. In the present study, we first measured the effect of acetate on zinc finger transcriptional repressor SNAI1 and acetyl-CoA synthetase 2 (ACSS2) under glucose limitation in renal cell carcinoma cell lines, 786-O and ACHN. Then, RNA interference and overexpression of ACSS2 were used to detect the role of acetate on SNAI1 expression and cell migration. Finally, chromatin immunoprecipitation assay (ChIP) was used to investigate the regulatory mechanism of acetate on SNAI1 expression. The results showed that acetate increased the expressions of SNAI1 and ACSS2 under glucose limitation. ACSS2 knockdown significantly decreased acetate-induced SNAI1 expression and cell migration, whereas overexpression of ACSS2 increased SNAI1 level and histone H3K27 acetylation (H3K27ac). ChIP results revealed that acetate increased H3K27ac levels in regulatory region of SNAI1, but did not increase ACSS2-binding ability. Our study identified a novel inducer, acetate, which can promote SNAI1 expression by ACSS2-mediated histone acetylation in partly. This finding has important implication in treatment of metastatic cancers. Show less
Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to Show more
Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to show metastasis-promoting property in LUAD. However, whether miR-24-3p could regulate LUAD metastasis by targeting KLF8 remains unclear. This study explored the functions and mechanisms of miR-24-3p/KLF8 signaling in advanced LUAD. The expression level of miR-24-3p and KLF8 were tested in LUAD patients, and the corelation of miR-24-3p and KLF8 was evaluated. The interaction of miR-24-3p and KLF8 was demonstrated by luciferase reporter activity assay, Show less
Lysyl oxidase‑like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been i Show more
Lysyl oxidase‑like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial‑mesenchymal transition by reducing E‑cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose‑1, 6‑biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail‑dependent manner. Overexpression of the point‑mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia‑inducible factor 1α (HIF‑1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild‑type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2‑IN‑1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF‑1α and VEGF in HCC cells, but not in FBP1‑knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF‑1α/VEGF signaling pathways via the Snail‑FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease. Show less
Cyclovirobuxine D (CVB‑D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB‑D has positive effects on breast cancer, gastric cancer and other malignant tumo Show more
Cyclovirobuxine D (CVB‑D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB‑D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB‑D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB‑D and further elucidate its molecular mechanism(s). DLD‑1 and LoVo cell lines were selected to evaluate the antitumor effect of CVB‑D. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVB‑D‑treated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVB‑D in vivo. It was identified that CVB‑D inhibited the proliferation, migration, stemness, angiogenesis and epithelial‑mesenchymal transition of CRC cells, and induced apoptosis and S‑phase arrest. In addition, CVB‑D significantly inhibited the growth of xenografts. It is notable that CVB‑D exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVB‑D exerted anticancer effects through the CTHRC1‑AKT/ERK‑Snail signaling pathway. Targeted therapy combining CTHRC1 with CVB‑D may offer a promising novel therapeutic approach for CRC treatment. Show less
Diabetic nephropathy (DN) is one of the severe complications of diabetes. Nowadays, effective treatment for end-stage renal disease (ESRD) patients is still limited. HK-2 cells were stimulated with se Show more
Diabetic nephropathy (DN) is one of the severe complications of diabetes. Nowadays, effective treatment for end-stage renal disease (ESRD) patients is still limited. HK-2 cells were stimulated with serum from phosphate-buffered saline (PBS) or Jiawei Shuilu Erxiandan (JSE)-treated DN mice, then long non-coding RNA (lncRNA) CLYBL-AS2 was discovered by RNA sequence, following the comparison of the serum from normal patients with DN patients to confirm the role of lncCLYBL-AS2. Next, we performed Show less
