Chunlin Jiang

Mcl-1 Is a Novel Target of miR-26b That Is Associated with the Apoptosis Induced by TRAIL in HCC Cells

Aim. To investigate the role of miR-26b and Mcl-1 in TRAIL-inducing cell death in hepatocellular carcinoma. Methods. The expression of miR-26b and Mcl-1 in HCC was detected by RT-qPCR and western blot. The regulation of Mcl-1 by miR-26b was determined by luciferase reporter assay. MTT and flow cytometry were employed to detect the cell viability and apoptosis. Results. miR-26b is commonly downregulated in HCC cell lines compared with the LO2 cell line. In contrast, the Mcl-1 expression is upregulated in HCC cell lines. Bioinformatic analysis identified a putative target site in the Mcl-1 mRNA for miR-26b and luciferase reporter assay showed that miR-26b directly targeted the 3′-UTR (3′-Untranslated Regions) of Mcl-1 mRNA. Transfection of miR-26b mimics suppressed Mcl-1 expression in HCC cells and sensitized the cancer cells to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) cytotoxicity. In addition, transfection of HCC cells with Mcl-1 expression plasmid abolished the sensitization effect of miR-26b to TRAIL-inducing apoptosis. Conclusions. Our study showed that miR-26b was a negative regulator of Mcl-1 gene and sensitized TRAIL-inducing apoptosis in HCC cells, suggesting that the miR-26b-Mcl-1 pathway might be a novel target for the treatment of HCC.

miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma

BackgroundmiR-500a-3p has been demonstrated to be involved in the development, progression and metastasis in several human cancers. Constitutive activation of JAK/STAT3 signaling pathway has been reported to play an important role in the development and progression of hepatocellular carcinoma (HCC).The purpose of this study was to determine the biological roles and clinical significance of miR-500a-3p in HCC and to identify whether miR-500a-3p has an effect on the activity of JAK/STAT3 signaling in HCC.MethodsmiR-500a-3p expression was examined by real-time PCR in 8 paired HCC tissues and individual 120 HCC tissues respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p expression and clinicopathological features and overall and relapse-free survival in HCC patients. In vitro and in vivo assays were performed to investigate the biological roles of miR-500a-3p in HCC. The bioinformatics analysis, real-time PCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-500a-3p and its potential targets. Clinical correlation of miR-500a-3p with its targets was examined in HCC tissues.ResultsmiR-500a-3p is dramatically elevated in HCC tissues and cells and high expression of miR-500a-3p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-500a-3p enhances, while silencing miR-500a-3p suppresses, the spheroid formation ability, fraction of side population and expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Moreover, the inhibitory effects of anti-miR-500a-3p on cancer stem cell phenotypes and activity of STAT3 signaling were reversed by silencing SOCS2, SOCS4 and PTPN11 in miR-500a-3p-downexpressing cells, respectively. Clinical correlation of miR-500a-3p with the targets was examined in human HCC tissues.Conclusionour results uncover a novel mechanism by which miR-500a-3p promotes the stemness maintenance of cancer stem cell in HCC, suggesting that silencing miR-500a-3p may serve as a new therapeutic strategy in the treatment of hepatocellular carcinoma.

MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF

We examined the expression pattern and functional roles of microRNA 15a-5p (miR-15a-5p) in human hepatocellular carcinoma (HCC). Possible miR-15a-5p aberrant expression in HCC cell lines or clinical HCC specimens was examined by quantitative real-time PCR (qRT-PCR). In HCC HepG2 and SNU-182 cells, miR-15a-5p was ectopically overexpressed by lentiviral transduction. Its effect on HCC proliferation, cancer division, and in vivo tumor growth were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle assay, and tumorigenicity assay, respectively. The targeting of miR-15a-5p on its downstream gene, brain-derived neurotrophic factor (BDNF), was examined by dual-luciferase assay, qRT-PCR, and Western blot, respectively. BDNF was then overexpressed in HepG2 and SNU-182 cells to evaluate its selective effect on miR-15a-5p in HCC modulation. MiR-15a-5p is aberrantly downregulated in in vitro HCC cell lines and in vivo HCC clinical specimens. Ectopic overexpression of miR-15a-5p suppressed cancer proliferation, induced cell cycle arrest in HepG2 or SNU-182 cells in vitro, and inhibited HCC tumor growth in vivo. MiR-15a-5p selectively and negatively regulated BDNF at both gene and protein levels in HCC cells. Forced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-15a-5p on HCC proliferation and cell division in vitro. Our study demonstrated that miR-15a-5p is a tumor suppressor in HCC and its regulation is through BDNF in HCC.

