Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying Show more
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy. Show less
Long non-coding RNAs (lncRNAs) modulate a variety of cancerous biological processes, including the promotion of tumorigenicity in tumor parenchymal cells. However, there is a lack of studies assessing Show more
Long non-coding RNAs (lncRNAs) modulate a variety of cancerous biological processes, including the promotion of tumorigenicity in tumor parenchymal cells. However, there is a lack of studies assessing the regulation of lncRNAs in cancer-associated fibroblasts. In the present study, a novel lncRNA, TIRY, was found to act as a miRNA sponge and to downregulate miR-14 expression in oral squamous cell carcinoma (OSCC). Fluorescence This study demonstrated the novel lncRNA, TIRY, enhances epithelial-to-mesenchymal transition in cancer-associated fibroblasts and promotes the metastasis of tumor via miR-14 sponging in oral squamous cell carcinoma, and thus provide a novel molecular mechanism underlying the role of TIRY in CAFs in tumor biology and a potential target in OSCC. Further, the data showed that TIRY expression was negatively correlated with miR-14 transcription levels and was associated with poor prognosis in OSCC specimens. Therefore, TIRY may be a potential prognostic biomarker of overall survival and progression-free survival in OSCC. Moreover, TIRY adds to the understanding of regulatory mechanisms involved in CAFs and epithelial cancer cells in OSCC and may provide novel insights for further understanding tumor biology. Show less
Ovarian cancer is a highly invasive type of cancer. A previous study demonstrated that E-cadherin expression was upregulated in a human ovarian cancer cell line with a high expression of WW domain-con Show more
Ovarian cancer is a highly invasive type of cancer. A previous study demonstrated that E-cadherin expression was upregulated in a human ovarian cancer cell line with a high expression of WW domain-containing oxidoreductase (WWOX), which is a tumor suppressor. Also, the migration and invasion ability of these cells was reduced. Snail family members are involved in the epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells, and the expression of Snail family members is regulated by the transcription factor Elf5. The aim of the present research was to elucidate the role of WWOX in EMT of ovarian carcinoma cells through the Elf5/Snail pathway by gain and loss of function approaches in in vitro experiments. First, a WWOX gene expressing plasmid was transfected into CD133+CD117+ HO8910 ovarian carcinoma cells, and an Elf5 shRNA plasmid was transfected into these cells to assess the changes in EMT-related factors, including Snail1, and the invasive ability of tumor cells ability. Second, the human ovarian carcinoma cell lines HO8910 and SKOV3 were divided into six groups to detect the same indicators. The results demonstrated that the high expression of WWOX resulted in an increased E-cadherin expression, decreased Snail1 activity, and decreased invasion ability in CD133+CD117+ HO8910 cells. Elf5 shRNA transfection did not affect the WWOX expression; however, it decreased the expression of E-cadherin and Elf5 activity, while increasing Snail1 activity and invasion ability in CD133+CD117+ HO8910 cells. It was also observed that WWOX overexpression in HO8910 and SKOV3 cells inhibited the expression of EMT-related proteins and inhibited cell migration and invasion. Taken together, the results of the present report suggest that WWOX can decrease Snail1 activity by enhancing the activity of Elf5, thus upregulating E-cadherin expression and eventually inhibiting EMT of ovarian carcinoma. Show less
Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. Utilizing b Show more
Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-β1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-β1/Smads signaling and Snail expression in DHA-treated cells, in TGFβ1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFβ1/TGFβ1 inhibitor SD-208. Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-β1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFβ1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-β1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-β1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-β1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-β1 pathway inhibitor. Show less
Fusobacterium nucleatum, an anaerobic oral opportunistic pathogen associated with periodontitis, has been considered to be associated with the development of oral squamous cell carcinoma (OSCC). Howev Show more
