[Show abstract][Hide abstract] ABSTRACT: Emerging evidence indicates that the neuronal guidance molecule SLIT plays a role in tumor suppression, as SLIT-encoding genes are inactivated in several types of cancer, including lung cancer; however, it is not clear how SLIT functions in lung cancer. Here, our data show that SLIT inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. We also determined that the ROBO intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, SLIT-dependent activation of RhoA is mediated by ROBO inhibition of Myo9b. In a murine model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis. Evaluation of human lung cancer and adjacent nontumor tissues revealed that Myo9b is upregulated in the cancer tissue. Moreover, elevated Myo9b expression was associated with lung cancer progression and poor prognosis. Together, our data identify Myo9b as a key player in lung cancer and as a ROBO-interacting protein in what is, to the best of our knowledge, a newly defined SLIT/ROBO/Myo9b/RhoA signaling pathway that restricts lung cancer progression and metastasis. Additionally, our work suggests that targeting the SLIT/ROBO/Myo9b/RhoA pathway has potential as a diagnostic and therapeutic strategy for lung cancer.
The Journal of clinical investigation 11/2015; 2015. DOI:10.1172/JCI81673 · 13.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and aim:
Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis. The effects of anticoagulation on these patients were still unclear, especially for more advanced PVT. The aim of this study was to retrospectively assess the resolution of PVT and liver disease progression in a large cohort of cirrhotic patients with PVT with or without anticoagulation therapy.
We analyzed data from 66 cirrhotic patients with PVT from January 2002 to June 2014. Thirty patients were anticoagulated with warfarin and 36 patients were untreated. PVT and hepatic decompensation were evaluated.
For anticoagulated patients, the thrombosis had improved in 15 (68.2%) patients, was stable in four patients (18.2%), and progressed in three patients (13.6%). For untreated patients, the thrombosis had improved in four patients (25%), was stable in six patients (37.5%), and progressed in six patients (37.5%). The anticoagulation group had significantly better recanalization rates than the untreated group (P=0.011). Degree of superior mesenteric vein (P=0.032, hazard ratio: 15.4; 95% confidence interval: 1.3-200) was a significant predictor. In addition, anticoagulation can effectively improve PVT with a degree less than 75% in the main portal vein compared with untreated patients (6/6 vs. 2/6, P=0.030). The probability of hepatic decompensation at 1 year was 15.6 and 17.9% between the anticoagulation and the untreated groups (P=0.847). Albumin (P=0.06, hazard ratio: 0.860; 95% confidence interval: 0.772-0.959) was a significant predictor.
Anticoagulation with warfarin might result in the resolution of more advanced PVT effectively and safely in patients with liver cirrhosis. In addition, we did not demonstrate the benefit of anticoagulation for the decompensation or death.
European journal of gastroenterology & hepatology 10/2015; DOI:10.1097/MEG.0000000000000482 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The strategy of using fecal microbiota transplantation (FMT) for refractory ulcerative colitis (UC) remains unclear if single FMT failed to induce remission. This study aimed to evaluate the efficacy and safety of a designed step-up FMT strategy for the steroid-dependent UC.
Fifteen patients with steroid-dependent UC were enrolled, and treated with step-up FMT strategy. Follow-up clinical data was collected for a minimum of 3 months. Fecal microbiota composition before and post FMT of patients and related donors were analyzed by 16S rRNA sequencing.
Eight of fourteen (57.1 %) patients achieved clinical improvement and were able to discontinue steroids following step-up FMT. One patient was lost to follow-up. Among the 8 patients who responded, five (35.7 %) received one FMT therapy, one (7.1 %) received two FMTs, and two (14.2 %) received two FMTs plus a scheduled course of steroids. Four (28.6 %) of the 8 patients who responded maintained long-term remission during follow-up (3–18 months). Six patients (42.9 %) failed to meet the criteria of clinical improvement and maintained steroid dependence, though three experienced transient or partial improvement. Microbiota analysis showed that FMT altered the composition greatly, and a microbiota composition highly similar to that of the donor emerged in the patients with successful treatment. No severe adverse events occurred during treatment and follow-up.
