MiR-196a promotes the proliferation and migration of esophageal cancer via the UHRF2/TET2 axis.

The aim of this study was to investigate the functions and molecular mechanism of miR-196a in esophageal cancer (EC). miR-196a as well as UHRF2 and TET2 mRNA and protein levels in EC tissues and cells were detected using quantitative real-time PCR or western blot, respectively. Cell proliferation was evaluated via MTT assay. Transwell assays were used to detect cell migration. In addition, the targeted relationship between miR-196a and UHRF2 was assessed through a dual luciferase reporter assay. Enzyme-linked immunosorbent assay was performed to detect the levels of the cytosine intermediates 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). We found increased miR-196a expression in EC tissues and cells but decreased UHRF2 and TET2 expression. Next, functional experiments showed that knockdown of miR-196a or UHRF2 overexpression suppress EC cell proliferation and migration. miR-196a negatively regulates TET2 expression by directly targeting UHRF2. UHRF2 overexpression decreased 5mC levels but increased 5hmC levels. Furthermore, TET2 downregulation reversed the functions of miR-196a inhibition on EC cell proliferation and migration. Collectively, our study suggested that miR-196a was closely related to the progression of EC possibly by regulating the UHRF2/TET2 axis. Thus, miR-196a represents a potential new EC therapeutic target.

The effect of Salvia miltiorrhiza in a mouse model of hepatic sinusoidal obstruction syndrome induced by Gynura segetum

Background and aims: to investigate the potential effect and mechanism of Salvia miltiorrhiza in Gynura segetum-induced hepatic sinusoidal obstruction syndrome (HSOS). Methods: the mice were gavaged with PBS, Gynura segetum or Gynura segetum, along with 100 or 200 mg/kg Salvia miltiorrhiza. Histological scoring and liver function were performed. The expression of tumor necrosis factor-alpha (TNF-alfa), vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and nuclear transcription factor P65 (NF-κBp65) were determined by reverse transcriptase polymerase chain reaction (RT-PCR) and western blot. Results: liver function were effectively improved in the Salvia miltiorrhiza groups. The levels of TNF-alfa, VCAM-1, ICAM-1 and NF-κBp65 were significantly lower in the Salvia miltiorrhiza groups than in the Gynura segetum group. Conclusions: Salvia miltiorrhiza has a therapeutic effect on Gynura segetum-induced HSOS

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The effect of Salvia miltiorrhiza in a mouse model of hepatic sinusoidal obstruction syndrome induced by Gynura segetum.

BACKGROUND AND AIMS: to investigate the potential effect and mechanism of Salvia miltiorrhiza in Gynura segetum-induced hepatic sinusoidal obstruction syndrome (HSOS). METHODS: the mice were gavaged with PBS, Gynura segetum or Gynura segetum, along with 100 or 200 mg/kg Salvia miltiorrhiza. Histological scoring and liver function were performed. The expression of tumor necrosis factor-alpha (TNF-α), vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and nuclear transcription factor P65 (NF-κBp65) were determined by reverse transcriptase polymerase chain reaction (RT-PCR) and western blot. RESULTS: liver function were effectively improved in the Salvia miltiorrhiza groups. The levels of TNF-α, VCAM-1, ICAM-1 and NF-κBp65 were significantly lower in the Salvia miltiorrhiza groups than in the Gynura segetum group. CONCLUSIONS: Salvia miltiorrhiza has a therapeutic effect on Gynura segetum-induced HSOS.

Histone deacetylase 6 is overexpressed and promotes tumor growth of colon cancer through regulation of the MAPK/ERK signal pathway.