Fusobacterium nucleatum, an anaerobic oral opportunistic pathogen associated with periodontitis, has been considered to be associated with the development of oral squamous cell carcinoma (OSCC). However, the initial host molecular alterations induced by F. nucleatum infection which may promote predisposition to malignant transformation through epithelial-mesenchymal transition (EMT) have not yet been clarified. In the present study, we monitored the ability of F. nucleatum to induce EMT-associated features, and our results showed that F. nucleatum infection promoted cell migration in either noncancerous human immortalized oral epithelial cells (HIOECs) or the two OSCC cell lines SCC-9 and HSC-4, but did not accelerate cell proliferation or cell cycle progression. Mesenchymal markers, including N-cadherin, Vimentin, and SNAI1, were upregulated, while E-cadherin was decreased and was observed to translocate to the cytoplasm. Furthermore, FadA adhesin and heat-inactivated F. nucleatum were found to cause a similar effect as the viable bacterial cells. The upregulated lncRNA MIR4435-2HG identified by the high-throughput sequencing was demonstrated to negatively regulate the expression of miR-296-5p, which was downregulated in F. nucleatum-infected HIOECs and SCC-9 cells. The binding of MIR4435-2HG and miR-296-5p was validated via a dual-luciferase reporter assay. Additionally, knockdown of MIR4435-2HG with siRNA leads to a decrease in SNAI1 expression, while miR-296-5p could further negatively and indirectly regulate SNAI1 expression via Akt2. Therefore, our study demonstrated that F. nucleatum infection could trigger EMT via lncRNA MIR4435-2HG/miR-296-5p/Akt2/SNAI1 signaling pathway, and EMT process may be a probable link between F. nucleatum infection and initiation of oral epithelial carcinomas. Show less
Tumor spread through air spaces (STAS) is a novel pathologic characteristic in lung adenocarcinomas that indicates invasive tumor behavior. We aimed to explore the relationship between Twist, Slug and Show more
Tumor spread through air spaces (STAS) is a novel pathologic characteristic in lung adenocarcinomas that indicates invasive tumor behavior. We aimed to explore the relationship between Twist, Slug and STAS in lung adenocarcinoma and to investigate the potential relationship between epithelial-mesenchymal transition (EMT) and STAS. Our study retrospectively analyzed 115 patients with resected lung adenocarcinomas to evaluate the relationship between Twist, Slug and STAS. STAS was diagnosed using hematoxylin-eosin (H&E) staining. Immunohistochemistry was used to evaluate the expression levels of Slug and Twist. In this study, 56 (48.7%) patients had STAS, 40 (34.8%) patients had Slug overexpression, and 28 (24.3%) patients had Twist overexpression. Patients with either STAS or Slug and Twist overexpression experienced poor recurrence-free survival (RFS) and overall survival (OS). There were significant associations between Twist overexpression, Slug overexpression and the presence of STAS. The logistic model further revealed that pathological stage, Twist overexpression and Slug overexpression were independent risk factors for STAS. A multivariate analysis that contained Twist, Slug, pathologic stage and STAS, showed that pathologic stage and STAS were independent prognostic factors for poor RFS and OS. Another multivariate model that contained Twist, Slug and pathologic stage, showed that pathologic stage, Twist overexpression and Slug overexpression were independent risk factors for poor RFS and OS. In the cohort with STAS, the multivariate analysis showed that pathologic stage and Twist overexpression were independent risk factors for poor survival. The subgroup analysis showed that patients with both Slug overexpression and Twist overexpression with STAS received a poor prognosis. STAS, Slug and Twist were correlated with poor RFS and OS in resected lung adenocarcinomas. Additionally, STAS was correlated with the overexpression of Twist and Slug, which could potentially provide information on the mechanism of STAS. Show less
Existing evidence has shown that circulating Epstein-Barr virus (EBV)-miR-BART13-3p is highly expressed in plasma of nasopharyngeal carcinoma (NPC) patients, especially among patients with advanced di Show more
Existing evidence has shown that circulating Epstein-Barr virus (EBV)-miR-BART13-3p is highly expressed in plasma of nasopharyngeal carcinoma (NPC) patients, especially among patients with advanced diseases. However, the exact role that EBV-miR-BART13-3p plays in the development of NPC remains poorly understood. Here we show that up-regulated expression of EBV-miR-BART13-3p leads to increased capacity in migration and invasion of NPC cells Show less
Recent evidence indicates that metformin inhibits mammalian cancer growth and metastasis through the regulation of microRNAs. Metformin regulates miR-381 stability, which plays a vital role in tumor p Show more
Recent evidence indicates that metformin inhibits mammalian cancer growth and metastasis through the regulation of microRNAs. Metformin regulates miR-381 stability, which plays a vital role in tumor progression. Moreover, increased YAP expression and activity induce non-small cell lung cancer (NSCLC) tumor growth and metastasis. However, the molecular mechanism underpinning how metformin-induced upregulation of miR-381 directly targets YAP or its interactions with the epithelial-mesenchymal transition (EMT) marker protein Snail in NSCLC is still unknown. Levels of RNA and protein were analyzed using qPCR, western blotting and immunofluorescence staining. Cellular proliferation was detected using a CCK8 assay. Cell migration and invasion were analyzed using wound healing and transwell assays. Promoter activity and transcription were investigated using the luciferase reporter assay. Chromatin immunoprecipitation was