Publications by authors named "Mudan Ren"

25 Publications

  • Page 1 of 1

Delphinidin modulates JAK/STAT3 and MAPKinase signaling to induce apoptosis in HCT116 cells.

Environ Toxicol 2021 May 6. Epub 2021 May 6.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Delphinidin is an anthocyanin that belongs to the group of flavonoids that exert numerous biological activities. However, the molecular mechanisms underlying the anticancer effects of delphinidin remain poorly understood. In our study we analyzed delphinidin modulate STAT-3 and MAPKinase signaling thereby inhbits cell proliferation and promote apoptosis. Our study demonstrated that delphinidin treatment significantly reduced the viability of human colon cancer HCT116 in a concentration-dependent manner. We noticed that delphinidin effectively induced oxidative stress-mediated apoptosis by generating intracellular ROS, decreasing antioxidant levels, inducing lipid peroxidation, and single-strand break on colon cancer cells. In this study, we observed that delphinidin treatment alters the mitochondrial membrane potential, thereby induces apoptosis was closely associated with the induction of pro-apoptotic Bax, Caspase- 3,8 & 9, cytochrome C, and inhibition of anti-apoptotic protein expression. Studies on STAT-3 and MAPKinase signaling showed delphinidin inhibited the phosphorylation of these transcription factors' activity. Inhibition of STAT-3, p38, and ERK1/2 phosphorylation and modulation pro-apoptotic protein expression might be responsible for the anticancer activity of delphinidin in colon cancer cells.
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http://dx.doi.org/10.1002/tox.23152DOI Listing
May 2021

Endoscopy-assisted magnetic compression anastomosis for rectal anastomotic atresia.

Endoscopy 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China.

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http://dx.doi.org/10.1055/a-1322-1899DOI Listing
January 2021

Screening value for gastrointestinal lesions of magnetic-controlled capsule endoscopy in asymptomatic individuals.

J Gastroenterol Hepatol 2021 May 14;36(5):1267-1275. Epub 2020 Oct 14.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background And Aim: Most patients with gastric tumors and precancerous lesions are asymptomatic, which often results in delayed diagnosis and treatment. Compared with conventional gastroscopy and capsule endoscopy, magnetic-controlled capsule endoscopy is a non-invasive, effective, and cost-efficient diagnostic modality for gastric examination. We retrospectively investigated magnetic-controlled capsule endoscopy as a screening tool for gastrointestinal lesions (particularly gastric tumors and precancerous lesions) in asymptomatic individuals.

Methods: In this retrospective study, 1757 patients who voluntarily underwent magnetic-controlled capsule endoscopy between January and December 2019 at nine medical centers across Shaanxi province based on strict inclusion and exclusion criteria were enrolled. The primary outcomes were gastric tumor and precancerous lesion detection rates and procedural safety.

Results: The upper and lower gastrointestinal lesion detection rates were 98.35% (1728/1757) and 21.61% (78/361), respectively; 2.28% of patients were diagnosed with gastric tumors including gastric cancer (4/1757) and submucosal tumors (36/1757). Three types of precancerous lesions were found in 591 patients (33.64%), including chronic atrophic gastritis (23.16%), gastric polyp (10.98%), and gastric ulcer (2.96%). For patients aged over 40 years, the detection rate of precancerous lesions was higher (14.36% vs 42.58%, P < 0.001). No patient was diagnosed with small intestinal cancer. No adverse events occurred.

Conclusions: Magnetic-controlled capsule endoscopy could be used as a promising novel screening modality for diagnosis of gastrointestinal lesions in asymptomatic individuals, specifically gastric tumors and precancerous lesions, with the advantages of safety, non-invasiveness, effectiveness, and cost-efficiency.
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http://dx.doi.org/10.1111/jgh.15282DOI Listing
May 2021

The Prognosis Analysis of Liver Cirrhosis with Acute Variceal Bleeding and Validation of Current Prognostic Models: A Large Scale Retrospective Cohort Study.

Biomed Res Int 2020 16;2020:7372868. Epub 2020 Aug 16.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Acute variceal bleeding is a major cause of death in liver cirrhosis. This large scale retrospective cohort study aims to analyze the prognosis of patients with cirrhosis and acute variceal bleeding and to validate the current prognostic models.

Methods: Patients with cirrhosis and acute variceal bleeding were enrolled from Jan 2019 to March 2020. The independent prognostic factors for in-hospital death were identified by logistic regression analyses. Area under curves (AUCs) was compared among Child-Pugh, cirrhosis acute gastrointestinal bleeding (CAGIB) score, and model for end-stage liver disease (MELD) and neutrophil-lymphocyte ratio (NLR) scores.