Step-up FMT strategy shows promise as a therapeutic strategy for patients with steroid-dependent UC, likely due to the successful restructuring of gut microbial composition.
Trial registration: ClinicalTrials.gov, Number NCT01790061
Journal of Translational Medicine 09/2015; 13(1):298. DOI:10.1186/s12967-015-0646-2 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effect of chemotherapy of gastric cancer (GC) remains very poor because of multidrug resistance (MDR). However, the mechanisms underlying MDR of GC remains far from fully understood. The aim of this study is to illustrate the potential mechanisms of the MDR of GC at mainly the long non-coding RNA (lncRNA) level. In this study, GC cell line, SGC7901, and two MDR sublines, SGC7901/VCR and SGC7901/ADR were subjected to an lncRNA microarray analysis. Bioinformatics and verification experiments were performed to investigate the potential lncRNAs involved in the development of MDR. Pathway analysis indicated that 15 pathways corresponded to down-regulated transcripts and that 20 pathways corresponded to up-regulated transcripts (p-value cut-off is 0.05). GO analysis showed that the highest enriched GOs targeted by up-regulated transcripts were "system development" and the highest esenriched GOs targeted by the down-regulated transcripts were "sterol biosynthetic process". Our study is the first to interrogate differentially expressed lncRNAs in human GC cell line and MDR sublines and indicates that lncRNAs are worthwhile for further study to be the novel candidate biomarkers for the clinical diagnosis of MDR and potential targets for further therapy.
PLoS ONE 08/2015; 10(8):e0135461. DOI:10.1371/journal.pone.0135461 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of transjugular intrahepatic portosystemic shunt (TIPS) for the secondary prophylaxis of variceal bleeding in cirrhotic patients with portal vein thrombosis (PVT) remains obscure.
This prospective cohort study aimed to assess the risk factors associated with TIPS technical success, outcome, and prognosis in cirrhotic patients with PVT and a history of variceal bleeding.
Between May 2009 and April 2011, 51 cirrhotic patients with PVT who attempted TIPS procedures for the prevention of variceal rebleeding were enrolled.
TIPS success rate was 84% (43/51). An increased degree of thrombosis within the portal trunk and portal vein branches was inversely associated with TIPS success. Median follow-up time was 40.07 months (range: 0.02-56.87). The cumulative risk of rebleeding was significantly different between TIPS success and failure group (p=0.002). The univariate analysis also demonstrated that TIPS failure was the only significant predictor associated with rebleeding (hazard ratio [HR]=4.174, 95% confidence interval [CI]: 1.558-11.186). In TIPS success group, the cumulative rates free of shunt dysfunction at the 6(th) and 12(th) month were 79% and 76%, respectively. Absence of total superior mesenteric vein (SMV) thrombosis was the only independent predictor (HR=0.189, 95%CI: 0.047-0.755). In TIPS success group, the 1- and 3-year cumulative survival rates were 77% and 62%, respectively. Albumin level was the only independent predictor (HR=0.877, 95% CI: 0.779-0.986).
Successful TIPS insertions could effectively prevent from rebleeding in cirrhotic patients with PVT and variceal bleeding. Degree of PVT and SMV thrombosis was associated with TIPS failure and shunt dysfunction, respectively. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Liver international: official journal of the International Association for the Study of the Liver 08/2015; DOI:10.1111/liv.12929 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The treatment effects of advanced solid cancer are unsatisfactory, and novel therapeutic approaches are much needed. Keratinocyte growth factor receptor (KGFR) is a receptor tyrosine kinase that is primarily localized on epithelial cells. KGFR may play important roles in epithelial cell proliferation and differentiation, epithelial wound repair, embryonic development, immunity, tumor formation and development.
This review summarizes the expression, function and mechanism of KGFR in solid cancer, and analyzes its value for the cancer therapy. Furthermore, this study discusses the limitations of KGFR-based therapy, and envisages future developments in the clinical applications of KGFR.
KGFR may function as an ideal therapeutic target for solid cancer. Continued basic investigation of KGFR-mediated pathways will push insight into the novel strategies of target therapy. More in vivo studies and clinical trials should be performed to promote the translational bridging of the latest research into clinical application.