used to detect the binding of YAP to the promoter of Snail. The interaction between miR-381 and the 3'UTR of YAP mRNA was analyzed using the MS2 expression system and co-immunoprecipitation with biotin. We observed that miR-381 expression is negatively correlated with YAP expression and plays an opposite role to YAP in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. The miR-381 function as a tumor suppressor was significantly downregulated in lung cancer tissue specimens and cell lines, which decreased the expression of its direct target YAP. In addition, metformin decreased cell growth, migration, invasion, and EMT via up-regulation of miR-381. Moreover, YAP, which functions as a co-transcription factor, enhanced NSCLC progression and metastasis by upregulation of Snail. Snail knockdown downregulated the mesenchymal marker vimentin and upregulated the epithelial marker E-cadherin in lung cancer cells. Furthermore, miR-381, YAP, and Snail constitute the miR-381-YAP-Snail signal axis, which is repressed by metformin, and enhances cancer cell invasiveness by directly regulating EMT. Metformin-induced repression of miR-381-YAP-Snail axis activity disrupts NSCLC growth and metastasis. Thus, we believe that the miR-381-YAP-Snail signal axis may be a suitable diagnostic marker and a potential therapeutic target for lung cancer. Show less
MicroRNA-27b (miR-27b) has been shown to play a role in the progression of many different forms of cancer, but its specific relevance in the context of non-small cell lung cancer (NSCLC) remains uncer Show more
MicroRNA-27b (miR-27b) has been shown to play a role in the progression of many different forms of cancer, but its specific relevance in the context of non-small cell lung cancer (NSCLC) remains uncertain. As such, this study sought to explore the role of miR-27b in NSCLC and the mechanisms whereby it functions. We quantified miR-27b and target gene expression via quantitative real-time PCR (RT-qPCR).We then used functional including proliferation assays, migration assay, flow cytometry, and western blotting to explore the mechanisms whereby miR-27b functions in vitro and in vivo. We additionally confirmed miR-27b target genes via luciferase reporter assay. We observed a marked decrease in miR-27b expression in NSCLC patient samples relative to paracancerous control tissues. We further found that altering miR-27b expression levels in vitro affected NSCLC tumor cell migration, proliferation, and ability to undergo epithelial-mesenchymal transition. Through the use of target prediction algorithms we identified Snail to be a miR-27b target protein that was suppressed when this miRNA was highlight expressed. Lastly, we found miR-27b expression to increase NSCLC cell sensitivity to cisplatin through its ability to target Snail. Our results clearly demonstrate that miR-27b can suppress NSCLC tumor development and progression, highlighting this miR-27b/Snail1 axis as putative target for the therapeutic treatment of NSCLC. Show less
Arginine deprivation is currently being evaluated for its efficacy and safety in clinical trials aimed at combating tumors. However, the cellular signaling and molecular changes in response to such de Show more
Arginine deprivation is currently being evaluated for its efficacy and safety in clinical trials aimed at combating tumors. However, the cellular signaling and molecular changes in response to such deprivation have not been systematically deciphered. Here, we evaluate the effect of arginine deprivation on human pancreatic cancer cells, with respect to their migratory and invasive potentials and their ability to undergo epithelial-mesenchymal transition (EMT). The transcription factors Snail, Slug, and Twist are regulators of EMT, as indicated by the suppression of E-cadherin and other epithelial markers and adhesion molecules. Our data indicated that arginine starvation inhibited the migration and impaired the adhesion and invasion of the pancreatic cancer cells, decreased Snail, Slug, and Twist expression, and increased E-cadherin expression without altering the expression of vimentin. It is well known that matrix metalloproteinases (MMPs) are important for the events that underlie tumor dissemination. Arginine starvation inhibited the expression of MMP-1 and MMP-9. Furthermore, the PI3K/Akt pathway was altered when the pancreatic cancer cells underwent arginine deprivation as exhibited by the decreased Akt phosphorylation. Thus, these data reveal that arginine deprivation has the potential to decrease the metastatic ability of pancreatic cancer cells. Show less
To investigate the effect of propofol on the migration and invasion of oral squamous cell carcinoma (OSCC) cells and explore the underlying mechanism. Cal-27 and SCC-25 cells treated with or without p Show more