Results: Overall, 379 patients with liver cirrhosis and acute variceal bleeding were consecutively evaluated. The majority of the patients were males (59.1%) and the mean age of all patients were 53.7 ± 1.3 years (range 14-89). Hepatitis B virus (HBV) was the most common underlying cause of liver cirrhosis (54.1%). 72 (19%) patients had hepatocellular carcinoma. Multivariate logistic regression analyses showed that age, HCC, WBC, total serum bilirubin, serum creatinine, and ALT were independently associated with in-hospital death. And the odds ratios (ORs) for in-hospital death were 1.066 (95% CI 1.017-1.118, = 0.008), 7.19 (95% CI 2.077-24.893, = 0.001), 1.123 (95% CI 1.051-1.201, = 0.001), 1.014 (95% CI 1.005-1.023, = 0.003), 1.012 (95% CI 1.004-1.021, = 0.006), and 1.005 (95% CI 1.000-1.009, = 0.036), respectively. In the whole cohort with HCC patients, the AUCs of Child-Pugh, CAGIB, MELD and NLR scores were 0.842 (95% CI 0.801-0.878), 0.840 (95% CI 0.799-0.876), 0.798 (95% CI 0.754-0.838), and 0.688 (95% CI 0.639-0.735), respectively. The differences were statistically significant between Child-Pugh and NLR scores ( = 0.0118), and between CAGIB and NLR scores ( = 0.0354).

Conclusion: Child-Pugh and CAGIB scores showed better predictive performance for prognosis of patients with cirrhosis and acute variceal bleeding than NLR scores.
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http://dx.doi.org/10.1155/2020/7372868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448238PMC
May 2021

LncRNA SNAI3-AS1 promotes PEG10-mediated proliferation and metastasis via decoying of miR-27a-3p and miR-34a-5p in hepatocellular carcinoma.

Cell Death Dis 2020 08 11;11(8):685. Epub 2020 Aug 11.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, P. R. China.

During recent years, long noncoding RNAs (lncRNAs) have received focal attention due to their important function in cancer regulation. Though the relation between lncRNA SNAI3-AS1 and the development of hepatocellular carcinoma (HCC) has been described in our previous study, the role and the exact mechanism of SNAI3-AS1 are still unclear. In this study, qRT-PCR analysis revealed that the expression of SNAI3-AS1 was elevated and was correlated with the levels of PEG10 in HCC tissues. Through functional experiments, we determined that knockdown of SNAI3-AS1 and PEG10 inhibited the proliferation and metastasis, whereas overexpression of SNAI3-AS1 and PEG10 promoted the proliferation and metastasis of HCC cells. In addition, rescue experiments confirmed that upregulation of PEG10 partially restored cell function inhibition induced by SNAI3-AS1 knockdown. Therefore, we hypothesized that PEG10 may be regulated by SNAI3-AS1, which in turn mediates the malignant biological processes of HCC cells regulated by PEG10. Further bioinformatics analysis and mechanistic experiments showed that SNAI3-AS1 functions as a competing endogenous RNA (ceRNA) to activate PEG10 by acting as a sponge for miR-27-3p and miR-34a-5p. In summary, our study revealed that SNAI3-AS1 is a tumor regulator of PEG10 in the progression of HCC, and may contribute to the improvement of HCC diagnosis and therapy.
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http://dx.doi.org/10.1038/s41419-020-02840-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442791PMC
August 2020

Telephone-Based Reeducation of Drug Administration for Eradication: A Multicenter Randomized Controlled Study.

Gastroenterol Res Pract 2020 31;2020:8972473. Epub 2020 Jul 31.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

Poor adherence to treatment instructions may play an important role in the failure of eradication. The aim of this study was to evaluate the effects of telephone-based reeducation on 14-day quadruple . eradication therapy. In total, 162 patients were randomly assigned (1 : 1) to either the intervention group (patients received telephone-based reeducation on the 4, 7, and 10 days of the course) or the control group (patients received instructions only at the time of getting the prescriptions). All patients received a 14-day quadruple . eradication therapy. The primary outcome was the . eradication rate. The secondary outcomes included the symptom relief rates and the incidence rates of adverse events. Seventy-five patients in the reeducation group and 74 patients in the control group completed the follow-up. The . eradication rate in the reeducation group was statistically higher than that in the control group (intention-to-treat: 72.8% vs. 50.6%, = 0.006; per-protocol: 78.7% vs. 55.4%, = 0.003). However, the symptom relief rates and the adverse event rates in these two groups were not significantly different. Overall, the results from this study suggest that telephone-based reeducation can be potentially applied to improve the . eradication rate in clinical practice, without significantly increasing the adverse effects.
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http://dx.doi.org/10.1155/2020/8972473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415080PMC
July 2020

THBS4 promotes HCC progression by regulating ITGB1 via FAK/PI3K/AKT pathway.

FASEB J 2020 08 22;34(8):10668-10681. Epub 2020 Jun 22.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China.

Our research aims to identify the role of thrombospondin 4 (THBS4) in hepatocellular carcinoma (HCC). First, bioinformatic analysis was applied for detection the expression of THBS4 in HCC samples, and qRT-PCR and western blot were performed to explore the expression of THBS4 in HCC tissues and adjacent samples. Next, colony formation assay and cell viability assay were used to assess the function of THBS4 on HCC cells growth while transwell assay and scratch test were for metastasis. Meanwhile Xenograft tumor models were further conducted to verify the function of THBS4 in HCC. As for mechanism in deep, we investigated the influence of THBS4 on epithelial-mesenchymal transition (EMT) development and the interaction between THBS4 and integrin (ITG) family using multiple experiments, including western blot, immunofluorescence and immunoprecipitation (IP). As a result, our research discovered that the overexpression of THBS4 in both HCC patients' tissues and cell lines mediates HCC cells proliferation and metastasis in vitro and in vivo. In-depth, THBS4 regulated EMT progression and interacted with ITG family to modulate FAK/PI3K/AKT pathway. In conclusion, THBS4 as an oncogene interacts with integrinβ1 (ITGB1) to regulate HCC development via FAK/PI3K/AKT pathway.
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http://dx.doi.org/10.1096/fj.202000043RDOI Listing
August 2020

TRPC1 exacerbate metastasis in gastric cancer via ciRS-7/miR-135a-5p/TRPC1 axis.

