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1.
Am J Cancer Res ; 10(2): 662-673, 2020.
Article in English | MEDLINE | ID: mdl-32195034

ABSTRACT

Type-2 11ß-hydroxysteroid dehydrogenase (HSD11B2) is a key enzyme which converts cortisol to inactive cortisone and is involved in tumor progression and metastasis. Several studies have shown that the promotion of tumor progression and metastasis by HSD11B2 resulted from its physiological function of inactivating glucocorticoids (GC). However, the underlying molecular mechanisms by which HSD11B2 drives metastasis, in addition to inactivating GC, are still unclear. In our study, a series of in vivo and in vitro assays were performed to determine the function of HSD11B2 and the possible mechanisms underlying its role in CRC metastasis. mRNA transcriptome array analysis was used to identify the possible downstream targets of HSD11B2. We found that the ectopic expression of HSD11B2 significantly promoted the migration, invasion and metastasis of colorectal cancer (CRC) cells both in vitro and in vivo, while it did not affect their proliferation in either case. Mechanically, HSD11B2 appeared to enhance cell migration and invasion by upregulating the expression of fibroblast growth factor binding protein 1 (Fgfbp1), and subsequently increasing the phosphorylation of AKT. Furthermore, AKT activation partially mediated the increased expression of Fgfbp1 induced by HSD11B2. HSD11B2 expression was positively correlated with Fgfbp1 and p-AKT expression in clinical samples of CRC. Additionally, knockdown of either Fgfbp1 or AKT impaired the migration and invasion capability of CRC cells with HSD11B2 overexpression, suggesting that HSD11B2 promoted the migration, invasion and metastasis of CRC cells via the Fgfbp1-AKT pathway. Therefore, targeting HSD11B2 or Fgfbp1 may be a novel treatment strategy for inhibiting the metastasis of CRC.

2.
J Cell Physiol ; 235(6): 5084-5095, 2020 06.
Article in English | MEDLINE | ID: mdl-31691973

ABSTRACT

Astrocyte elevated gene 1 (AEG-1) is overexpressed in hepatocellular carcinoma (HCC) and is strongly associated with tumor metastasis. Anoikis resistance and autophagy may play an important role in the survival of circulating tumor cells. However, the relationship among AEG-1, anoikis resistance, autophagy, and metastasis in HCC is still not clear. The results of this study indicate that AEG-1 expression is increased in HCC cell lines grown in suspension culture. AEG-1 could enhance anoikis resistance to promote the survival of detached HCC cells. Moreover, the anoikis resistance appears to be partly dependent on autophagy. Regulating AEG-1 expression changed the autophagy levels to modulate anoikis resistance, likely acting via the protein kinase RNA-like ER kinase (PERK)-eIF2α-ATF4-CHOP signaling axis. Finally, inhibiting autophagy by RNA interference prevented the AEG-1-promoted metastasis of HCC xenografts to the liver and lungs of nude mice. Taken together, AEG-1 is a key contributor to anoikis resistance and metastasis by inducing autophagy in vitro and in vivo, and it may be a potential target for therapeutic intervention in HCC.


Subject(s)
Activating Transcription Factor 4/genetics , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Membrane Proteins/genetics , RNA-Binding Proteins/genetics , eIF-2 Kinase/genetics , Animals , Anoikis/genetics , Autophagy/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Flow Cytometry , Gene Expression Regulation, Neoplastic/genetics , Heterografts , Humans , Liver Neoplasms/pathology , Mice , Neoplasm Metastasis , Signal Transduction/genetics
3.
Medicine (Baltimore) ; 98(22): e15751, 2019 May.
Article in English | MEDLINE | ID: mdl-31145291

