Epigenetic deregulation of MLF1 drives intrahepatic cholangiocarcinoma progression through EGFR/AKT and Wnt/ß-catenin signaling.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with multiple etiologies and is largely refractory to current treatment strategies. Myeloid leukemia factor 1 (MLF1) is associated with human cancer progression. Nevertheless, the function of MLF1 in iCCA remains unknown. METHODS: We performed expression analyses of MLF1 in human iCCA. In vitro and in vivo experiments were conducted to investigate the role of MLF1 in iCCA progression. The upstream regulatory mechanism of MLF1 upregulation in iCCA was deciphered by luciferase and DNA methylation analyses. RESULTS: MLF1 was significantly upregulated in clinical iCCA tissue specimens and human iCCA cell lines. MLF1 was positively correlated with KRT19 and MUC1 expression and epithelial-mesenchymal transition (EMT) gene set enrichment score in clinical iCCA. High MLF1 expression was independently associated with worse prognoses in iCCA patients after curative resection. In addition, experimental knockdown of MLF1 attenuated, while overexpression of MLF1 promoted the proliferation, invasiveness, and growth of iCCA cells in vitro and in vivo. Mechanically, MLF1 comodulated EGFR/AKT and Wnt/ß-catenin signalings through regulating EGFR, AKT, WNT3, and p-GSK3ß expression. Promoter CpG sites' hypermethylation-induced downregulation of miR-29c-3p contributed to MLF1 upregulation in iCCA patients. The upregulation of DNA methyltransferase (DNMT)1, 3A, and 3B downregulated miR-29c-3p by dictating promoter DNA methylation pattern. MiR-29c-3p showed therapeutic potential by targeting MLF1 in iCCA. CONCLUSIONS: Our results demonstrated that hypermethylation-mediated miR-29c-3p downregulation contributes to MLF1 upregulation in iCCA, which resulted in tumor cells' proliferation and metastasis through comodulating EGFR/AKT and Wnt/ß-catenin signalings.

Epigenetic dysregulation-mediated COL12A1 upregulation predicts worse outcome in intrahepatic cholangiocarcinoma patients.

BACKGROUND: Collagen type XII alpha 1 chain (COL12A1) is associated with human cancer progression. Nevertheless, the expression pattern and the function of COL12A1 in intrahepatic cholangiocarcinoma (iCCA) remain unknown. The present study was performed to assess the role of COL12A1 in iCCA. RESULTS: A total of 1669 genes, differentially expressed between iCCA and nontumor liver tissue samples, were identified as potential tumor-specific biomarkers for iCCA patients. Of these, COL12A1 was significantly upregulated in clinical iCCA tissue samples and correlated with epithelial-mesenchymal transition gene set enrichment score and advanced tumor stage in clinical iCCA. COL12A1-high expression was associated with the poor prognoses of iCCA patients (n = 421) from four independent cohorts. Promoter hypermethylation-induced downregulation of miR-424-5p resulted in COL12A1 upregulation in clinical iCCA. Experimental knockout of COL12A1 inhibited the proliferation, invasiveness and growth of iCCA cells. MiR-424-5p had a therapeutic potential in iCCA via directly targeting COL12A1. CONCLUSIONS: Promoter hypermethylation-induced miR-424-5p downregulation contributes to COL12A1 upregulation in iCCA. COL12A1 is a promising druggable target for epigenetic therapy of iCCA.

Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2.

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.

Demethylation at enhancer upregulates MCM2 and NUP37 expression predicting poor survival in hepatocellular carcinoma patients.

BACKGROUND: Identification of novel biomarker is important for development of molecular-targeted therapy agents for patients with hepatocellular carcinoma (HCC). This study aims to identify potential prognostic biomarkers and investigate epigenetic mechanism of HCC development. METHODS: Public bulk-RNA seq datasets and proteomic dataset were screened for identification of potential prognostic biomarkers for HCC patients. Public methylomic datasets were analyzed for deciphering the epigenetic mechanism regulating HCC-associated gene expression. Immunoblotting, immunohistochemistry, real-time PCR, and pyrosequencing were used to validate the findings from bioinformatic analyses. RESULTS: Minichromosome maintenance complex component 2 (MCM2) and nucleoporin 37 (NUP37) were overexpressed in human HCC tissues and hepatoma cell lines. MCM2 significantly positively correlated with NUP37 expression. Higher expression of MCM2 or NUP37 was significantly associated with advanced tumor stage and worse overall survival in 3 large independent HCC cohorts (n = 820). MCM2 and NUP37 overexpression are independent prognostic risk factors for HCC patients. Demethylation at an enhancer of MCM2 gene was a common event in patients with HCC, which significantly negatively correlated with MCM2 and NUP37 mRNA expression. CONCLUSIONS: Demethylation at enhancer regulates MCM2 and NUP37 expression in HCC. MCM2 and NUP37 are promising prognostic biomarkers and potential targets for epigenetic therapy in HCC patients.