Advanced Recurrent Hepatocellular Carcinoma: Treatment with Sorafenib Alone or in Combination with Transarterial Chemoembolization and Radiofrequency Ablation

Purpose To retrospectively investigate the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, TACE-RFA) in the treatment of recurrent hepatocellular carcinoma (rHCC) with portal vein tumor thrombosis, extrahepatic metastases (advanced hepatocellular carcinoma), or both after initial hepatectomy. Materials and Methods The study was centrally approved by the ethics committee of three tertiary medical centers in China. From January 2010 to January 2015, 207 consecutive patients with advanced rHCC after initial hepatectomy received sorafenib combined with TACE-RFA (combination group, n = 106) or sorafenib alone (sorafenib group, n = 101) at the three medical centers. Overall survival (OS) and time to progression (TTP) were compared between the two groups. Complications were assessed. Survival curves were constructed with the Kaplan-Meier method and were compared with the log-rank test. Results Baseline characteristics were balanced between the two groups. No treatment-related death occurred in either group. The toxicity profile in the combination group was similar to that in the sorafenib group. After treatment, median OS (14.0 vs 9.0 months, respectively; P < .001) and TTP (7.0 vs 4.0 months, respectively; P < .001) were significantly longer in the combination group than in the sorafenib group. Multivariate analysis showed that treatment allocation was a significant predictor of OS and TTP, while the number of intrahepatic tumors was another prognostic factor of OS. Conclusion Sorafenib combined with TACE-RFA was well tolerated and safe and was superior to sorafenib alone in improving survival outcomes in patients with advanced rHCC after initial hepatectomy.

Combined radiofrequency ablation and ethanol injection versus repeat hepatectomy for elderly patients with recurrent hepatocellular carcinoma after initial hepatic surgery

Abstract Purpose: To retrospectively compare the efficacy and safety of combined radiofrequency ablation and percutaneous ethanol injection (RFA–PEI) with repeat hepatectomy for elderly patients with initial recurrent hepatocellular carcinoma (HCC) after hepatic surgery. Methods: From January 2009 to June 2015, 105 elderly patients (≥70 years) who underwent RFA–PEI (n = 57) or repeated hepatectomy (n = 48) for recurrent HCC ≤ 5.0 cm were included in the study. The overall survival (OS) and recurrence-free survival (RFS) were analysed with the Kaplan–Meier method and compared by the log-rank test. Non-tumour-related death, complications and hospital stays were assessed. Univariate and multivariate analyses were performed to identify the prognostic significance of the variables in predicting the OS and RFS. Results: OS rates were 78.2%, 40.8% and 36.7% at 1, 3 and 5 years after RFA–PEI and 76.3%, 52.5% and 42.6% after repeat hepatectomy, respectively (p = 0.413). Correspondingly, the 1-, 3- and 5-year RFS rates after RFA–PEI and repeat hepatectomy were 69.5%, 37.8%, 33.1% and 73.1%, 49.7%, 40.7%, respectively (p = 0.465). Non-tumour-related deaths in the RFA–PEI group (2/57) were significantly fewer than those in the repeat hepatectomy group (10/48) (p = 0.016). RFA–PEI was superior to repeat hepatectomy regarding the major complication rates and length of in-hospital stay (both p < 0.001). Multivariate analysis showed that the tumour number was the significant prognostic factor for the OS (hazard ratio (HR) = 1.961, 95% CI = 1.043–3.686, p = 0.037) and RFS (HR = 1.866, 95% CI = 1.064–3.274, p = 0.030). Conclusion: RFA–PEI provides comparable OS and RFS to repeat hepatectomy for elderly patients with small recurrent HCC after hepatectomy but with fewer non-tumour-related deaths, major complications and shorter hospital stays.

Ultrasound-Guided Percutaneous Radiofrequency Ablation of Liver Metastasis From Ovarian Cancer: A Single-Center Initial Experience

Objective The aim of this study was to evaluate the feasibility, effectiveness, and safety of ultrasound-guided percutaneous radiofrequency ablation (RFA) for the treatment of liver metastasis from ovarian cancer (OC). Methods A retrospective review was performed on 11 patients (mean age, 53.0 ± 10.1 years) with 22 liver metastases (mean diameter, 2.0 ± 0.8 cm) from OC undergone RFA. Radiofrequency ablation was carried out with Starburst XL electrodes (RITA Medical System, Mountain View, CA) or Cool-tip electrodes (Cool-tip Systems; Valleylab, Boulder, CO). The tumor response, time to progression, and survival after RFA were assessed. Results Complete ablation was achieved for all lesions. The technique effectiveness was 100%. During the follow-up period, local tumor progression was observed in 1 (4.5%) of 22 lesions. The median time to progression was 8.0 months after RFA. Three patients died because of disease progression after 13, 18, and 24 months, respectively. The mean overall survival time after RFA was 53.1 ± 10.0 months, with the 1-, 3-, and 5-year overall survival rates of 100%, 61%, and 61%, respectively. No major complications were encountered. Conclusions Radiofrequency ablation as an alternative treatment strategy is feasible and effective for selected patients with liver metastasis from OC, providing a high rate of local tumor control.