To investigate the effect of propofol on the migration and invasion of oral squamous cell carcinoma (OSCC) cells and explore the underlying mechanism. Cal-27 and SCC-25 cells treated with or without propofol, then the cells metastasis were determined. The levels of SNAI1 mRNA and protein were detected by real-time PCR and western blot. Cell migration ability was evaluated by wound healing assay, and the invasion of cells was measured using transwell assay. Propofol treatment significantly promoted cell migration and invasion of OSCC. Further mechanistic studies of the stimulating effects of propofol on OSCC cell metastasis revealed that propofol treatment dose-dependently upregulated the expression of SNAI1, a member of the Snail superfamily of zinc-finger transcription factors. Additionally, the inhibition of endogenous SNAI1 expression reversed the effect of propofol on cell migration and invasion in Cal-27 and SCC-25 cells. Our results demonstrate that propofol at clinically relevant concentrations facilitates cell migration and invasion through up-regulation of SNAI1 in OSCC cells, and suggest propofol may not be suitable for anesthesia management in OSCC patients. Show less
Although accumulating evidence has indicated the intimate association between epithelial-mesenchymal transition (EMT) and acquired resistance to chemotherapy for colorectal cancer (CRC), the underlyin Show more
Although accumulating evidence has indicated the intimate association between epithelial-mesenchymal transition (EMT) and acquired resistance to chemotherapy for colorectal cancer (CRC), the underlying mechanisms remain elusive. Herein, we reported that Snail, a crucial EMT controller, was upregulated in CRC tissues. Colorectal cancer cells overexpressing Snail were found to be more resistant to 5-fluorouracil (5-Fu). Mechanistic studies reveal that Snail could increase the expression of ATP-binding cassette subfamily B member 1 (ABCB1) rather than the other 23 chemoresistance-related genes. Additionally, knockdown of ABCB1 significantly attenuated Snail-induced 5-Fu resistance in CRC cells. Oxaliplatin increased Snail and ABCB1 expression in CRC cells. Snail and ABCB1 were upregulated in 5-Fu-resistant HCT-8 (HCT-8/5-Fu) cells and inhibition of Snail decreased ABCB1 in HCT-8/5-Fu cells. These results confirm the vital role played by ABCB1 in Snail-induced chemoresistance. Further investigation into the relevant molecular mechanism revealed Snail-mediated ABCB1 upregulation was independent of β-catenin, STAT3, PXR, CAR and Foxo3a, which are commonly involved in modulating ABCB1 transcription. Instead, Snail upregulated ABCB1 transcription by directly binding to its promoter. Clinical analysis confirms that increased Snail expression correlated significantly with tumor size (P = .018), lymph node metastasis (P = .033), distant metastasis (P = .025), clinical stage grade (P = .024), and poor prognosis (P = .045) of CRC patients. Moreover, coexpression of Snail and ABCB1 was observed in CRC patients. Our study revealed that direct regulation of ABCB1 by Snail was critical for conferring chemoresistance in CRC cells. These findings unraveled the mechanisms underlying the association between EMT and chemoresistance, and provided potential targets for CRC clinical treatment. Show less
Breast cancer is one of the most common types of cancer in women. Although the mortality rate of breast cancer has fallen over the past 10 years, effective treatments that reduce the occurrence of bre Show more
Breast cancer is one of the most common types of cancer in women. Although the mortality rate of breast cancer has fallen over the past 10 years, effective treatments that reduce the occurrence of breast cancer metastasis remain lacking. In this study, we explored the role of receptor for hyaluronan mediated motility (RHAMM) and the associated signaling pathway in cell migration in luminal A breast cancer. We first examined RHAMM expression levels using human breast tissue microarray and patient breast tissues. We then studied the role of RHAMM in migration in luminal A breast cancer using loss-of-function and gain-of-function strategies in in vitro models and confirmed these findings in an in vivo model. Finally, we investigated signaling molecules that play a role in cell migration using western blot. Our results demonstrated the following: (a) RHAMM shows high expression levels in malignant breast tissue, (b) RHAMM shows low expression levels in luminal A breast cancer compared to other subtypes of breast cancer, (c) RHAMM inhibits cell migration in luminal A breast cancer, and (d) RHAMM inhibits cell migration via the AKT/GSK3β/Snail axis in luminal A breast cancer. This study demonstrates a novel role of RHAMM in cell migration in luminal A breast cancer and suggests that therapeutic strategies involving RHAMM should be considered for various subtypes of breast cancer. Show less
The opacity of the lens capsule after cataract surgery is caused by epithelial‑to‑mesenchymal transition (EMT) of lens epithelial cells. Snail family transcriptional repressor 1 (SNAI1) is a transcrip Show more