Recombinant Human Thrombopoietin Accelerates the Recovery of Platelet in Patients With Lower-Risk Myelodysplastic Syndrome: A Proof-of-Concept Study.

AIM: The effect of recombinant human thrombopoietin (rhTPO) is largely unknown in lower-risk myelodysplastic syndrome (LR-MDS). This study aimed at investigating the safety and efficacy of rhTPO in patients with LR-MDS. METHODS: LR-MDS patients receiving stanozolol (2 mg, t.i.d.) and supportive care alone (non-rhTPO) or additional rhTPO were enrolled in this study prospectively. rhTPO was given at 15,000 U (q.d.) for 7 days/month for at least 3 months. Patients stopped rhTPO if the platelet count was higher than 50 × 109/L or had no effects after 3 months of treatment. The overall response (OR), complete response (CR), platelet response, side effects, clone evolution, and clinical outcome were evaluated. RESULT: Thirty-five patients were enrolled: 20 (57.1%) patients in the rhTPO group and 15 (42.9%) patients in the non-rhTPO group. The demographic and baseline characteristics were balanced between the two groups. Platelet response was higher at 1 and 2 months as compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). Meanwhile, the rhTPO group had a shorter time to achieve a platelet transfusion-free state compared with the non-rhTPO group (p = 0.034). Hematologic response was higher at 1 and 2 months compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). There was no significant difference in the overall response or complete response at 1, 2, 3, 6, and 12 months between the two groups. One patient in the rhTPO group evolved into higher-risk MDS at 9 months. No significant difference in disease progression, infection, gastrointestinal disorders, or drug-related liver/renal injuries was found between the two groups (p > 0.05). CONCLUSION: Adding short-term rhTPO can accelerate the early platelet response and decrease platelet transfusion, with no obvious side effects. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04324060?cond=NCT04324060&draw=2, identifier NCT04324060.

Comparisons Between Frontline Therapy and a Combination of Eltrombopag Plus Immunosuppression Therapy and Human Leukocyte Antigen-Haploidentical Hematopoietic Stem Cell Transplantation in Patients With Severe Aplastic Anemia: A Systematic Review.

Background and Aims: This study aimed at comparing the efficacy and safety of eltrombopag (EPAG) plus immunosuppressive therapies (ISTs) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the frontline treatment for severe aplastic anemia (SAA) patients. Methods: Four electronic databases and Clinicaltrials.gov were comprehensively searched from January 2010 to August 2020. Studies that aimed at evaluating the efficacy and safety of EPAG+IST or haplo-HSCT in SAA patients were included. One-/2-year overall survival (OS), complete response (CR), and overall response rates (ORRs) were indirectly compared between EPAG+IST and haplo-HSCT. Results: A total of 447 patients involved in 10 cohort studies were found to be eligible for this study. A narrative synthesis was performed due to lack of data directly comparing the outcome of EPAG+IST and haplo-HSCT. Consistent with the analysis results in the whole population, subgroup analyses in the age-matched population showed that there was no significant difference in ORR between EPAG+IST and haplo-HSCT groups. However, the CR rate was lower in the EPAG+IST group when compared with the haplo-HSCT group. The incidence rate of clonal evolution/SAA relapse ranged at 8-14 and 19-31% in the EPAG+IST group but not reported in the haplo-HSCT group. The incidence rate for acute graft vs. host disease (aGVHD) and chronic graft vs. host disease (cGVHD) ranged at 52-57 and 12-67%, respectively, for the haplo-HSCT group. The main causes of deaths were infections in the EPAG+IST group, and GVHD and infections in the haplo-HSCT group. Conclusion: EPAG+IST has a comparable ORR and 1-/2-year OS but lower CR rate when indirectly compared with haplo-HSCT in the frontline treatment of patients with SAA. Patients treated with haplo-HSCT may exhibit a high incidence of GVHD, whereas patients treated with EPAG+IST may experience more relapses or clone evolution.

Oncolytic virus combined with traditional treatment versus traditional treatment alone in patients with cancer: a meta-analysis.