Biochem Biophys Res Commun 2020 08 6;529(1):85-90. Epub 2020 Jun 6.

Department of Thoracic Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China. Electronic address:

Metastasis is frequently occurred in end-stage GC. Nevertheless, the initiation and progression of metastasis in GC remains unclear. The transient receptor potential canonical (TRPC) has been confirmed to be crucial for metastasis in many kinds of tumors, including GC. However, the molecular mechanisms regulating TRPC1 is unclear. Therefore, we investigated the role and mechanisms of TRPC1 in GC metastasis. We first evaluated the role of TRPC1 in GC by searching the public database, and tested the expression of TRPC1 in 50 paired GC tissues by qRT-PCR and IHC assays. Then, we generated BGC-823-shTRPC1 cells and MKN-45-TRPC1 cells to investigate the effects of TRPC1 on metastasis in vitro. For the mechanism study, we applied luciferase reporter assay, RNA pull-down assay, as well as RIP assay to validate the interation of ciRS-7, miR-135a-5p and TRPC1 in GC cells. This study, we showed that TRPC1 exacerbate EMT in gastric cancer via ciRS-7/miR-135a-5p/TRPC1 axis, and target TRPC1 could be beneficial for end-stage GC patients.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.181DOI Listing
August 2020

The Effect of Helicobacter pylori Eradication in Patients with Gastroesophageal Reflux Disease: A Meta-Analysis of Randomized Controlled Studies.

Dig Dis 2020 12;38(4):261-268. Epub 2020 May 12.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China,

Aim: Helicobacter pylori infection has been established as a definite risk factor for gastric cancer. However, the consequence of H. pylori eradication on the progression of gastroesophageal reflux disease (GERD) remains controversial. The purpose of our study was to investigate the relationship between H. pylori eradication and the development of GERD.

Methods: A comprehensive, English literature search was performed from January 1990 to April 2019. Only randomized controlled trials (RCT) that evaluated the effect of H. pylori eradication on GERD were included. Meta-analysis of pooled OR was performed using Review Manger 5.1.7.

Results: Seventeen articles with 6,889 subjects (intention-to-treat) that fulfilled the inclusion criteria were finally included in the analysis. Of them, 8 RCTs have the similar study design and inclusion criterion, which included patients with H. pylori infection but without GERD at baseline. The OR for the development of erosive GERD after H. pylori eradication was 1.67 (95% CI 1.12-2.48, p = 0.01). The OR for the development of GERD-related symptoms after H. pylori eradication in eradication group compared with control group was 1.04 (95% CI 0.84-1.29, p = 0.71). In addition, 9 RCTs included patients with both baseline H. pylori infection and GERD. The OR for the healing rates and relapse rates after H. pylori eradication in the H. pylori eradication group vs. control group was 0.92 (95% CI 0.47-1.82, p = 0.82) and 1.12 (95% CI 0.60-2.09, p = 0.71), respectively.

Conclusions: Our meta-analyses showed H. pylori eradication may lead to the development of new erosive GERD. However, eradication of H. pylori may affect neither the healing rates nor relapse rates of preexisting GERD.
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http://dx.doi.org/10.1159/000504086DOI Listing
August 2020

Rectal Nonsteroidal Anti-Inflammatory Drugs for Endoscopic Retrograde Cholangiopancreatography Postoperative Pancreatitis Prevention: A Network Meta-Analysis.

J Clin Gastroenterol 2020 04;54(4):305-313

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an.

Background: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP procedure. Nonsteroidal anti-inflammatory drugs (NSAIDs) are reported to be one protective pharmacological agent with great efficacy regarding this complication. Recently, more trails have addressed this issue and some inconsistent results appeared. Therefore, this study aims to evaluate the efficacy and safety of different rectal NSAIDs schemes to prevent PEP.

Materials And Methods: Eligible studies published on PubMed, the Cochrane Library, Embase, Web of Science before November 2018 were reviewed, and those which met the inclusion criteria were included in the analysis. The preventions were divided as placebo/no treatment, post-ERCP rectal diclofenac, pre-ERCP rectal diclofenac, post-ERCP rectal indomethacin, pre-ERCP rectal indomethacin, indomethacin using during ERCP, and pre-ERCP rectal naproxen. The main outcomes included the incidence of PEP and its severity. Other complications were also analyzed.

Results: A total of 23 randomized controlled trials were included. The results of network meta-analysis illustrated that compared with the control, post-ERCP rectal diclofenac, pre-ERCP rectal diclofenac, and indomethacin were significantly associated with lower incidences of PEP. Moreover, it is notable that pre-ERCP rectal NSAIDs might reduce the severity of pancreatitis. Also, rectal NSAIDs may lead to less occurrence of asymptomatic hyperamylasemia. On the basis of the clustered ranking, pre-ERCP diclofenac appeared to be the superior intervention for PEP with satisfying efficacy.