Purpose: To investigate the expression of histone deacetylase 6 (HDAC6) in colon cancer and its role in colon cancer cell growth and migration. Materials and methods: We detected the expression of HDAC6 in a colon cancer tissue chip using immunochemical staining, and analyzed the difference in HDAC6 expression between cancer and adjacent noncancerous tissues. Then, we explored the relationship between HDAC6 expression and patients' clinicopathological characteristics and prognoses. In adidition, the role of HDAC6 in colon cancer cell growth and migration, as well as its potential related signal pathway, through HDAC6 knockdown was explored. Results: The immunochemical score of HDAC6 expression was higher in cancer tissue than in the adjacent noncancerous tissue (4.54 vs 3.08, P<0.005); similarly, as well as the rate of high HDAC6 expression was higher in cancer tissue than in the adjacent noncancerous tissue (71.1% vs 40.9%, P<0.001). Patients showing high HDAC6 expression had a shorter overall survival time. Additionally, Cox regression analysis showed that high HDAC6 expression was an independent risk factor for poor prognosis. HDAC6 knockdown decreased cell viability, colony formation, and number of migrated colon cancer cells (HCT116 and HT29); the expression of p-MEK, p-ERK, and p-AKT was also decreased, but had no influence on MEK, ERK, and AKT expression. Conclusion: HDAC6 is highly expressed in colon cancer and associated with a poor prognosis. HDAC6 knockdown inhibits colon cancer cell growth and migration, partly through the MAPK/ERK pathway.

[Expression of Wnt and integrin pathways in colorectal laterally spreading tumors and their correlation with endoscopic subtypes].

OBJECTIVE: To investigate the expression of Wnt and integrin pathways in colorectal laterally spreading tumors (LSTs) and their correlation with the different endoscopic subtypes of LSTs to better understand the special growth mechanism of LSTs. METHODS: Fifty-two patients with colorectal LSTs were randomly selected from the cases diagnosed between January 1, 2010 and June 10, 2015 in our hospital, including 37 of nodular mixed type (LST-G-M), 60 of homogeneous type (LST-G-H), 5 of flat elevated type (LST-NG-FE), and 4 of pseudodepressed type (LST-NG-PD). The expression of ß-catenin, phospho- GSK-3ß, paxillin and ILK in 52 colorectal LSTs and 15 protruded adenomas (PAs) were investigated by immunohistochemical staining. The correlation of ß-catenin, phospho-GSK-3ß, paxillin and ILK expressions among the endoscopic subtypes of LSTs were analyzed. RESULTS: ß-catenin expression was significantly higher in LSTs than in Pas (P<0.05). ß-catenin, phospho-GSK-3ß, paxillin and ILK expressions were significantly higher in LST-NG-PD than in Pas (P<0.05). The expressions of ß-catenin, phospho-GSK-3ß and ILK expression were significantly correlated in LSTs (P<0.05) but not in PAs (P>0.05). CONCLUSION: The macroscopic feature of LST-NG-PD may result from a special mechanism of development distinct from other endoscopic subtypes; ILK may play a role in regulating Wnt signaling in LSTs.

Alcohol consumption and corresponding factors: A novel perspective on the risk factors of esophageal cancer.

Esophageal cancer is the eighth most common type of cancer in the world, and the sixth most common cause of mortality from cancer. Alcohol consumption is the major risk factor for esophageal cancer, due to the worldwide prevalence and high carcinogenicity of the ethanol metabolite. In epidemiological studies, the efficiency of alcohol intake to enhance the risk of esophageal cancer is altered by daily ethanol consumption, type of alcoholic beverages ingested, time since quitting drinking, age of drinking initiation, differences in population and subtypes of esophageal cancer. Corresponding factors, including gene polymorphisms, tobacco smoking, oral microorganisms and folate deficiency, reveal a synergistic effect in concurrent alcohol users that may lead to an increased risk of developing esophageal cancer. Consequently, esophageal cancer prevention involves multiple aspects, including quitting drinking and smoking, maintaining an adequate oral health and ingesting adequate quantities of folate, particularly in genetically high-risk populations.

Primary intratesticular rhabdomyosarcoma: A case report and literature review.