The opacity of the lens capsule after cataract surgery is caused by epithelial‑to‑mesenchymal transition (EMT) of lens epithelial cells. Snail family transcriptional repressor 1 (SNAI1) is a transcriptional repressor that recruits multiple chromatin enzymes including lysine‑specific histone demethylase 1A, histone deacetylase (HDAC) 1/2, polycomb repressive complex 2, euchromatic histone lysine methyltransferase 2 and suppressor of variegation 3‑9 homolog 1 to the E‑cadherin promoter, thereby suppressing E‑cadherin expression. However, the functional relationship between SNAI1 and HDAC in the induction of EMT in human lens epithelial cells (HLECs) is still unclear. Therefore, the objective of the present study was to explore the possible functional relationship between SNAI1 and HDAC1 in the induction of EMT in HLECs. In the present study, SNAI1 was found to be increased in HLECs during transforming growth factor‑β2 (TGF‑β2)‑induced EMT. Knockdown of SNAI1 by siRNA reversed TGF‑β2‑induced downregulation of E‑cadherin and upregulation of α‑Smooth Muscle Actin. Furthermore, SNAI1 was found to be associated with HDAC1 in the E‑cadherin promoter in TGF‑β2‑treated HLECs. Inhibition of HDAC by trichostatin A and suberoylanilide hydroxamic acid could prevent TGF‑β2‑induced EMT in HLECs. Collectively, SNAI1 interacted with HDAC1 to repress E‑cadherin in the TGF‑β2‑induced EMT in HLECs, suggesting that HDAC inhibitors may have potential therapeutic value for the prevention of EMT in HLECs. Show less
Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression. However, how cancer cells integrate lipid metabolic signaling with cance Show more
Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression. However, how cancer cells integrate lipid metabolic signaling with cancer progression is not well understood. In the present study, we demonstrated that C/EBPδ, a critical lipid metabolic regulator, is a TGF-β1 downstream gene and promotes lung adenocarcinoma metastasis. Importantly, C/EBPδ caused significant oscillations in both lipid metabolic and epithelial to mesenchymal transition (EMT) gene networks. Mechanistically, we demonstrated that C/EBPδ recruited oncogene NCOA3 to transcriptionally activate Slug, a canonical EMT transcription factor, which in turn induced oxLDL receptor-1 (Lox1) expression and enhanced oxLDL uptake to promote cancer metastasis, which could be blocked with LOX1 neutralizing antibody. In summary, our results unveiled a previously unappreciated interplay between lipid metabolic and metastatic program, as well as the existence of a pivotal C/EBPδ-Slug-Lox1 transcription axis to promote oxLDL levels and cancer metastasis. Show less
Increasing evidence shows that long non-coding RNAs (lncRNAs) are closely associated with the development of cancers, including triple-negative breast cancer (TNBC). LncRNA FAM201A has been identified Show more
Increasing evidence shows that long non-coding RNAs (lncRNAs) are closely associated with the development of cancers, including triple-negative breast cancer (TNBC). LncRNA FAM201A has been identified as a key regulator in some cancers. However, its role has not been explored in TNBC. In this work, we investigated the biological role and regulatory mechanism of FAM201A in TNBC. The expression pattern of FAM201A was determined by RT-qPCR analysis. The biological effect of FAM201A on cellular process of TNBC was tested using colony formation, EdU, caspase-3 activity detection, flow cytometry, wound healing, and Transwell assays. ChIP and luciferase reporter assays were performed to verify the interaction between transcription factor 3 (TCF3) and FAM201A. The interaction among FAM201A, microRNA-186-5p (miR-186-5p), and tankyrase 1 binding protein 1 (TNKS1BP1) was evaluated by luciferase reporter and RIP assays. The results showed that FAM201A expression was significantly upregulated in TNBC tissues and cells. Functionally, FAM201A knockdown inhibited TNBC cell proliferation, migration and invasion, and accelerated cell apoptosis. In mechanism, it was confirmed that FAM201A was transcriptionally activated by TCF3 and served as a sponge for miR-186-5p to upregulate TNKS1BP1 expression in TNBC cells. Collectively, our study revealed that TCF3-activated FAM201A promoted aggressive phenotypes of TNBC cells by upregulating TNKS1BP1 expression. Show less
Genetic mutations associated with early-onset Parkinson's disease (EOPD) vary widely among different ethnicities. We detected the genes associated with EOPD in a Chinese cohort using next-generation s Show more
Genetic mutations associated with early-onset Parkinson's disease (EOPD) vary widely among different ethnicities. We detected the genes associated with EOPD in a Chinese cohort using next-generation sequencing (NGS) combined with multiplex ligation-dependent probe amplification (MLPA) and analyzed the phenotypic characteristics of the mutation carriers. Cohort of 23 sporadic EOPD patients (onset age ≤ 45 years) were recruited. Genetic causes were identified by a targeted NGS panel containing 136 known extrapyramidal disease-causative genes. Multiplications or deletions of PD-causing genes were detected using the MLPA method. Demographic and clinical data were obtained, analyzed, and compared between patients with and those without Parkin gene variants. We identified 14 pathogenic or likely pathogenic variants (12 in Parkin, 1 in LRRK2, and 1 in VPS13C) in 10 patients (43.5%) and 8 rare variants of uncertain significance in 9 patients (39.1%). Parkin (34.8%) was the most common causative gene among our patients cohort, and exon deletion (62.5%) was the main type of variant. Patients with Parkin mutations had a younger age of onset, longer delay in diagnosis, slower disease progression, higher frequency of hyperreflexia, fatigue, and less hyposmia compared to patients without Parkin mutations. Our results revealed a higher prevalence of Parkin mutations in Chinese sporadic EOPD patients, and notably, exon deletion was the most common type of mutation. EOPD patients with Parkin mutations showed unique clinical characteristics. Show less