Conclusions: The present study showed that pre-ERCP diclofenac is the optimal prevention method for PEP. However, more high quality head-to-head randomized controlled trials and observational studies are expected in the future.
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http://dx.doi.org/10.1097/MCG.0000000000001322DOI Listing
April 2020

Myocardin and myocardin-related transcription factor-A synergistically mediate actin cytoskeletal-dependent inhibition of liver fibrogenesis.

Am J Physiol Gastrointest Liver Physiol 2020 03 13;318(3):G504-G517. Epub 2020 Jan 13.

Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina.

Activation of hepatic stellate cells (HSCs), characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins, such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis, as well as the molecular mechanism under the process, remain unclear. Here, we report that myocardin and MRTF-A's expression and nuclear accumulation are prominently increased during the HSC activation process, accompanied by robust activation of actin cytoskeleton dynamics. Targeting myocardin and MRTF-A binding and function with a novel small molecule, CCG-203971, led to dose-dependent inhibition of HSC actin cytoskeleton dynamics and abrogated multiple functional features of HSC activation (i.e., HSC contraction, migration and proliferation) and decreased COL.1 expression in vitro and liver fibrosis in vivo. Mechanistically, blocking the myocardin and MRTF-A nuclear translocation pathway with CCG-203971 directly inhibited myocardin/MRTF-A-mediated serum response factor (SRF), and Smad2/3 activation in the COL.1α2 promoter and indirectly abrogated actin cytoskeleton-dependent regulation of Smad2/3 and Erk1/2 phosphorylation and their nuclear accumulation. Finally, there was no effect of CCG-203971 on markers of inflammation, suggesting a direct effect of the compound on HSCs and liver fibrosis. These data reveal that myocardin and MRTF-A are two important cotranscriptional factors in HSCs and represent entirely novel therapeutic pathways that might be targeted to treat liver fibrosis. Myocardin and myocardin-related transcription factor-A (MRTF-A) are upregulated in activated hepatic stellate cells (HSCs) in vitro and in vivo, closely associated with robustly increased actin cytoskeleton remodeling. Targeting myocardin and MRTF-A by CCG-203971 leads to actin cytoskeleton-dependent inhibition of HSC activation, reduced cell contractility, impeded cell migration and proliferation, and decreased COL.1 expression in vitro and in vivo. Dual expression of myocardin and MRTF-A in HSCs may represent novel therapeutic targets in liver fibrosis.
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http://dx.doi.org/10.1152/ajpgi.00302.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099496PMC
March 2020

Gastrectomy Versus Endoscopic Resection for Patients With Early-stage Gastric Adenocarcinoma: A Population-based Propensity Matching Study.

J Clin Gastroenterol 2020 Nov/Dec;54(10):871-878

Departments of Gastroenterology.

Background: This study aimed to compare the long-term results of patients who received these therapies.

Materials And Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried in this research for data of patients with early gastric adenocarcinoma who underwent gastrectomy or endoscopic resection from 2007 to 2015. Propensity score matching was selected to generate a balanced cohort. Competing-risk regression analysis was carried out on the matched cohort. Cancer-specific mortality (CSM) and other cause-specific mortality (OCSM) were compared using adjusted subdistribution hazard ratios (SHRs).

Results: In this study, 2214 patients with 191 underwent endoscopic treatment (ET) and 2023 who underwent surgery were identified. After propensity score matching, 474 patients were included in the analysis. The use of ET increased over time in patients, especially for those with cardia diseases. The ratio of 5-year CSM between ET and gastrectomy groups was 13.12% to 14.24% and the ratio of 5-year OCSM between them was 22.48% versus 14.31%. After adjusting for associated clinicopathologic factors, patients in both groups had similar CSM (SHR=0.87, 95% credible interval: 0.47-1.64, P=0.69) and OCSM (SHR=1.59, 95% credible interval: 0.94-2.68, P=0.08) in multivariable analysis.

Conclusion: The long-term prognosis appears equivalent t in patients with endoscopic resection and gastrectomy.
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http://dx.doi.org/10.1097/MCG.0000000000001306DOI Listing
December 2019

[Histone deacetylase 3 inhibitor alleviates alcohol-induced disruption of intestinal epithelial barrier via inhibiting nuclear factor κB].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2019 Sep;35(9):800-805

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. *Corresponding authors, E-mail:

Objective To investigate the role and mechanism of histone deacetylase 3 (HDAC3) in alcohol-induced inflammation and permeability of intestinal epithelial cells. Methods To select the proper concentration of alcohol, differentiated Caco-2 cells were treated with different concentrations (10, 25, 50, 100 and 200 mmol/L) of alcohol, and then cell viability was assayed by MTT assay; the mRNA and protein levels of HDAC3 were analyzed by real-time PCR and Western blot analysis. Differentiated Caco-2 cells were divided into three groups: control group, alcohol group (treatment with 50 mmol/L alcohol for 60 minutes), and alcohol combined with HDAC3 inhibitor group (pretreatment with 2 μmol/L RGFP966 1 hour before alcohol). ELISA was performed to detect tumor necrosis factor α (TNF-α) level in cell supernatant. Transepithelial electrical resistance (TER) was measured using a resistance meter. Western blot analysis was used to determine the protein levels relevant to tight junction (occludin and claudin-1) and NF-κB activation (IκB and phosphorylated NF-κBp65). Results Alcohol at 10, 25 and 50 mmol/L did not affect cell viability. The mRNA and protein expression levels of HDAC3 increased in a dose-dependent manner after alcohol treatment at these concentration s. Compared with the control group, TNF-α and phosphorylated NF-κBp65 levels increased, whereas TER and protein levels of occludin, claudin-1 and IκB decreased in the alcohol group. Compared with the alcohol group, TNF-α and phosphorylated NF-κBp65 levels were reduced, while TER and protein levels of occludin, claudin-1 and IκB were elevated in the alcohol combined with HDAC3 inhibitor group. Conclusion HDAC3 inhibition can attenuate alcohol-induced inflammation and permeability of intestinal epithelial cells, which may be related to the inactivation of NF-κB.
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September 2019