Rhabdomyosarcoma (RMS) that primarily occurs in the testes is particularly rare, with only retrospective studies and sporadic cases reported in the literature. The present study describes the case of a large, primary intratesticular RMS (ITRMS) that was treated with a radical inguinal orchiectomy (RIO) and a regimen of chemotherapy. The study also presents a review of the literature regarding primary ITRMSs, aiming to elucidate the clinical characteristics and optimal treatment of the disease. A 14-year-old male presented with a 1-year history of a slow-growing, painless, left scrotal mass. Magnetic resonance imaging identified a mass in the left scrotum with mixed signal intensity; no abnormal signals were identified in the right testicle and retroperitoneal lymph node. An X-ray of the chest demonstrated no evidence of metastasis. Subsequent to this, a left RIO was performed. Histopathological and immunohistochemical examination confirmed the final diagnosis of embryonal ITRMS. At 21 days post-surgery, an 18F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT) scan identified widespread metastatic lesions in the lungs, local lymph nodes and bones, presenting as increased glucose metabolism nodules. Subsequently, the patient received six sequential cycles of adjunct chemotherapy. The patient is alive with disease in October 2015. The case described is noteworthy as it is an example of ITRMS, in which the patient received successful treatment. However, multidisciplinary treatment may further improve the outcome of the disease.

Involvement of F-box proteins in esophageal cancer (Review).

The F-box proteins (FBPs) in esophageal tumorigenesis are pivotal as they govern a broad array of basic physiological responses including cell growth, cell death and DNA damage repair. Esophageal cancer (EC) is a common and highly aggressive cancer worldwide. Aberrant stabilization of crucial proteins participates in esophageal tumorigenesis. Recently, growing evidence has shown that FBPs play a critical role in oncogenesis, invasion, metastasis and prognosis assessment of EC. In this review we summarized published data on the roles of known FBPs, their respective substrates and the key signaling pathways, in the development of EC, aiming to uncover new ways for the rational design of targeted therapies in EC.

MicroRNA-1246 promotes growth and metastasis of colorectal cancer cells involving CCNG2 reduction.

Colorectal cancer (CRC) is the third most common cancer type and the fourth leading cause of cancer­associated mortality worldwide. MicroRNA (miR)­1246 is involved in differentiation, invasion, metastasis and chemoresistance of certain types of tumor cells. CCNG2 encodes an unconventional cyclin homolog, cyclin G2 (CycG2), associated with growth inhibition, which correlated significantly with lymph node metastasis, clinical stage, histological grade and poor overall survival in numerous cancer types. To investigate the regulation of miR­1246 on CycG2 expression, and their effects on proliferation and metastasis of CRC, HCT­116 and LOVO cells were transfected with pre­miR­1246 anti­miR­1246 and their negative controls. It was demonstrated that the expression of miR­1246 was significantly increased in CRC tissues and cell lines, which was the opposite of CycG2. miR­1246 negatively regulated the expression of CycG2 in HCT­116 and LOVO CRC cells. CCNG2 is a direct target of miR­1246 in CRC cells. Overexpression of miR­1246 induced cell proliferation, migration and invasion, while knockdown of miR­1246 inhibited proliferation, migration and invasion in the CRC cells. Upregulation of miR­1246 mediated the malignant progression of CRC and is partly attributed to the downregulation of the expression of CycG2. Consequently, these findings provided a molecular basis for the role of miR­1246/CCNG2 in the progression of human CRC and suggested a novel target for the treatment of CRC.

Function and mechanism of F-box proteins in gastric cancer (Review).