[Show abstract][Hide abstract] ABSTRACT: Esophageal cancer (EC) remains a leading cause of cancer-related death in Asian countries. Due to the biology of EC, including aggressive local invasion, early metastasis and drug resistance, EC has a low survival rate. Therefore, molecular markers for prognosis judgment are urgently required so as to identify subgroups of patients that will benefit from more aggressive therapeutic interventions. So far, many genes and miRNAs, such as VEGF, cyclin D1, and miR-21, have been shown to be valuable when predicting the prognosis of EC. Some circulating molecules, including miR-200c, miR-1246, miR-31, have been identified as the independent risk factors for poor survival. However, the function and mechanism of these molecules in EC remains unclear. More clinical studies should be performed to promote the clinical use of prognosis-related markers in the management of EC.
[Show abstract][Hide abstract] ABSTRACT: Multi-drug resistance is the main cause of treatment failure in cancer patients. How to identify molecules underlying drug resistance from multi-omics data remains a great challenge. Here, we introduce a data biased strategy, ProteinRank, to prioritize drug-resistance associated proteins in cancer cells. First, we identified differentially expressed proteins in Adriamycin and Vincristine resistant gastric cancer cells compared to their parental cells using iTRAQ combined with LC-MS/MS experiments, and then mapped them to human protein-protein interaction network; second, we applied ProteinRank to analyze the whole network and rank proteins similar to known drug resistance related proteins. Cross validations demonstrated a better performance of ProteinRank compared to the method without usage of MS data. Further validations confirmed the altered expressions or activities of several top ranked proteins. Functional study showed PIM3 or CAV1 silencing was sufficient to reverse the drug resistance phenotype. These results indicated ProteinRank could prioritize key proteins related to drug resistance in gastric cancer and provided important clues for cancer research.
[Show abstract][Hide abstract] ABSTRACT: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis due to its high frequency of metastasis and invasion. Recent studies have suggested glucose-regulated protein 78KD (GRP78) may play important roles in progression and development of malignant tumors. However, the mechanisms of invasion and metastasis of ESCC in relation to GRP78 still remain obscure.
The aim of this study was to investigate the effect of GRP78 on invasion and metastasis of ESCC and to explore its potential mechanism.
GRP78 expression levels in ESCC tissues were examined by immunohistochemistry. RT-PCR and western blot were used to test the relative expression of GRP78 in non-metastatic and high-metastatic ESCC cells. In vitro and in vivo studies were both performed to investigate the role of GRP78 in invasion and metastasis of ESCC cells. The expression of metastasis-related proteins was examined by western blot in GRP78-depleted cells.
The expression of GRP78 is correlated with invasion, metastasis and poor prognosis in ESCC patients. GRP78 expression was significantly higher in highly metastatic cells compared with ESCC non-metastatic cells. In addition, down-regulation of GRP78 significantly inhibited the metastatic potential of ESCC cells in both in vitro and in vivo studies. The expression of MMP-2 and MMP-9 were down-regulated in GRP78-depleted ESCC cells.
The present study demonstrated that GRP78 plays important roles in invasion and metastasis of ESCC, indicating that GRP78 might be used as a potential prognostic and therapeutic marker in patients with ESCC by modulating the expression of MMP-2 and MMP-9.
[Show abstract][Hide abstract] ABSTRACT: Metastasis, the capability of tumor cells to spread and grow at distant sites, is the main factor in cancer mortality. Because metastasis in sentinel lymph nodes suggests the original spread of tumors from a primary site, the detection of lymph node involvement with cancer serves as an important prognostic and treatment parameter. Here we have developed a panel of DNA aptamers specifically binding to colon cancer cells SW620 derived from metastatic site-lymph node, with high affinity after 14 rounds of selection by the cell-SELEX method. The selected aptamers were subjected to flow cytometry to evaluate their binding affinity. Aptamer XL-33 with the best binding affinity (0.7 nM) and its truncated sequence XL-33-1 with 45 nt showed excellent selectivity for the recognition of target cells SW620. The binding entity of the selected aptamer has been preliminarily determined as a membrane protein on the cell surface. Tissue imaging results showed that XL-33-1 was highly specific to the metastatic tumor tissue or lymph node tissue with corresponding cancer metastasis, and displayed an 81.7% detection rate against colon cancer tissue with metastasis in regional lymph nodes, as well as a 72.4% positive rate against lymph node tissue with colon cancer metastasis. These results suggest that XL-33-1 holds great potential to become a molecular imaging agent for early detection of lymph node tissue with colon cancer metastasis. More importantly, this study clearly demonstrates that metastatic-cell-based SELEX can be used to generate DNA ligands specifically recognizing metastatic cancer cells, which is of great significance for metastatic cancer diagnosis and treatment.