Long non-coding RNA SNAI3-AS1 promotes the proliferation and metastasis of hepatocellular carcinoma by regulating the UPF1/Smad7 signalling pathway.

J Cell Mol Med 2019 09 2;23(9):6271-6282. Epub 2019 Jul 2.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Emerging evidence has indicated that deregulation of long non-coding RNAs (lncRNAs) can contribute to the progression of human cancers, including hepatocellular carcinoma (HCC). However, the role and exact mechanism of most lncRNAs in tumours remains largely unknown. In the current study, we found a novel long non-coding RNA termed SNAI3-AS1 which was generally up-regulated in HCC tissues compared with normal control. Higher expression of SNAI3-AS1 was significantly correlated with shorter overall survival of HCC patients. Knockdown of SNAI3-AS1 inhibited the proliferation and metastasis of HCC cells in vitro, whereas overexpression of SNAI3-AS1 promoted the proliferation and metastasis of HCC cells. Further investigations showed that SNAI3-AS1 could affect HCC tumorigenesis by binding up-frameshift protein 1 (UPF1), regulating Smad7 expression and activating TGF-β/Smad pathway. Functionally, SNAI3-AS1 promoted HCC growth and metastasis by inducing tumour epithelial to mesenchymal transition (EMT). Taken together, these findings showed that SNAI3-AS1 promotes the progression of HCC by regulating the UPF1 and activating TGF-β/Smad pathway.
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http://dx.doi.org/10.1111/jcmm.14513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714236PMC
September 2019

Saikosaponin-d Suppresses COX2 Through p-STAT3/C/EBPβ Signaling Pathway in Liver Cancer: A Novel Mechanism of Action.

Front Pharmacol 2019 29;10:623. Epub 2019 May 29.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiao tong University, Xi'an, China.

Saikosaponin-d (SSd) is an active extract from , the dried root from the plant used in China for thousands of years to treat liver diseases. The SSd extract possesses valuable pharmacological activities including anti-cancer and anti-inflammatory effects; however, the mechanism underlying the anti-cancer activity of SSd is largely unknown. Here, we explored the mechanism of action of SSd as an anti-cancer agent for liver cancer in two human hepatocellular carcinoma cell lines. Using MTT and annexin-V-FITC/PI assays, Western blots, immunohistochemistry, qRT-PCR, luciferase reporter assay, and a JAK2-specific inhibitor (AG490), we demonstrated that the anti-tumorigenic effects of SSd act through the intermediatory p-STAT3/C/EBPβ signaling pathway to suppress cyclooxygenase (COX)-2. SSd effectively inhibited cell proliferation in a dose-dependent manner. Apoptosis was significantly increased in cells treated with SSd (2.5-15 µg/ml) with concurrent increase and decrease in pro- and anti-apoptosis proteins, respectively. COX-2, C/EBPβ, and p-STAT3 were significantly decreased, at both the translational and transcriptional levels, by SSd treatment. AG490 produced similar inhibitory effects on STAT3, p-STAT3, C/EBPβ, and COX-2. In conclusion, our data suggest that SSd controls liver cancer proliferation through suppression of the p-STAT3/C/EBPβ signaling pathway inhibiting COX2 expression. These findings further our understanding of the pharmacological action of SSd, providing new information on SSd mechanism of action and showing potential for SSd as a novel therapy for liver cancer.
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http://dx.doi.org/10.3389/fphar.2019.00623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549044PMC
May 2019

DANCR promotes HCC progression and regulates EMT by sponging miR-27a-3p via ROCK1/LIMK1/COFILIN1 pathway.

Cell Prolif 2019 Jul 30;52(4):e12628. Epub 2019 Apr 30.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Objectives: This research aims to verify that the long non-coding RNA differentiation antagonizing nonprotein coding RNA (LncRNA DANCR) could modulate the proliferation and metastasis of hepatocellular carcinoma (HCC), and it thus may work as a novel biomarker to render new orientation for early diagnosis and clinical therapy of HCC.

Materials And Methods: Firstly, qRT-PCR was used to detect the expression of genes including LncRNA DANCR and miR-27a-3p. Next, MTT assay, Ethynyldeoxyuridine (EdU) analysis and clone formation assay were used for investigating cell growth and proliferation. Meanwhile, transwell assay and wound healing assay were applied to evaluate the capacity of cell metastasis and motility, respectively. In addition, bioinformatic analysis and dual-luciferase reporter assay were applied to analyse molecular interaction. Next, we conducted immunofluorescence and Western blot for mechanic investigation. Last but not the least, xenograft tumours in nude mice were built by subcutaneously injecting Hep3B cells stably transfected with sh-NC and sh-DANCR to detect proliferation and SMMC-7721 cells stably transfected with sh-NC and sh-DANCR to investigate metastasis.