BACKGROUND: Oncolytic virus therapy has shown benefits for multiple cancers, while limitations remain for traditional treatment. However, few studies have concentrated on comparing whether oncolytic virus combined with traditional treatment is better than traditional treatment alone in patients with cancer. We conducted a meta-analysis of the curative effect and safety of oncolytic virus combination therapy. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases comprehensively for articles comparing oncolytic virus combined with traditional treatment to traditional treatment alone in patients with cancer. A meta-analysis and trial sequential analysis were performed. RESULTS: A total of 12 studies involving 1494 patients (combination therapy group, 820 patients; traditional treatment group, 674 patients) were included in the study. Compared with traditional treatment alone, combination therapy was significantly associated with high objective response rate [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.01-1.82, p = 0.04]. There were no significant differences for other outcomes such as 1- and 2-year survival rate, and 4- and 12-month progression-free survival rate. Combination therapy was significantly associated with high incidence of grade ≥ 3 adverse effects (OR 1.47, 95% CI 1.06-2.05, p = 0.02) and high incidence of grade ≥ 3 neutropenia (OR 1.65, 95% CI 1.13-2.43, p = 0.01). There were no significant differences for other grade ≥ 3 adverse effects, e.g., gastrointestinal adverse effects, influenza-like illness, fatigue, anemia, and thrombocytopenia. CONCLUSION: Despite partially increased toxicity, the combination therapy improves the effectiveness of cancer treatment. However, high-quality, large-scale studies are needed to evaluate its effectiveness and safety.

Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement.

Among hundreds of thousands of signal receptors contributing to oncogenic activation, tumorigenesis, and metastasis, the hepatocyte growth factor (HGF) receptor - also called tyrosine kinase MET - is a promising target in cancer therapy as its axis is involved in several different cancer types. It is also associated with poor outcomes and is involved in the development of therapeutic resistance. Several HGF/MET-neutralizing antibodies and MET kinase-specific small molecule inhibitors have been developed, resulting in some context-dependent progress in multiple cancer treatments. Nevertheless, the concomitant therapeutic resistance largely inhibits the translation of such targeted drug candidates into clinical application. Until now, numerous studies have been performed to understand the molecular, cellular, and upstream mechanisms that regulate HGF/MET-targeted drug resistance, further explore novel strategies to reduce the occurrence of resistance, and improve therapeutic efficacy after resistance. Intriguingly, emerging evidence has revealed that, in addition to its conventional function as an oncogene, the HGF/MET axis stands at the crossroads of tumor autophagy, immunity, and microenvironment. Based on current progress, this review summarizes the current challenges and simultaneously proposes future opportunities for HGF/MET targeting for therapeutic cancer interventions.

The impact of iron chelation therapy on patients with lower/intermediate IPSS MDS and the prognostic role of elevated serum ferritin in patients with MDS and AML: A meta-analysis.

Serum ferritin (SF) has been identified as a potential prognostic factor for patients undergoing stem cell transplantation, but the prognostic value of SF in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients and the impact of iron chelation therapy (ICT) on MDS patients are controversial. The present meta-analysis aimed to better elucidate these relationships.Three electronic databases were searched systematically to identify reports on the prognostic role of SF in MDS and AML patients, and those investigating the impact of ICT on prognosis of MDS patients. The hazard ratios (HRs) and its 95% confidence interval (95%CI) were extracted from the identified studies using Cox proportional hazard regression model for overall survival (OS) and progression of MDS to AML.Twenty reports including 1066 AML patients and 4054 MDS patients were included in present study. The overall pooled HRs for OS of AML and MDS patients with elevated SF prior to transplantation was 1.73 (1.40-2.14), subgroup analyses stratified by the cut-off value of SF ≥1400/1000 ng/mL showed that the pooled HRs were 1.45 (0.98-2.15) and 1.65 (1.30-2.10), respectively. The pooled HRs for ICT in MDS patients was 0.30 (0.23-0.40). For ICT, the pooled HRs for the progression of MDS to AML was 0.84 (0.61-1.61).SF has a negative impact on the OS of AML and MDS patients when it is higher than 1000 ng/mL. ICT can improve the OS of MDS patients with iron overload but it is not associated with the progression of MDS to AML.

Quantitative Proteomic Analysis and Evaluation of the Potential Prognostic Biomarkers in Cholangiocarcinoma.