Gastric cancer (GC) is one of the commonest cancers with high mortality. Despite improvement in early detection and treatments, the outcome of advanced GC remains unsatisfactory due to the poor understanding of the intricate pathogenesis of GC. GC is a multifactorial and multistep disease which involves activation of oncogenes and inactivation of tumor suppressor genes. Ubiquitin proteasome system (UPS) catalyzing many critical protein substrates is involved in initiation and development of cancer. F-box proteins (FBPs) are the main functional components of UPS. Accumulated evidence strongly suggests that abnormal regulations of FBPs contribute to uncontrolled proliferation, genomic instability and cancer. In this review, we discuss how the dysregulated FBPs promote the occurrence and development of GC.

microRNA-214 functions as a tumor suppressor in human colon cancer via the suppression of ADP-ribosylation factor-like protein 2.

microRNAs (miRNAs/miRs) are a conserved class of endogenous, short non-coding RNAs that post-transcriptionally regulate the expression of genes involved in diverse cellular processes. miR-214 has been reported to be associated with several cancers, including human colon cancer. However, the function of miR-214 in colon cancer development is poorly understood. In the current study, miR-214 was demonstrated to be downregulated in colon cancer tissues compared with healthy colon tissues. Functional studies showed that miR-214 overexpression results in the inhibition of cell viability, colony formation and proliferation, and the induction of cell apoptosis. ADP-ribosylation factor-like protein 2 (ARL2) is predicted to be a target candidate of miR-214. A luciferase reporter assay, western blot analysis and quantitative polymerase chain reaction were performed, which revealed that miR-214 negatively regulates ARL2 expression by targeting its 3' untranslated region directly. In conclusion, the results of the present study revealed that miR-214 suppresses colon cancer cell growth via the suppression of ARL2, and indicated that miR-214 may present a significant potential therapeutic target for colon cancer.

Large gastric folds arising in polyposis syndromes.

Large gastric folds (LGF) can be caused by benign conditions as well as malignancies. Unfortunately, endoscopic features and biopsy results are often equivocal, making the diagnosis and management of large gastric folds difficult. Polyposis syndromes encompass a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gut. Large gastric folds are extremely rare in these syndromes. We present the case of a patient with polyposis who was found to have large gastric folds in the entire gastric fundus and body, mimicking malignancy. The patient's medical history and endoscopic ultrasonography (EUS) with mucosal resection confirmed the diagnosis of a pre-malignant disease. The lesion was monitored by serial endoscopic ultrasonography and biopsy, abdominal computed tomography (CT), and positron emission and computed tomography (PET-CT) for 6 years. The lesion remained stable, with the exception of abnormal fluorodeoxyglucose uptake on PET-CT in the gastric folds, which was determined to be a false-positive sign. To date, the patient remains healthy. We further discuss the mechanisms underlying the formation of large gastric folds caused by polyposis syndromes. Helicobacter pylori (H. pylori) or cytomegalovirus (CMV) is unnecessary for this progression. Immunohistochemistry (IHC) staining suggested that overexpression of transforming growth factor alpha (TGF-alpha) and down-regulation of myocyte enhancer-binding factor 2 (MEF2) may be involved in this case.

Large gastric folds arising in polyposis syndromes / Grandes pliegues gástricos en síndromes de poliposis

Large gastric folds (LGF) can be caused by benign conditions as well as malignancies. Unfortunately, endoscopic features and biopsy results are often equivocal, making the diagnosis and management of large gastric folds difficult. Polyposis syndromes encompass a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gut. Large gastric folds are extremely rare in these syndromes. We present the case of a patient with polyposis who was found to have large gastric folds in the entire gastric fundus and body, mimicking malignancy. The patient’s medical history and endoscopic ultrasonography (EUS) with mucosal resection confirmed the diagnosis of a pre-malignant disease. The lesion was monitored by serial endoscopic ultrasonography and biopsy, abdominal computed tomography (CT), and positron emission and computed tomography (PET-CT) for 6 years. The lesion remained stable, with the exception of abnormal fluorodeoxyglucose uptake on PET-CT in the gastric folds, which was determined to be a false-positive sign. To date, the patient remains healthy. We further discuss the mechanisms underlying the formation of large gastric folds caused by polyposis syndromes. Helicobacter pylori (H. pylori) or cytomegalovirus (CMV) is unnecessary for this progression. Immunohistochemistry (IHC) staining suggested that overexpression of transforming growth factor alpha (TGF-Alpha) and down-regulation of myocyte enhancerbinding factor 2 (MEF2) may be involved in this case (AU)

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[5-aza-2'-deoxycytidine-induced inhibition of CDH13 expression and its inhibitory effect on methylation status in human colon cancer cells in vitro and on growth of xenograft in nude mice].