Results: The results of qRT-PCR and bioinformatic analysis revealed the high expression of DANCR in HCC. DANCR accelerated proliferation and metastasis of HCC cells and the knockdown of DANCR had the opposite effect. Meanwhile, xenograft tumours in sh-DANCR group grow slower and have smaller volumes compared with negative control group. Next, the antineoplastic effect of miR-27a-3p on cell growth and motility of HCC was confirmed. In addition, we clarified that DANCR acted as a ceRNA to decoy miR-27a-3p via mediating ROCK1/LIMK1/COFILIN1 pathway. In the end, we validated that DANCR/miR-27a-3p axis regulates EMT progression by cell immunofluorescence and Western blot.

Conclusions: In a word, DANCR promotes HCC development and induces EMT by decoying miR-27a-3p to regulate ROCK1/LIMK1/COFILIN1 pathway.
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http://dx.doi.org/10.1111/cpr.12628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668976PMC
July 2019

Long noncoding RNA NNT-AS1 promotes gastric cancer proliferation and invasion by regulating microRNA-363 expression.

J Cell Biochem 2019 04 15;120(4):5704-5712. Epub 2018 Oct 15.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Increasing studies showed that long noncoding RNAs (lncRNAs) had crucial regulatory roles in various tumors, including gastric cancer (GC). Recent studies demonstrated that lncRNA nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) played an important role in several tumors. However, the role and expression of NNT-AS1 in GC progression remain unknown. In our study, we indicated that NNT-AS1 expression was upregulated in GC samples compared with the nontumor tissues. We also showed that NNT-AS1 expression was upregulated in the GC cell lines. Ectopic expression of NNT-AS1 promoted GC cell line HGC-27 cell proliferation, cell cycle progression, and invasion. In addition, we showed that NNT-AS1 acted as a sponge competing endogenous RNA for microRNA-363 (miR-363), which was downregulated in the GC samples and cell lines. miR-363 expression was negatively related with NNT-AS1 expression in GC samples. Upregulated expression of miR-363 suppressed GC cell growth, cycle, and invasion. Furthermore, we reported that elevated expression of NNT-AS1 promoted GC cell proliferation, cycle, and invasion partly by suppressing miR-363 expression. These results indicated that lncRNA NNT-AS1 acted as an oncogene in the development of GC partly by inhibiting miR-363 expression.
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http://dx.doi.org/10.1002/jcb.27855DOI Listing
April 2019

Long non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-26a-5p/GSK3β signal pathway.

Cell Death Dis 2018 08 30;9(9):888. Epub 2018 Aug 30.

Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.

Accumulating evidence have suggested that long non-coding RNAs (lncRNAs) had malfunctioning roles in the development of human cancers. The present study aimed to investigate the role of lncRNA small nucleolar RNA host gene 5 (SNHG5) in hepatocellular carcinoma (HCC) progression using human tissues and cell lines. The quantitative real-time PCR results showed that SNHG5 was up-regulated in both HCC tissues and hepatoma cell lines and was closely associated with tumor size, hepatitis B virus infection, histologic grade, TNM stage, and portal vein tumor thrombus (PVTT) in HCC patients. Knockdown of SNHG5 induced apoptosis and repressed cell cycle progression, cell growth, and metastasis in hepatoma cell lines, whereas overexpression of SNHG5 had the opposite effects. In vivo functional assay, xenograft tumors grown from SNHG5-knockdown cells had smaller mean volumes than the tumors grown from negative control cells. Further investigations showed that SNHG5 may act as a competing endogenous RNA by competitively binding miR-26a-5p and thereby modulating the derepression of downstream target GSK3β, which were further confirmed by luciferase reporter assay. Functionally, SNHG5 promotes tumor growth and metastasis by activating Wnt/β-catenin pathway and inducing epithelial to mesenchymal transition (EMT). Taken together, SNHG5 promotes HCC progression by competitively binding miR-26a-5p and regulating GSK3β and Wnt/β-catenin signal pathway.
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http://dx.doi.org/10.1038/s41419-018-0882-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117363PMC
August 2018

The Comparison between Endoscopic Submucosal Dissection and Surgery in Gastric Cancer: A Systematic Review and Meta-Analysis.

Gastroenterol Res Pract 2018 18;2018:4378945. Epub 2018 Feb 18.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.

Aims: There are two treatment modalities for early gastric cancer (EGC)-surgery and endoscopic submucosal dissection (ESD). We aimed to compare the safety and efficacy of ESD with surgery.

Method: The article was performed by searching PubMed databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) calculated and value.

Results: 13 studies were identified. The incidence of perforation in two groups was different [OR = 6.18 (95% CI: 1.37-27.98), = 0.02]. The prevalences of synchronous and metachronous cancer in the ESD group were higher than those in the surgery group [OR = 8.52 (95% CI: 1.99-36.56),  = 0.004 and OR = 7.15 (95% CI: 2.95-17.32), < 0.0001]. The recurrence and complete resection rates were different [OR = 6.93 (95% CI: 2.83-16.96), < 0.0001 and OR = 0.32 (95% CI: 0.20-0.52), < 0.00001]. Compared with the surgery group, the hospital stay was shorter [IV = -7.15 (95% CI: -9.08-5.22), < 0.00001], the adverse event rate was lower, and the quality of life (QOL) was better in the ESD group. The difference of bleeding was not found.