Background & Aims: Cholangiocarcinoma (CCA) patients have poor outcomes since the late diagnosis limits the benefits of surgery therapy and curative treatment options. The present study was designed to screen the biomarkers for CCA patients. Methods: Quantitative iTRAQ proteomic analysis was used to identify differentially expressed proteins between CCA and pericarcineous tissue. We examined the expression profile of PRDX2, BGN, LUM, and PPP3CA in CCA tissue using immunohistochemistry. We further investigated the correlation between PPP3CA expression and the survival of CCA patients (n=91). Results: 2,886 confidential proteins were identified by using the iTRAQ technique, 233 of which were differentially expressed. PRDX2, BGN, PPP3CA, and LUM were expressed in CCA tissue, whereas they were not expressed in choledocal cyst tissue except for LUM. PPP3CA was expressed in the cytoplasm of carcinoma cells in 22 cases (24.2%) of 91 CCA patients. Patients with PPP3CA-positive expression showed a significantly shorter survival period than did non-expressing patients (P = 0.030). The univariate analysis showed that tumor size (P = 0.002), vascular invasion (P = 0.001), histological grading (P = 0.011), and PPP3CA expression (P = 0.033) were statistically significant risk factors affecting the prognosis of CCA patients. The multivariate analysis demonstrated PPP3CA expression (P = 0.009) and vascular invasion (P = 0.012) were statistically significant independent risk factors of CCA patients. Conclusions: The results suggested that the expression of PPP3CA in CCA patients is a new independent factor for poor prognosis and a useful prognostic predictor for patients with CCA.

Meta-analysis of the diagnostic value of Wisteria floribunda agglutinin-sialylated mucin1 and the prognostic role of mucin1 in human cholangiocarcinoma.

OBJECTIVE: Serum carbohydrate antigen 19-9 (CA19-9) is a widely used tumour marker for cholangiocarcinoma (CCA). However, it is not a necessarily good CCA marker in terms of diagnostic accuracy. The purpose of this study is to evaluate the diagnostic value of Wisteria floribundaagglutinin-sialylated Mucin1 (WFA-MUC1) and the prognostic role of Mucin1 (MUC1) in human CCA. DESIGN: Meta-analysis. DATA SOURCES: Studies published in PubMed, Web of Science, The Cochrane Library and the China National Knowledge Infrastructure up to 11 October 2017. ELIGIBILITY CRITERIA: We included reports assessing the diagnostic capacity of WFA-MUC1 and the prognostic role of MUC1 in CCA. The receiver operating characteristic curve (ROC) of WFA-MUC1 and/or CA19-9 was described, and the HRs including 95% CI and the corresponding p value for MUC1 can be extracted. DATA EXTRACTION AND SYNTHESIS: Two independent researchers extracted data and assessed risk of bias. The diagnostic sensitivity and specificity data of WFA-MUC1 were extracted and analysed as bivariate data. Pooled HRs and its 95% CI for MUC1 were calculated with a random-effects meta-analysis model on overall survival of resectable CCA. RESULTS: Sixteen reports were included in this study. The pooled sensitivity and specificity of WFA-MUC1 were 0.76 (95% CI 0.71 to 0.81) and 0.72 (95% CI 0.59 to 0.83) in serum, 0.85 (95% CI 0.81 to 0.89) and 0.72 (95% CI 0.64 to 0.80) in bile and 0.72 (95% CI 0.50 to 0.87) and 0.85 (95% CI 0.70 to 0.93) in tissue, respectively. The summary ROC (SROC) were 0.77 (95% CI 0.73 to 0.81) in serum, 0.88 (95% CI 0.85 to 0.90) in bile and 0.86 (95% CI 0.83 to 0.89) in tissue, respectively. Furthermore, the pooled sensitivity and specificity and the SROC of CA19-9 in serum were 0.67 (95% CI 0.61 to 0.72), 0.86 (95% CI 0.75 to 0.93) and 0.75 (95% CI 0.71 to 0.79), respectively. The pooled HRs for MUC1 was 2.20 (95% CI 1.57 to 3.01) in CCA and 4.17 (95% CI 1.71 to 10.17) in mass-forming intrahepatic CCA. CONCLUSIONS: Compared with CA19-9, WFA-MUC1 was shown to possess stronger diagnostic capability. MUC1 could serve as a prognosis factor for poor outcomes of CCA, particularly, mass-forming intrahepatic CCA.

Early precut sphincterotomy does not increase the risk of adverse events for patients with difficult biliary access: A systematic review of randomized clinical trials with meta-analysis and trial sequential analysis.