Homozygous and compound heterozygous mutations in the vacuolar protein sorting 13C (VPS13C) gene can cause autosomal recessive parkinsonism via mitochondrial pathway. The present study aimed to screen Show more
Homozygous and compound heterozygous mutations in the vacuolar protein sorting 13C (VPS13C) gene can cause autosomal recessive parkinsonism via mitochondrial pathway. The present study aimed to screen the mutations of VPS13C in a cohort of Chinese patients with early-onset Parkinson's disease (EOPD) and further explore its pathogenicity via burden analysis. A total of 669 patients with EOPD were sequenced with whole-exome sequencing and analyzed homozygous or compound heterozygous mutations in VPS13C. Moreover, rare variants with minor allele frequency <0.1% were included in the burden analysis. In total, 7 (1.05%) patients with EOPD carried compound heterozygous mutations in VPS13C, including 3 patients with novel compound heterozygous missense mutations and 4 patients with at least 1 nonsense or splicing-site mutations. Furthermore, burden analysis indicated that patients with EOPD had an enrichment of rare variants in VPS13C. In conclusion, our findings of compound missense mutations expanded the mutation spectrum of VPS13C in EOPD. Burden analysis further elucidated the importance of VPS13C in the pathogenesis of PD. Show less
F Zhang, J Zeng, W W Li+5 more · 2020 · Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases · added 2026-04-24
WW domain containing E3 Ub-protein ligase 2 (WWP2) plays an important role in tumor progression as an E3 ligase of PTEN. Here, we investigated the role of WWP2 in gastric cancer (GC). We found that WW Show more
WW domain containing E3 Ub-protein ligase 2 (WWP2) plays an important role in tumor progression as an E3 ligase of PTEN. Here, we investigated the role of WWP2 in gastric cancer (GC). We found that WWP2 is overexpressed in GC tissues, which is closely related to poor prognosis of GC patients. Using a WWP2-shRNA lentivirus expressing system, we established WWP2 stable-knockdown GC cell lines and found that knockdown of WWP2 inhibits the proliferation of GC cells both in vitro and in vivo. Also, WWP2 silencing induced the up-regulation of PTEN protein level and down-regulation of AKT phosphorylation level. We further investigated the role of PTEN in this regulating process by performing rescue assay and found that PTEN is essential for WWP2-mediated regulation of GC cells proliferation. Taken together, our results demonstrated that WWP2 promotes proliferation of GC cells by downregulating PTEN, which may provide new therapeutic targets for GC. Show less
Rho GTPase-activating proteins (RhoGAPs) have been reported to be of great importance in the initiation and development of many different cancers. However, their biological roles and regulatory mechan Show more
Rho GTPase-activating proteins (RhoGAPs) have been reported to be of great importance in the initiation and development of many different cancers. However, their biological roles and regulatory mechanisms in lung cancer development and progression are poorly defined. Real-time PCR or western blotting analysis was used to detect Rho GTPase-activating protein 24 (ARHGAP24), WWP2, p27, p-STAT6 and STAT6 expression levels as well as the activity of RhoA and Rac1 in lung cancer. Cell proliferation, apoptosis and cell cycle were measured by CCK-8 and flow cytometry analysis. Tumor growth of lung cancer cells was measured using a nude mouse xenograft experiment model in vivo. The correlation between WWP2 and p27 was measured by co-immunoprecipitation and ubiquitination analysis. We found that ARHGAP24 expression was lower in lung cancer tissues collected from the The Cancer Genome Atlas and independent hospital database. Overexpression of ARHGAP24 significantly suppressed cell proliferation and the activity of RhoA and Rac1, induced cell apoptosis and arrested cell cycle at the G0-G1 phase. ARHGAP24 overexpression also inhibited tumor growth in nude mice, whereas knockdown of ARHGAP24 significantly promoted cell proliferation and WWP2 expression and inhibited cell cycle arrest at G1 phase through activating STAT6 signaling. ARHGAP24 overexpression inhibited WWP2 overexpression-induced cell proliferation, cell cycle progression and the decreased p27 expression. Moreover, WWP2 was found interacted with p27, and WWP2 overexpression promoted the ubiquitination of p27. In conclusion, our findings suggest that ARHGAP24 inhibits cell proliferation and cell cycle progression and induces cell apoptosis of lung cancer via a STAT6-WWP2-p27 axis. Show less
The knowledge about the effects of environmental temperature on human epigenome is a potential key to understand the health impacts of temperature and to guide acclimation under climate change. We per Show more