ABSTRACT

Mallory-Weiss syndrome (MWS) is a relatively less common cause of nonvariceal upper gastrointestinal bleeding. There is limited data on whether scoring systems could be used to predict the clinical outcomes in patients with bleeding due to MWS. The aim of our study is to evaluate whether the Glasgow-Blatchford score (GBS), AIMS65, and shocking index are effective in predicting the clinical outcomes of MWS.One hundred twenty-eight patients from January 2010 to January 2017 with MWS in middle China were enrolled. Clinical features such as age, gender, causes of vomiting, endoscopic findings, GBS, AIMS65, and shocking index were recorded. The clinical outcomes including endoscopic treatment and transfusion were analyzed.MWS accounted for 6.1% of nonvariceal upper gastrointestinal bleeding. Male-to-female ratio was 3.6:1 and median age was 51 years. Patients between 40 and 60 years were more commonly affected; 43.8% of MWS was caused by overdrinking followed by underlying gastric diseases (33.6%). However, for female patients alone, underlying gastric diseases were the leading cause (42.9%). The tears were usually single and most frequently located on the left lateral wall. In receiver-operating characteristic curve analyses, GBS system and shocking index were useful in predicting transfusion (0.856 vs 0.675). But for endoscopic intervention, these scoring systems are not helpful (P > .05).Apart from drinking, underlying gastric disease is another important cause of MWS especially for female patients and should be paid more attention under endoscopy examination. GBS system and shocking index can be used to predict transfusion.


Subject(s)
Gastrointestinal Hemorrhage/pathology , Mallory-Weiss Syndrome/pathology , Risk Assessment/methods , Severity of Illness Index , Adolescent , Adult , Aged , Aged, 80 and over , Area Under Curve , Child , Child, Preschool , Endoscopy , Female , Gastrointestinal Hemorrhage/etiology , Glasgow Outcome Scale , Humans , Infant , Male , Mallory-Weiss Syndrome/complications , Middle Aged , Predictive Value of Tests , Prognosis , ROC Curve , Retrospective Studies , Young Adult
4.
Sci Rep ; 8(1): 4108, 2018 03 07.
Article in English | MEDLINE | ID: mdl-29515134

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is a kind of liver lipid synthesis and degradation imbalance related with metabolic syndrome. Celecoxib shows the function of ameliorating NAFLD, but the underlying mechanisms remain unknown. Here, we discuss the possible mechanisms of celecoxib alleviating NAFLD by restoring autophagic flux. Lipids were accumulated in L02 cells treated with palmitate as well as SD rats fed with high-fat diet. Western blot showed that LC3 II/I was higher and p62 was lower on the early stage of steatosis while on the late stage both of them were higher, indicating that autophagic flux was activated on the early stage of steatosis, but blocked on the late stage. Rapamycin alleviated steatosis with activating autophagic flux while chloroquine aggravated steatosis with inhibiting autophagic flux. COX-2 siRNA and celecoxib were used to inhibit COX-2. Western blot and RFP-GFP-LC3 double fluorescence system indicated that celecoxib could ameliorate steatosis and restore autophagic flux in L02 cells treated with palmitate as well as SD rats fed with high-fat diet. In conclusion, celecoxib partially restores autophagic flux via downregulation of COX-2 and alleviates steatosis in vitro and in vivo.


Subject(s)
Autophagy/drug effects , Celecoxib/pharmacology , Diet, High-Fat/adverse effects , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , Cell Line , Chloroquine/adverse effects , Chloroquine/pharmacology , Humans , Male , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Rats , Rats, Sprague-Dawley , Sirolimus/adverse effects , Sirolimus/pharmacology
5.
Oncol Rep ; 34(2): 539-46, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26035424

ABSTRACT

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, yet effective treatment for this disease is lacking. Thus, there is an urgent need to identify novel therapeutic targets for this dreadful disease. Numerous studies have established that overexpression of astrocyte-elevated gene-1 (AEG-1) is frequently observed in multiple types of cancers including HCC, and its expression levels are correlated with the stage and grade of the disease. Further studies revealed that AEG-1 plays a key role in several crucial aspects of HCC progression, including growth, transformation, cell survival, invasion, metastasis and chemoresistance. Moreover, AEG-1 overexpression activates the Wnt/ß-catenin, mitogen-actived protein kinase (MAPK), nuclear factor (NF)-κB, and PI3K/Akt signaling pathways, and promotes its downstream gene expression to facilitate malignant potential. Recently, transgenic mice with hepatocyte-specific expression of AEG-1 (Alb/AEG-1) and AEG-1-knockout mouse both revealed novel aspects of the functions of AEG-1 in an in vivo context. This review evaluates the multi-functions of AEG-1 and describes the major signaling pathways and molecular alterations regulated by AEG-1 in HCC, indicating its key roles and potential as a biomarker or significant target for the therapy of HCC.


Subject(s)
Carcinoma, Hepatocellular/pathology , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Liver Neoplasms/pathology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Proliferation , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Membrane Proteins , Neoplasm Invasiveness , Prognosis , RNA-Binding Proteins , Up-Regulation , Wnt Signaling Pathway
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