High-mobility group protein B1 (HMGB1) has important functions in cancer cell proliferation and metastasis. However, the mechanisms of HMGB1 function in non-small-cell lung cancer (NSCLC) remain uncle Show more
High-mobility group protein B1 (HMGB1) has important functions in cancer cell proliferation and metastasis. However, the mechanisms of HMGB1 function in non-small-cell lung cancer (NSCLC) remain unclear. This study aimed to investigate the underlying mechanism of HMGB1-dependent tumor cell proliferation and NSCLC metastasis. Firstly, we found high HMGB1 expression in NSCLC and showed that HMBG1 promoted proliferation, migration, and invasion of NSCLC cells. HMGB1 could bind to SNAI1 promoter and activate the expression of SNAI1. In addition, HMGB1 could transcriptionally regulate the lncRNA RSF1-IT2. RSF1-IT2 was found to function as ceRNA, sponging miR-129-5p, which targets SNAI1. Notably, HMGB1 was also identified as a target of miR-129-5p, which indicates the establishment of a positive feedback loop. Consequently, high expression of RSF1-IT2 and SNAI1 was found to closely correlate with tumor progression in both HMGB1-overexpressing xenograft nude mice and patients with NSCLC. Taken together, our findings provide new insights into molecular mechanisms of HMGB1-dependent tumor metastasis. Components of the HMGB1-RSF1-IT2-miR-129-5p-SNAI1 pathway may have a potential as prognostic and therapeutic targets in NSCLC. Show less
Gliomas are aggressive brain tumors accounting for significant mortality across the globe. Biomarkers for early detection and therapeutic targets for efficient treatment are lacking for glioma. This s Show more
Gliomas are aggressive brain tumors accounting for significant mortality across the globe. Biomarkers for early detection and therapeutic targets for efficient treatment are lacking for glioma. This study was undertaken to investigate the role and therapeutic implications of miR-22 in glioma. U-87 glioma cell line was used in this study. qRT-PCR was employed for expression analysis. MTT assay was used for determination of cell viability. Lipofectamine 2000 was used for transfection. Flow cytometry was used for cell analysis. Wound healing assay and transwell assay were used for monitoring cell migration and invasion. Western blot analysis was used for estimation of protein expression. The miR-22 expression was found decreased in glioma cells. Overexpression of miR-22 resulted in arrest of the U-87 glioma cells at G2/M checkpoint of the cell cycle. The percentage of apoptotic U-87 cells in G2/M phase were 13.05% in negative control (NC) and 29.06% in miR-22 mimics transfected cells. The cell cycle arrest promoted by miR-22 overexpression was also associated with depletion of cyclin B1 expression in U-87 cells. Furthermore, miR-22 could also significantly increase the sensitivity of glioma U-87 cells to cisplatin. The TargetScan analysis and dual luciferase assay showed SNAIL1 to be the target of miR-22. The expression of SNAIL1 was also enhanced in all the glioma cells and miR-22 overexpression could cause suppression of the SNAIL1 expression in U-87 cells. Furthermore, SNAIL1 silencing could also cause decline in the viability of the U-87 cells. The wound healing assay showed that miR-5 overexpression caused decrease in the migration of U-87 cells, while the transwell assay showed decline in the invasion of miR-22 mimics transfected U-87 cells. Taken together, miR-22 may exhibit therapeutic implications in glioma and may prove useful in glioma treatment. Show less
Long noncoding RNA (lncRNA) AC026904.1 has been confirmed to be necessary for breast cancer metastasis. This work aims to investigate the effects of lncRNA AC026904.1 on lung cancer metastasis. We fou Show more
Long noncoding RNA (lncRNA) AC026904.1 has been confirmed to be necessary for breast cancer metastasis. This work aims to investigate the effects of lncRNA AC026904.1 on lung cancer metastasis. We found that lncRNA AC026904.1 displayed a higher level in metastatic lung cancer tissues than adjacent tissues and nonmetastatic lung cancer tissues, and lung cancer cells treated with TGF-β. The expression of AC026904.1 was increased by the non-canonical TGF-β signaling. Additionally, AC026904.1 acts as an enhancer of the key metastatic factor Slug in the nucleus. This AC026904.1/Slug axis is necessary for TGF-β-mediated migration and epithelial-mesenchymal transition in lung cancer cells. This work firstly uncovers that AC026904.1 increases Slug expression at transcriptional level and subsequently plays critical effects in lung cancer metastasis, providing novel evidences that AC026904.1 holds great potential to be used as a marker for metastatic lung cancer. Show less