OBJECTIVE: To determine the inhibitory effect of 5-aza-2'-deoxycytidine (5-Aza-CdR) on the growth of human colon carcinoma cells and xenografts in nude mice, to observe its effect on CDH13 gene expression and methylation in the xenografts, and to explore the possible mechanisms. METHODS: Human colon carcinoma cell line HCT116 cells were treated with 5-Aza-CdR, and the cell morphology was observe by phase contrast microscopy. The cell growth was assessed by MTT assay. A tumor-bearing mouse model was generated by subcutaneous inoculation of human colon carcinoma HCT116 cells into nude mice. The tumor growth in the nude mice was observed, the CDH13 gene expression and its methylation status in the tumors were detected using methylation specific PCR (MSP), RT-PCR, Western blotting and immunohistochemistry. RESULTS: After treatment with 5-Aza-CdR, the inhibition rate of the growth of cultured HCT116 cells was increased as the concentration was increasing. The growth of the xenografts in nude mice was significantly inhibited, and the methylated CDH13 gene was reactivated. After 4 weeks of 5-Aza-CdR treatment, no significant difference was found between the body weights of nude mice in the 5-Aza-CdR group [(18.06 ± 1.29) g] and control group [(17.07 ± 0.84) g], (P > 0.10), and the average volume of xenografts of the 5-Aza-CdR group was (907.00 ± 87.29) mm(3), significantly smaller than the (1370.93 ± 130.20) mm(3) in the control group (P < 0.005). No expression of CDH13 gene was found in the control group. The expression of CDH13 gene in the 5-Aza-CdR group was increased along with the increasing concentration of 5-Aza-CdR. CONCLUSIONS: 5-Aza-CdR inhibits the growth of human colon cancer cells in culture and in nude mice, and induces the cancer cells to re-express CDH13 in nude mice. Its mechanism may be that demethylation of the methylated CDH13 promoter induced by 5-Aza-CdR restores CDH13 expression and thus inhibits the tumor growth in nude mice.

ZEB2 promotes the metastasis of gastric cancer and modulates epithelial mesenchymal transition of gastric cancer cells.

BACKGROUND: Invasion and metastasis are the hallmarks of advanced gastric cancer progression. Therefore, it is urgent to overcome metastasis in order to improve the survival of gastric cancer patients. AIMS: This study aimed to examine the expression of ZEB2 in gastric cancer samples and analyze its correlation with clinicopathologic features. In addition, the molecular mechanism by which ZEB2 contributes to gastric cancer metastasis will be explored. METHODS: ZEB2 expression in clinical gastric cancer samples was evaluated by immunohistochemical analysis. ZEB2 was knocked-down in HGC27 gastric cancer cells by shRNA and the effects on cell invasion and migration were examined by in vitro cell invasion and migration assays. The expression of epithelial marker E-cadherin, mesenchymal markers fibronecin and vimentin, and MMPs was detected by western blot analysis. RESULTS: The expression of ZEB2 was positively correlated with the depth of invasion, lymph node metastasis and TNM stage. In addition, patients with positive ZEB2 expression showed a significantly shorter overall survival time than did patients with negative ZEB2. shRNA mediated knockdown of ZEB2 resulted in reduced invasion and migration of HGC27 cells, along with the upregulation of E-cadherin and downregulation of fibronecin, vimentin, MMP2, and MMP9. CONCLUSIONS: ZEB2 expression is closely associated with the clinicopathological parameters of gastric cancer. ZEB2 promotes gastric cancer cell migration and invasion at least partly via the regulation of epithelial-mesenchymal transition. ZEB2 is a potential target for gene therapy of aggressive gastric cancer.

Correlation between T-cadherin gene expression and aberrant methylation of T-cadherin promoter in human colon carcinoma cells.