[Show abstract][Hide abstract] ABSTRACT: The coagulation abnormalities in non-cirrhotic Budd-Chiari syndrome (NC-BCS) and non-cirrhotic portal vein thrombosis (NC-PVT) are unclear. We conducted this case-control study to investigate the coagulation profile of NC-BCS and NC-PVT in Chinese patients.
We measured the levels of factors II, V, VII, VIII, IX, X, XI, XII, protein C (PC), protein S (PS) and antithrombin (AT) in blood samples from 37 NC-BCS patients, 74 NC-PVT patients, and 100 healthy controls. The levels and ratios of pro- and anti-coagulation factors were compared between patients with NC-BCS and healthy controls, between different types of NC-BCS and between NC-PVT and healthy controls.
In patients with NC-BCS, factor VIII (P<0.001) was significantly elevated; factor V (P<0.001), VII (P<0.001), IX (P = 0.003), X (P<0.001), XI (P<0.001), XII (P<0.001), PC (P<0.001) and AT (P<0.001) were significantly decreased; and no difference was observed for factor II (P = 0.088) and PS (P = 0.199) compared with healthy controls. Factor VIII-to-PC (P = 0.008), factor VIII-to-PS (P = 0.037) and factor VIII-to-AT (P = 0.001) were significantly increased; other ratios were significantly reduced or did not show any difference. No differences were observed between different types of NC-BCS for individual pro- and anti-coagulation factors or the ratios between them. Among patients with NC-PVT, factor VIII (P<0.001) was significantly elevated and other factors were significantly decreased. Factor II-to-PC (P<0.001), factor VIII-to-PC (P<0.001), factor IX-to-PC (P<0.001), factor VIII-to-PS (P<0.001), factor II-to-AT (P<0.001), factor VIII-to-AT (P<0.001) and factor IX-to-AT (P<0.001) were significantly increased; all other ratios for NC-PVT were significantly reduced or did not show any significant difference.
NC-BCS and NC-PVT are associated with elevated levels of factor VIII and the decreased levels of PC and AT were probably the most significant features of coagulation imbalance. Additionally, NC-PVT was associated with decreased levels of PS.
PLoS ONE 03/2015; 10(3):e0119909. DOI:10.1371/journal.pone.0119909 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This paper aimed to systematically review the survival of Budd-Chiari syndrome and to identify the most robust prognostic predictors. Overall, 79 studies were included. According to the treatment modalities, the median 1-, 5- and 10-year survival rate was 93, 83 and 73% after interventional radiological treatment; 81, 75 and 72.5% after surgery other than liver transplantation; 82.5, 70.2 and 66.5% after liver transplantation and 68.1, 44.4% and unavailable after medical therapy alone. According to the publication years, the median 1-, 5- and 10-year survival rate was 68.6, 44.4% and unavailable before 1990; 75.1, 69.5 and 57% during the year 1991-1995; 77, 69.6 and 65.6% during the year 1996-2000; 86.5, 74 and 63.5% during the year 2001-2005 and 90, 82.5 and 72% after 2006. Bilirubin, creatinine and ascites were more frequently identified as significant prognostic factors in univariate analyses. But their statistical significance was less frequently achieved in multivariate analyses.
Expert Review of Gastroenterology and Hepatology 03/2015; DOI:10.1586/17474124.2015.1024224 · 2.42 Impact Factor