The aim of this study was to investigate the expression of Snail, galectin-3, and IGF1R in benign and malignant pheochromocytoma and paraganglioma (PPGL) and explore their role in the diagnosis of mal Show more
The aim of this study was to investigate the expression of Snail, galectin-3, and IGF1R in benign and malignant pheochromocytoma and paraganglioma (PPGL) and explore their role in the diagnosis of malignant PPGL. We retrospectively collected and analyzed surgical tumor tissue from 226 patients initially diagnosed with PPGL who underwent surgery from Jan. 2009 to Jan. 2016 at West China Hospital, Sichuan University. We observed and quantified the expression of Snail, galectin-3, and IGF1R in paraffin-embedded samples by immunohistochemical staining. The significant difference in survival time among the three groups (benign PHEO, benign PGL, and potentially malignant PPGL) was compared by Kaplan-Meier survival analysis. The positive staining of Snail, galectin-3, and IGF1R in the benign PHEO group was significantly lower than that in the other three groups ( The intense expression of Snail, galectin-3, and IGF1R may be valuable indicators for the diagnosis of malignant PPGL. Show less
Endothelial-mesenchymal transition (EnMT) plays a pivotal role in various diseases, including pulmonary hypertension (PH), and transcription factors like Snail are key regulators of EnMT. In this stud Show more
Endothelial-mesenchymal transition (EnMT) plays a pivotal role in various diseases, including pulmonary hypertension (PH), and transcription factors like Snail are key regulators of EnMT. In this study we investigated how these factors were regulated by PH risk factors (e.g. inflammation and hypoxia) in human umbilical vein endothelial cells (HUVECs). We showed that treatment with interleukin 1β (IL-1β) induced EnMT of HUVECs via activation of NF-κB/Snail pathway, which was further exacerbated by knockdown of protein tyrosine phosphatase L1 (PTPL1). We demonstrated that PTPL1 inhibited NF-κB/Snail through dephosphorylating and stabilizing IκBα. IL-1β or hypoxia could downregulate PTPL1 expression in HUVECs. The deregulation of PTPL1/NF-κB signaling was validated in a monocrotaline-induced rat PH (MCT-PH) model and clinical PH specimens. Our findings provide novel insights into the regulatory mechanisms of EnMT, and have implications for identifying new therapeutic targets for clinical PH. Show less
Breast cancer stem cells (BCSCs) are typically seed cells of breast tumor that initiate and maintain tumor growth. MiR-7, as a cancer inhibitor, decreases the BCSC subset and inhibits tumor progressio Show more
Breast cancer stem cells (BCSCs) are typically seed cells of breast tumor that initiate and maintain tumor growth. MiR-7, as a cancer inhibitor, decreases the BCSC subset and inhibits tumor progression through mechanisms that remain unknown. We examined miR-7 expression in breast cancer and developed a BCSC-driven xenograft mouse model, to evaluate the effects of miR-7 overexpression on the decrease of the BCSC subset in vitro and in vivo. In addition, we determined how miR-7 decreased the BCSC subset by using the ALDEFLUOR, lentivirus infection, dual-luciferase reporter, and chromatin immunoprecipitation-PCR assays. MiR-7 was expressed at low levels in breast cancer tissues compared with normal tissues, and overexpression of miR-7 directly inhibited lncRNA XIST, which mediates the transcriptional silencing of genes on the X chromosome, and reduced epithelium-specific antigen (ESA) expression by increasing miR-92b and inhibiting slug. Moreover, miR-7 suppressed CD44 and ESA by directly inhibiting the NF-ÎşB subunit RELA and slug in breast cancer cell lines and in BCSC-driven xenografts, which confirmed the antitumor activity in mice injected with miR-7 agomir or stably infected with lenti-miR-7. The findings from this study uncover the molecular mechanisms by which miR-7 inhibits XIST, modulates the miR-92b/Slug/ESA axis, and decreases the RELA and CD44 expression, resulting in a reduced BCSC subset and breast cancer growth inhibition. These findings suggest a potentially targeted treatment approach to breast cancer. Show less