OBJECTIVE: The present study was conducted to investigate whether early precut sphincterotomy (EPS) itself increases the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), bleeding, and perforation, or improves the overall success rates of biliary cannulation. METHODS: Four electronical databases were searched systematically for randomized controlled trials (RCTs) reporting the incidence of adverse events for difficult biliary access (DBA) between EPS groups and persistent cannulation attempts (PCA). The primary endpoint was the incidence of PEP. Secondary outcomes were the incidence of bleeding and perforation, and the overall success rates of biliary cannulation. The Mantel-Haenszel method was used to pool data on the outcomes into random-effect models. Heterogeneity, sensitivity, and stratified analyses were performed with Review Manager 5.3. Furthermore, we performed trial sequential analysis (TSA) to evaluate the reliability of the primary endpoint and secondary outcomes. RESULTS: Seven RCTs (999 patients with DBA of 10450, 9.5%) were included. The incidence of PEP was significantly lower in EPS groups than PCA (risk ratio [RR] = 0.57, 95% confidence interval [CI] 0.36, 0.92, P = .02). Furthermore, TSA (TSA-adjusted 95% CI 0.30-0.82, P = .0061) and subgroup analysis stratified by the fellow involvement in initial cannulation before randomization, technique of precut, and the definition of DBA confirmed this finding. Success rates of overall cannulation (RR = 1.00, P = .94), bleeding (RR = 1.22, P = .58), and perforation (RR = 1.59, P = .32) were similar in both groups; however, the results of TSA could not confirm these findings. CONCLUSION: Both the quality and the quantity of evidence supporting, compared with PCA, EPS itself do not increase the risk of PEP for DBA patients. Moreover, subgroup analysis demonstrated that EPS can significantly decrease the risk of PEP when it is performed by qualified staff endoscopists with using needle-knife fistulutomy earlier for patients with DBA.

The clinicopathological factors associated with prognosis of patients with resectable perihilar cholangiocarcinoma: A systematic review and meta-analysis.

The refinement in surgical techniques combined with the preoperative management has improved the resectability rate of perihilar cholangiocarcinoma (pCCA). However, the prognosis of pCCA with curative resection is still dismal. This meta-analysis was performed to investigate the prognostic clinicopathological factors in resectable pCCA.PubMed, the Cochran Library, ScienceDirect, and Web of Science were searched systematically to identify reports focusing on studying the prognostic clinicopathological factors in resectable pCCA. The hazard ratios (HRs) and its 95% confidence interval (95%CI) from the identified studies using Cox proportional hazard regression model were extracted for overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) analysis.Three prospective and 35 retrospective cohort studies including 5681 resectable pCCA were included in the pooled analysis. Among more than 20 clinicopathological factors associated with negative survival of pCCA, only 6 were included in quantitative analysis which showed that lymph node involvement was associated with a reduced OS (HR = 2.04; 95%CI: 2.10-2.62), DSS (HR = 1.80; 95%CI: 1.39-2.34), DFS (HR = 4.38; 95%CI: 1.89-10.14), negative resection margin (HR = 2.04; 95%CI:1.73-2.41), operative transfusion (HR = 1.82; 95%CI: 1.06-3.11), and T3 or T4-stage (HR = 2.04; 95%CI: 2.04-2.53) were poor prognostic factors of OS, and poor or moderate differentiation was also an adverse prognostic factor of OS (HR = 2.71; 95%CI: 1.80-4.07) and DSS (HR = 1.74; 95%CI: 1.25-2.44). The overall median resectability rate (95CI%), R0 resection (95CI%), and 5-year OS (95CI%) in Eastern and Western countries were 74.9 (66.4-78.4) % and 41.3 (32.6-80.8) %, 70.7 (65.6-80.8) % and 75.9 (64.0-80.4) %, and 33.0 (29.7-39.7) % and 25.5 (20.0-31.6) %, respectively.Negative resection margin, lymph node involvement, poor or moderate differentiation grade was identified as the negative predictor factors of resectable pCCA. Operative transfusion and T3/T4 stage were also associated with a reduced survival of resectable pCCA.

Effect of preoperative cholangitis on prognosis of patients with hilar cholangiocarcinoma: A systematic review and meta-analysis.