Conclusion: ESD appears to be preferable for EGC, due to a lower rate of adverse events, shorter hospital stay, cheaper cost, and higher QOL.
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http://dx.doi.org/10.1155/2018/4378945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835246PMC
February 2018

CENP-H regulates the cell growth of human hepatocellular carcinoma cells through the mitochondrial apoptotic pathway.

Oncol Rep 2017 Jun 26;37(6):3484-3492. Epub 2017 Apr 26.

Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

The genomic alterations of hepatocellular carcinoma (HCC) are still unclear. Centromere protein-H (CENP-H) has been shown to be associated with many solid tumors. Our previous study found that CENP-H was upregulated in HCC and was related to patient prognosis. However, the biological functions of CENP-H in HCC and the possible underlying mechanisms have not been well elucidated. In the present study, we demonstrated that CENP-H knockdown inhibited the proliferation of Hep3B cells and decreased colony formation ability of single cells in vitro. Furthermore, CENP-H knockdown induced Hep3B cell apoptosis, and apoptotic bodies were observed using transmission electron microscopy. The protein expression of cleaved caspase-3 was upregulated in Hep3B cells after CENP-H knockdown. Additionally, a Bax/Bcl-2 ratio imbalance with a significant increase of Bax and a substantial decrease of Bcl-2 at both the mRNA and protein levels were determined in this study. In an animal experiment, CENP-H knockdown blocked the growth of Hep3B subcutaneous xenografts. Immunohistochemistry revealed that the protein expression of cleaved caspase-3 and Bax was increased, whereas the protein expression of Bcl-2 and Ki-67 was decreased in subcutaneous xenografts of the CENP-H-knockdown group. In summary, CENP-H may be involved in cell proliferation and apoptosis of HCC cells through the mitochondrial apoptotic pathway. Combined with previous studies, the data provide a new perspective on HCC development and progression.
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http://dx.doi.org/10.3892/or.2017.5602DOI Listing
June 2017

MicroRNA-26a inhibits proliferation and metastasis of human hepatocellular carcinoma by regulating DNMT3B-MEG3 axis.

Oncol Rep 2017 Jun 19;37(6):3527-3535. Epub 2017 Apr 19.

Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

miR-26a is known to play an important oncosuppressive role in HCC. However, its regulatory role and relationship with other non-coding RNAs is less clear. In the present study, we report that the expression levels of miR-26a and long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) were frequently downregulated in HCC tissues compared to matched non-malignant tissues. In addition, the expression levels of miR-26a and MEG3 were negatively correlated with the tumor sizes and TNM clinical stage in HCC patients. Overexpression of miR-26a significantly reduced the capacity of proliferation, invasion and migration of HCC cells. Moreover, we demonstrated that DNA methyltransferase 3b (DNMT3B) was a direct target gene of miR-26a. Overexpression of miR-26a suppressed the expression level of DNMT3B. Inhibited expression of DNMT3B showed similar tumor suppressive effects induced by miR-26a upregulation, and resulted in the upregulation of MEG3. Furthermore, we found that the expression levels of DNMT3B were upregulated in the HCC tissues compared with non-malignant tissues, and it was inversely correlated with miR-26a and MEG3 in HCC tissues. Thus, these results provided a plausible link between the observed reduction of miR-26a and MEG3 in HCCs. Together, the present study added miR-26a/DNMT3B/MEG3 axis to the complex mechanisms of HCC development.
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http://dx.doi.org/10.3892/or.2017.5579DOI Listing
June 2017

Efficacy and Safety of Radiofrequency Ablation Combined with Transcatheter Arterial Chemoembolization for Hepatocellular Carcinomas Compared with Radiofrequency Ablation Alone: A Time-to-Event Meta-Analysis.

Korean J Radiol 2016 Jan-Feb;17(1):93-102. Epub 2016 Jan 6.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.

Objective: To compare the efficacy and safety of combined radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE) with RFA alone for hepatocellular carcinomas (HCC).

Materials And Methods: Randomized controlled trial (RCT) studies that compared the clinical or oncologic outcomes of combination therapy of TACE and RFA versus RFA for the treatment of HCC were identified through literature searches of electronic databases (Pubmed, Embase, Cochrane Library, China Biology Medicine disc, China National Knowledge Infrastructure, and Google Scholar). Hazard ratios (HRs) or odds ratios (ORs) with their corresponding 95% confidence interval (CI) were combined as the effective value to assess the summary effects. The strength of evidence was rated by the Grading of Recommendations Assessment, Development, and Evaluation system.

Results: Six RCTs with 534 patients were eligible for inclusion in this meta-analysis. The meta-analysis showed that the combination of TACE and RFA is associated with a significantly longer overall survival (HR = 0.62, 95% CI: 0.49-0.78, p < 0.001) and recurrence-free survival (HR = 0.55, 95% CI: 0.40-0.76, p < 0.001) in contrast with RFA monotherapy. The seemingly higher incidence of major complications in the combination group compared with RFA group did not reach statistical significance (OR = 1.17, 95% CI: 0.39-3.55, p = 0.78).