The knowledge about the effects of environmental temperature on human epigenome is a potential key to understand the health impacts of temperature and to guide acclimation under climate change. We performed a systematic review on the epidemiological studies that have evaluated the association between environmental temperature and human epigenetic modifications. We identified seven original articles on this topic published between 2009 and 2019, including six cohort studies and one cross-sectional study. They focused on DNA methylation in elderly people (blood sample) or infants (placenta sample), with sample size ranging from 306 to 1798. These studies were conducted in relatively low temperature setting (median/mean temperature: 0.8-13 °C), and linear models were used to evaluate temperature-DNA methylation association over short period (≤28 days). It has been reported that short-term ambient temperature could affect global human DNA methylation. A total of 15 candidate genes (ICAM-1, CRAT, F3, TLR-2, iNOS, ZKSCAN4, ZNF227, ZNF595, ZNF597, ZNF668, CACNA1H, AIRE, MYEOV2, NKX1-2 and CCDC15) with methylation status associated with ambient temperature have been identified. DNA methylation on ZKSCAN4, ICAM-1 partly mediated the effect of short-term cold temperature on high blood pressure and ICAM-1 protein (related to cardiovascular events), respectively. In summary, epidemiological evidence about the impacts of environment temperature on human epigenetics remains scarce and limited to short-term linear effect of cold temperature on DNA methylation in elderly people and infants. More studies are needed to broaden our understanding of temperature related epigenetic changes, especially under a changing climate. Show less
Type 2 diabetes mellitus (T2DM) is a metabolic disorder which accounts for high morbidity and mortality due to complications like renal failure, amputations, cardiovascular disease, and cerebrovascula Show more
Type 2 diabetes mellitus (T2DM) is a metabolic disorder which accounts for high morbidity and mortality due to complications like renal failure, amputations, cardiovascular disease, and cerebrovascular events. We collected medical reports, lifestyle details, and blood samples of individuals and used the polymerase chain reaction-ligase detection reaction method to genotype the SNPs, and a visit was conducted in August 2016 to obtain the incidence of Type 2 diabetes in the 2113 eligible people. To explore which genes and environmental factors are associated with type 2 diabetes mellitus in a Chinese Han population, we used elastic net to build a model, which is to explain which variables are strongly associated with T2DM, rather than predict the occurrence of T2DM. The genotype of the additive of rs964184, together with the history of hypertension, regular intake of meat and waist circumference, increased the risk of T2DM (adjusted OR = 2.38, p = 0.042; adjusted OR = 3.31, p < 0.001; adjusted OR = 1.05, p < 0.001). The TT genotype of the additive and recessive models of rs12654264, the CC genotype of the additive and dominant models of rs2065412, the TT genotype of the additive and dominant models of rs4149336, together with the degree of education, regular exercise, reduced the risk of T2DM (adjusted OR = 0.46, p = 0.017; adjusted OR = 0.53, p = 0.021; adjusted OR = 0.59, p = 0.021; adjusted OR = 0.57, p = 0.01; adjusted OR = 0.59, p = 0.021; adjusted OR = 0.57, p = 0.01; adjusted OR = 0.50, p = 0.007; adjusted OR = 0.80, p = 0.032) . Eventually we identified a set of SNPs and environmental factors: rs5805 in the SLC12A3, rs12654264 in the HMGCR, rs2065412 and rs414936 in the ABCA1, rs96418 in the ZPR1 gene, waistline, degree of education, exercise frequency, hypertension, and the intake of meat. Although there was no interaction between these variables, people with two risk factors had a higher risk of T2DM than those only having one factor. These results provide the theoretical basis for gene and other risk factors screening to prevent T2DM. Show less
Ubiquitin chain specificity has been described for some deubiquitinases (DUBs) but lacks a comprehensive profiling in vivo. We used quantitative proteomics to compare the seven lysine-linked ubiquitin Show more
Ubiquitin chain specificity has been described for some deubiquitinases (DUBs) but lacks a comprehensive profiling in vivo. We used quantitative proteomics to compare the seven lysine-linked ubiquitin chains between wild-type yeast and its 20 DUB-deletion strains, which may reflect the linkage specificity of DUBs in vivo. Utilizing the specificity and ubiquitination heterogeneity, we developed a method termed DUB-mediated identification of linkage-specific ubiquitinated substrates (DILUS) to screen the ubiquitinated lysine residues on substrates modified with certain chains and regulated by specific DUB. Then we were able to identify 166 Ubp2-regulating substrates with 244 sites potentially modified with K63-linked chains. Among these substrates, we further demonstrated that cyclophilin A (Cpr1) modified with K63-linked chain on K151 site was regulated by Ubp2 and mediated the nuclear translocation of zinc finger protein Zpr1. The K48-linked chains at non-K151 sites of Cpr1 were mainly regulated by Ubp3 and served as canonical signals for proteasome-mediated degradation. Show less