BACKGROUND: The aim of this study was to compare the clinical outcomes between patients with preoperative cholangitis and noncholangitis patients to determine whether the preoperative cholangitis would be able to serve as an independent predictive factor on hilar cholangiocarcinoma (HCC) outcomes. METHODS: A systematic literature search for reported preoperative cholangitis in patients with hilar cholangiocarcinoma was performed in 4 databases: PubMed, Web of Science, Embase, and the Cochrane Library, published from 1979 to 2017. RESULTS: In total, the initial search identified 1228 articles. Of these studies only 9 studies met the inclusion criteria and were included in this analysis. Differences between preoperative cholangitis existing and noncholangitis patients were observed in terms of mortality (RR = 2.29; 95% CI = 1.48-3.52; P = .0002), overall morbidity (RR = 1.15;95% CI = 1.00-1.32; P = .04), Liver failure (RR = 1.15;95% CI = 1.00-1.32; P = .04), Infection (RR = 1.52;95% CI = 1.16-2.00; P = .003), sepsis (RR = 2.40;95% CI = 1.25-4.5; P = .008). CONCLUSIONS: The results lend support to the notion that in hilar cholangiocarcinoma patients, the existence of preoperative cholangitis is statistically associated with the higher postoperative mortality and morbidity. Also that it increases the risk of liver failure and infection. therefore, it is very important to properly control the preoperative cholangitis before surgery.

Curcumol Exerts Anticancer Effect in Cholangiocarcinoma Cells via Down-Regulating CDKL3.

Curcumol is the major component extracted from root of Rhizoma Curcumae. Recent studies have shown that curcumol exerts therapeutic effects against multiple conditions, particularly cancers. However, the therapeutic role and mechanism of curcumol against cholangiocarcinoma cells are still unclear. In our current research, we tested the effect of curcumol in cholangiocarcinoma cells, and using two-dimensional electrophoresis, proteomics and bioinformatics, we identified cyclin-dependent kinase like 3 (CDKL3) as a potential target for curcumol. We have demonstrated that curcumol can evidently suppress growth and migration of cholangiocarcinoma cells. Furthermore, curcumol could significantly block the cell cycle progression of the cholangiocarcinoma cells. These effects could be largely attributed to the inhibition of CDKL3 by curcumol. Further studies have recapitulated the oncogenic role of CDKL3 in that knockdown of CDKL3 by lentiviral mediated transfection of shRNA against CDKL3 also led to a significant inhibition on cell proliferation, migration, invasion, and cell cycle progression. Given the high level of CDKL3 expression in human cholangiocarcinoma tissues and cell lines, we speculated that CDKL3 may constitute a potential biological target for curcumol in cholangiocarcinoma.

Best option for preoperative biliary drainage in Klatskin tumor: A systematic review and meta-analysis.

The operative treatment combined with preoperative biliary drainage (PBD) has been established as a safe Klatskin tumor (KT) treatment strategy. However, there has always been a dispute for the preferred technique for PBD technique. This meta-analysis was conducted to compare the biliary drainage-related cholangitis, pancreatitis, hemorrhage, and the success rates of palliative relief of cholestasis between percutaneous transhepatic biliary drainage (PTBD) and endoscopic biliary drainage (EBD), to identify the best technique in the management of KT.PubMed, EMBASE, and Web of Science were searched systematically for prospective or retrospective studies reporting the biliary drainage-related cholangitis, pancreatitis, hemorrhage, and the success rates of palliative relief of cholestasis in patients with KT. A meta-analysis was performed, using the fixed or random-effect model, with Review Manager 5.3.PTBD was associated with lower risk of cholangitis (risk ratio [RR] = 0.49, 95% confidence interval [CI]: 0.36-0.67; P < .00001), particularly in patients with Bismuth-Corlette type II, III, IV KT (RR = 0.50, 95% CI: 0.33-0.77; P = .05). Compared with EBD, PTBD was also associated with a lower risk of pancreatitis (RR = 0.35, 95% CI: 0.17-0.69; P = 0.003) and with higher successful rates of palliative relief of cholestasis (RR = 1.20, 95% CI: 1.10-1.31; P < .0001). The incidence of hemorrhage was similar in these 2 groups (RR 1.29, 95% CI: 0.51-3.27; P = .59). The risk of biliary drainage-related cholangitis (RR = 1.96, 95% CI: 0.96-4.01; P = .06) and pancreatitis (RR = 1.62, 95% CI: 0.76-3.47; P = .21) was similar between endoscopic nasobiliary drainage groups and biliary stenting.In patients with type II or type III or IV KT who need to have PBD, PTBD should be performed as an initial method of biliary drainage in terms of reducing the incidence of procedure related cholangitis, pancreatitis, and improving the rates of palliative relief of cholestasis. Well-conducted randomized controlled trials with a universial criterion for PBD are required to confirm these findings.