Conclusion: In patients with HCC, the combination of TACE and RFA is associated with significantly higher overall survival and recurrence-free survival, as compared with RFA monotherapy, without significant difference in major complications.
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http://dx.doi.org/10.3348/kjr.2016.17.1.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720818PMC
September 2016

miR-488 acts as a tumor suppressor gene in gastric cancer.

Tumour Biol 2016 Jul 6;37(7):8691-8. Epub 2016 Jan 6.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.

MicroRNAs (miRNAs) are small, non-coding RNAs that modulate development, cell proliferation, and apoptosis. The deregulated expression of microRNAs is found in carcinogenesis including gastric cancer (GC). In this study, we showed that the expression levels of miR-488 were downregulated in GC tissues compared to in non-tumor tissues. In addition, the expression of miR-488 was also lower in GC cell lines in contrast with the gastric epithelial cell line (GES). In addition, the expression level of miR-488 was negatively correlated with the TNM stage in GC patients, and lower miR-488 expression was found in tumors with advanced TNM stage. The ectopic expression of miR-488 suppressed the GC cell proliferation, cell cycle, colony information, and migration. PAX6 was identified as a direct target gene of miR-488 in HGC-27. Moreover, we found that the expression level of PAX6 was upregulated in the GC tissues compared with the non-tumor tissues. The PAX6 expression level was correlated with the cancer TNM stage, and higher PAX6 expression was found in tumors with advanced TNM stage. Furthermore, there was an inverse correlation between PAX6 and miR-488 expression levels in GC tissues. Therefore, these studies demonstrated that miR-488 might act as a tumor suppressor miRNA in the development of GC.
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http://dx.doi.org/10.1007/s13277-015-4645-yDOI Listing
July 2016

TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of Notch signaling.

Oncotarget 2015 Oct;6(32):32610-21

Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

Thymoquinone (TQ) has been reported to possess anti-tumor activity in various types of cancer. However, its effects and molecular mechanism of action in hepatocellular carcinoma (HCC) are still not completely understood. We observed that TQ inhibited tumor cell growth in vitro, where treatment with TQ arrested the cell cycle in G1 by upregulating p21 and downregulating cyclinD1 and CDK2 expression; moreover, TQ induced apoptosis by decreasing expression of Bcl-2 and increasing expression of Bax. Simultaneously, TQ demonstrated a suppressive impact on the Notch pathway, where overexpression of NICD1 reversed the inhibitory effect of TQ on cell proliferation, thereby attenuating the repressive effects of TQ on the Notch pathway, cyclinD1, CDK2 and Bcl-2, and also diminishing upregulation of p21 and Bax. In a xenograft model, TQ inhibited HCC growth in nude mice; this inhibitory effect in vivo, as well as of HCC cell growth in vitro, was associated with a discernible decline in NICD1 and Bcl-2 levels and a dramatic rise in p21 expression. In conclusion, TQ inhibits HCC cell growth by inducing cell cycle arrest and apoptosis, achieving these effects by repression of the Notch signaling pathway, suggesting that TQ represents a potential preventive or therapeutic agent in HCC patients.
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http://dx.doi.org/10.18632/oncotarget.5362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741716PMC
October 2015

Overexpression of CENP-H as a novel prognostic biomarker for human hepatocellular carcinoma progression and patient survival.

Oncol Rep 2013 Nov 20;30(5):2238-44. Epub 2013 Aug 20.

Department of Gastroenterology, First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

Centromere protein H (CENP-H) has been shown to be significantly upregulated in many types of cancers and is associated with disrupted cell cycle regulation, cell proliferation and genetic instability. The aim of the present study was to explore the expression and localization of CENP-H in hepatocellular carcinoma (HCC) and determine whether its overexpression is a prognostic biomarker for HCC. Reverse transcription-polymerase chain reaction (pcr), real-time qPCR and western blotting were used to compare CENP-H expression at the mRNA and protein levels in HCC samples and corresponding adjacent non-cancerous samples. CENP-H protein levels were determined in 60 paired paraffin-embedded HCC tissues using immunohistochemistry (IHC), and the correlation with clinicopathological features and patient prognosis was analyzed. In addition, an immunofluorescence assay was performed to test the expression and localization of CENP-H protein in HCC cells. Results showed that levels of CENP-H mRNA and protein were higher in HCC samples than in the corresponding adjacent non-cancerous samples. In 60 paired paraffin-embedded tissues, CENP-H was upregulated in the HCC samples (38/60, 63.3%) relative to the adjacent non-cancerous samples (21/60, 35%, P=0.003), and a higher level of upregulation was associated with tumor size (P=0.032); higher histological grade (P=0.001); more advanced TNM stage (P=0.002) and Chinese clinical stage (P=0.008); and poorer prognosis. In addition, consistent with the results of IHC, the immunofluorescence assay showed that CENP-H was localized in the nucleus of Hep3B cells. CENP-H was overexpressed in HCC, and its level of upregulation was an independent prognostic indicator, suggesting that CENP-H may be an effective therapeutic strategy for the treatment of HCC.
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http://dx.doi.org/10.3892/or.2013.2675DOI Listing
November 2013