Previous researches showed T-cadherin (CDH13) expression was downregulated in colon cancer tissues and was associated with increase of invasive and metastatic potential. This research was to observe the mechanisms responsible for inactivation of T-cadherin gene in colon carcinoma; we investigated the methylation status around the 5' promoter region of T-cadherin gene of Hct116 colon cancer cell line by methylation-specific polymerase chain reaction (MSP), also detected the expression change of T-cadherin mRNA and protein in Hct116 cell line after 5-Aza-CdR treatment by reverse transcriptase polymerase chain reaction and Western blotting, and compared the T-cadherin methylation status with T-cadherin mRNA and protein expression. We found that hypermethylation of T-cadherin was involved in Hct116 cell line, while T-cadherin mRNA and protein expression was almost lost or downregulated in Hct116 cell line. Therefore, methylation of the T-cadherin promoter region was correlated with the loss or downregulation of T-cadherin mRNA and protein expression in Hct116 colon cancer cell line. Treatment of T-cadherin-negative carcinoma cells with the demethylating agent, 5-aza-2'-deoxycytidine, induced re-expression of this gene. Our findings demonstrate that 5' CpG island methylation is common in colon carcinoma and may play an important role in the inaction of T-cadherin. Our results also suggest that demethylation of the T-cadherin gene may be a potential therapeutic strategy for colon carcinoma.

Effect of ligustrazine on mice model of hepatic veno-occlusive disease induced by Gynura segetum.

BACKGROUND AND AIM: To investigate the therapeutic effect of ligustrazine on hepatic veno-occlusive disease (HVOD) induced by Gynura segetum and the possible mechanism of it. METHODS: Female Kunming mice (115) were randomly divided into four groups, gavaged with 30 g/kg per day Gynura segetum (group A), 30 g/kg per day Gynura segetum + 100 mg/kg per day ligustrazine (group B), 30 g/kg per day Gynura segetum + 200 mg/kg per day ligustrazine (group C) or 30 mL/kg per day phosphate-buffered saline (PBS) (group D). Thirty days later, all of the mice were killed. Blood samples and livers were harvested. Histological changes were evaluated by light microscopy. Liver function was measured, and the expression of tissue factor (TF), early growth response factor-1 (Egr-1) and nuclear factor-KBp65 (NF-KBp65) were determined by reverse transcription-polymerase chain reaction and Western blot. RESULTS: A total of 24 mice in group A developed HVOD. Compared with the controls, they had increased liver ratio, serum total bilirubin (TBIL), direct bilirubin (DBIL), transaminase and decreased albumin (ALB) (P < 0.05). Administration of ligustrazine improved the clinical signs and biochemistry parameters in a dose-dependent manner. Compared with group A, the expression of TF, Egr-1 and NF-KB p65 decreased in groups B and C (P < 0.05). CONCLUSION: Ligustrazine has a therapeutic effect on HVOD, improving clinical manifestations and liver function. The possible mechanism may be that ligustrazine could reduce the expression of TF by downregulating the expression of transcription factors: Egr-1 and NF-KB p65.

Hepatic veno-occlusive disease associated with toxicity of pyrrolizidine alkaloids in herbal preparations.

Hepatic veno-occlusive disease (VOD) is frequently linked to stem cell transplantation (SCT), mainly related to the conditioning regime, and contributes to considerable morbidity and mortality. However, pyrrolizidine alkaloid (PA)-induced VOD has long been overlooked. The pathogenesis of VOD remains poorly understood; studies suggest that endothelial cell injury, cytokines and haemostatic derangement are all involved in the pathogenesis of VOD. Until recently, treatment options have been limited and no uniformly effective therapy has been established. Thus, treatment is largely supportive and symptomatic. Ongoing work, including development of new animal models and clinical studies, is needed to help us fully understand the pathogenesis of VOD and enable us to devise effective solutions. Furthermore, it is strongly advised that supervisory measures be taken to standardise the use of herbal medication.