Multipronged ethanol ablation combined with TACE for intermediate hepatocellular carcinoma

Abstract Purpose: To retrospectively investigate the efficacy of multipronged ethanol ablation with or without transarterial chemoembolization (TACE) in the treatment of intermediate hepatocellular carcinoma (HCC) (3.1-5.0 cm in diameter) at high-risk locations . Material and methods: From March 2009 to April 2014, 25 consecutive patients with intermediate HCC who underwent multipronged ethanol ablation combined with TACE were included in the combination treatment group, while 50 patients who underwent multipronged ethanol ablation alone were included in the control group. Results: Primary technique effectiveness was achieved in 70 patients (25/25, 100% in the combination treatment group; 45/50, 90% in the control group; p = .162). The local tumor progression (LTP) rates at 1, 3, 5, and 7 years were 8.0%, 24.0%, 24.0%, and 24.0% in the combination treatment group, respectively, which were significantly lower than those in the control group (24.4%, 44.1%, 66.5% and 66.5%, respectively; p = .043). However, no significant differences of overall survival and disease-free survival were found between the two groups (p = .996 and .974, respectively). Conclusion: Multipronged ethanol ablation combined with TACE could improve local tumor control for patients with intermediate HCC at high-risk locations when compared with multipronged ethanol ablation alone, although the survival outcomes were comparable.

Safety margin after radiofrequency ablation of hepatocellular carcinoma: precise assessment with a three-dimensional reconstruction technique using CT imaging

Abstract Purpose: To analyse the precise ablative margin (AM) after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and the correlation between AM and local tumour progression (LTP) with a three-dimension (3D) reconstruction technique. Methods: From March 2011 to May 2013, 134 patients who underwent RFA for 159 primary or recurrent HCCs within Milan criteria were enrolled. Contrast-enhanced computed tomography (CECT) scans were performed 1 week before and 1 month after treatment. The AM was measured in various directions using a 3D reconstruction technique that shows the index tumour and ablated zone on the same image. The average of all obtained AMs (average AM) and the smallest AM (min-AM) were calculated. Results: The min-AM after RFA ranged from 1 to 9.3 mm (median ± standard deviation, 4.8 ± 1.8 mm). LTP was observed in 19 tumours from 19 patients. The median min-AM was 3.1 ± 1.6 mm for patients with LTP, while the median min-AM of patients without LTP was 5.1 ± 1.8 mm (p = 0.023). After RFA, the 1-, 2- and 3-year LTP rates were 10.9, 25.9 and 35.1%, respectively, for patients with min-AM <5 mm, and 4.1, 4.1 and 4.1%, respectively, for patients with min-AM ≥5 mm (p = 0.016). Multivariate analysis showed that only min-AM <5 mm was an independent risk factor for LTP after RFA (p = 0.044, hazard ratio =4.587, 95% confidence interval, 1.045–22.296). Conclusions: The 3D reconstruction technique is a precise method for evaluating the post-ablation margin. Patients with min-AM less than 5 mm had a higher probability of developing LTP.

Combined transcatheter arterial chemoembolization and radiofrequency ablation versus hepatectomy for recurrent hepatocellular carcinoma after initial surgery: a propensity score matching study

ObjectivesTo compare retrospectively the efficacy of transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) (TACE-RFA) with that of repeat hepatectomy in the treatment of initial recurrent hepatocellular carcinoma (HCC) after hepatectomy by propensity score matching (PSM).MethodsFrom September 2006 to June 2015, 186 patients who underwent TACE-RFA (n=107) or repeat hepatectomy (n=79) for recurrent HCC ≤ 5.0 cm were included. The overall survival (OS) and disease-free survival (DFS) were compared. PSM was used to correct potential confounding factors between these two groups.Results1-, 3-, and 5-year OS rates after TACE-RFA and repeat hepatectomy were 84.6%, 66.9%, 49.1%, and 84.8%, 60.2%, 51.9%, respectively (p=.871). The corresponding DFS rates were 58.2%, 35.2%, 29.6% and 64.8%, 41.6%, 38.3% (p=.258). TACE-RFA has lower major complication rates (p=.009) and shorter hospital stay (p<.001). After PSM, 1-, 3-, 5- year OS rates after TACE-RFA (n=51) and repeat hepatectomy (n=51) were 84.3%, 60.4%, 46.4% and 84.3%, 64.5%, 49.8% (p=.951), the corresponding DFS rates were 54.9%, 35.0%, 30.6% and 58.7%, 35.8%, and 33.6% (p=.733). AFP and micro-vessel invasion of initial tumour were significant prognostic factors for OS and DFS, respectively.ConclusionsTACE-RFA provides comparable OS and DFS to repeat hepatectomy, fewer major complications and shorter hospital stay.Key Points• TACE-RFA achieved similar OS and DFS with repeat hepatectomy for recurrent HCC• Major complication rate was lower in the TACE-RFA group• The hospital stay was shorter in the TACE-RFA group• AFP was a predictor for OS, MVI was a predictor for DFS• The treatment strategies were not significant prognostic factor for OS or DFS