Leaf color mutants are ideal materials for chloroplast development and photosynthetic mechanism research. Here, we characterized an EMS (ethyl methane sulfonate)-mutagenized sorghum (Sorghum bicolor) Show more
Leaf color mutants are ideal materials for chloroplast development and photosynthetic mechanism research. Here, we characterized an EMS (ethyl methane sulfonate)-mutagenized sorghum (Sorghum bicolor) mutant, sbe6-a1, in which the severe disruption in chloroplast structure and a chlorophyll deficiency promote an albino leaf phenotype and lead to premature death. The proteomic analyses of mutant and its progenitor wild-type (WT) were performed using a Q Exactive plus Orbitrap mass spectrometer and 4,233 proteins were accurately quantitated. The function analysis showed that most of up-regulated proteins in mutant sbe6-a1 had not been well characterized. GO-enrichment analysis of the differentially abundant proteins (DAPs) showed that up-regulated DAPs were significantly enriched in catabolic process and located in mitochondria, while down regulated DAPs were located in chloroplasts and participated in photosynthesis and some other processes. KEGG pathway-enrichment analyses indicated that the degradation and metabolic pathways of fatty acids, as well as some amino acids and secondary metabolites, were significantly enhanced in the mutant sbe6-a1, while photosynthesis-related pathways, some secondary metabolites' biosynthesis and ribosomal pathways were significantly inhibited. Analysis also shows that some DAPs, such as FBAs, MDHs, PEPC, ATP synthase, CABs, CHLM, PRPs, pathogenesis-related protein, sHSP, ACP2 and AOX may be closely associated with the albino phenotype. Our analysis will promote the understanding of the molecular phenomena that result in plant albino phenotypes. Show less
Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistan Show more
Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca Show less
Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treat Show more
Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that induce glucose-dependent insulin secretion, promote β-cell proliferation, and enhance resistance to apoptosis. GLP-1 mimetics are marketed as treatments for type 2 diabetes mellitus (T2DM) and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. The aim of this study is to evaluate the potential neuroprotective effects of liraglutide, a GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.) injections. We then investigated the effects of these drugs on mTBI-induced cognitive impairments, neurodegeneration, and neuroinflammation. Finally, we assessed their effects on neuroprotective proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and neuroinflammation, as quantified by immunohistochemical staining with Fluoro-Jade/anti-NeuN and anti-Iba-1 antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the neuroprotective effects and mechanism of action of incretin-based therapies for neurological disorders. Show less
Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these Show more
Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis. Specifically, we identified 12 common, 9 low-frequency, and 8 rare InDels that explained approximately 1.29% of the heritability of psoriasis. Further analyses identified KIAA0319, RELN, NCAPG, ABO, AADACL2, LMAN1, FLG, HERC5, CCDC66, LEKR1, AFF3, ABCG2, ANXA7, SYTL2,GIPR, METTL1, and FYCO1 as unreported genes for psoriasis. In addition, identified InDels were associated with the following reported genes: IFIH1, ERAP1, ERAP2, LNPEP, UBLCP1, and STAT3; unreported independent associations for exonic InDels were found within GJB2 and ZNF816A. Our study enriched the genetic basis and pathogenesis of psoriasis and highlighted the non-negligible impact of InDels on complex human diseases. Show less
Studies have shown that a normal circadian rhythm is crucial to learning and memory. Circadian rhythm disturbances that occur at early stages of Alzheimer's disease (AD) aggravate the progression of t Show more
Studies have shown that a normal circadian rhythm is crucial to learning and memory. Circadian rhythm disturbances that occur at early stages of Alzheimer's disease (AD) aggravate the progression of the disease and further reduce learning and memory in AD patients. The novel, dual GLP-1R/GIPR agonist DA-JC1 has been found to exert a stronger hypoglycemic effect than a GLP-1R agonist alone and has been shown to exert neuroprotective effects. However, it is not clear whether DA-JC1 improves the Aβ31-35-induced decline in learning and memory ability by restoring disrupted circadian rhythms. In the present study, we carried out a mouse wheel-running experiment and Morris water maze test (MWM) and found that DA-JC1 could effectively improve the decline of learning and memory and circadian rhythm disorders induced by Aβ31-35. After downregulating Per2 expression via lentivirus-shPer2 in the hippocampus and the hippocampal HT22 cells, we found that circadian rhythm disorders occurred, and that DA-JC1 could not improve the impaired learning and memory. These results suggest that DA-JC1 improves damage to learning and memory by antagonizing circadian rhythm disorders induced by Aβ31-35. The outcome of this ongoing study may provide a novel therapeutic intervention for AD in the future. Show less