Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-κB signaling pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor usually resistant to chemotherapy. MicroRNAs play important roles in modulation of carcinogenesis and chemoresistance, which miR-16 has been reported to mediate chemoresistance in many types of cancers. However, the role of miR-16 in HCC remains unknown. The aim of this study was to investigate whether miR-16 is participated in chemoresistance in HCC and shed light on the underlying molecular mechanisms. The findings of the current study discover that miR-16 is down-regulated in HCC tissue and cell lines. The results demonstrate that the inhibition of miR-16 renders resistance to paclitaxel in vitro and in vivo by targeting IKBKB via NF-κB signaling pathway, suggesting that miR-16 may be a meaningful therapeutic potential to overcome drug resistance in HCC.

Up-Regulation of HMGB1 Exacerbates Renal Ischemia-Reperfusion Injury by Stimulating Inflammatory and Immune Responses through the TLR4 Signaling Pathway in Mice.

BACKGROUND/AIMS: The aim of this study was to elucidate how high-mobility group box 1 (HMGB1) exacerbates renal ischemic-reperfusion injury (IRI) by inflammatory and immune responses through the toll-like receptor 4 (TLR4) signaling pathway. METHODS: A total of 30 wild-type (WT) mice and 30 TLR4 knockout (TLR4-/-) mice were selected and then randomly assigned to the Sham, I/R or HMGB1 groups. The serum and kidney tissues of all mice were collected 24 h after the perfusion. The fully automatic biochemical detector and ELISA were applied to determine the blood urea nitrogen (BUN) and serum creatinine (Scr) levels, and TNF-α, IL-1ß, IL-6, IFN-γ and IL-10 levels, respectively. HE staining was used to evaluate kidney tissue damage, immunofluorescence and immunohistochemical staining were performed to observe CD68 and MPO cell infiltration, and flow cytometry was applied to detect immune cells. qRT-PCR and Western blotting were used to detect the expressions of TLR signaling pathway-related genes and proteins, respectively. RESULTS: Compared with the Sham group, the levels of BUN, Scr, TNF-α, IL-1ß, IL-6, IFN-γ and IL-10, kidney tissue damage score, CD68 and MPO cell infiltration, the numbers of immune cells, and the expressions of TLR signaling pathway-related genes and proteins in the I/R and HMGB1 groups were significantly up-regulated. In the I/R and HMGB1 groups, the levels of BUN and Scr, TNF-α, IL-1ß, IL-6 and IFN-γ, kidney tissue damage score, CD68 and MPO cell infiltration, immune cell numbers, and TLR signaling pathway-related gene and protein expressions in the WT mice were all higher than those in the TLR4-/- mice, but IL-10 level was significantly lower. Similarly, all aforementioned indexes but IL-10 level in the WT and TLR4-/- mice were higher in the HMGB1 group than in the I/R group. CONCLUSION: Our study indicated that the up-regulation of HMGB1 could exacerbate renal IRI by stimulating inflammatory and immune responses through the TLR4 signaling pathway.c.

A simplified multivisceral transplantation procedure for patients with combined end-stage liver disease and type 2 diabetes mellitus.

In liver transplant patients with type 2 diabetes mellitus (DM), the disease worsens after transplantation because of longterm use of diabetogenic immunosuppressive drugs, making management of those patients a great challenge. The objective of our study was to evaluate the safety and efficacy of a simplified multivisceral transplantation (SMT) procedure for the treatment of patients with end-stage liver disease and concurrent type 2 DM. Forty-four patients who had pretransplant type 2 DM were included. A total of 23 patients received SMT, and 21 patients received orthotopic liver transplantation (OLT). Patient and graft survivals, complications, diabetic control, and quality of life (QOL) were retrospectively analyzed in both groups. The 1-, 3-, and 5-year cumulative patient and graft survival rates were 91.5%, 75.4%, and 75.4% in the SMT group and were 94.4%, 64.4%, and 64.4% in the OLT group, respectively (P = 0.70). Interestingly, 95.7% (22/23) of patients achieved complete remission from DM after SMT compared with 16.7% (3/18) of patients after OLT. The occurrence of biliary complication was significantly higher in the OLT group than that in the SMT group (23.8% versus 0.0%; P = 0.01). Moreover, better QOL was observed in the SMT group than that in the OLT group. In conclusion, the SMT procedure we described here is a safe and viable option for patients with end-stage live disease and concurrent type 2 DM. This SMT procedure offers excellent transplant outcomes and QOL. Liver Transplantation 23 1161-1170 2017 AASLD.

SSRP1 Contributes to the Malignancy of Hepatocellular Carcinoma and Is Negatively Regulated by miR-497.

The aim of this study is to clarify the clinical implication and functional role of structure specific recognition protein 1 (SSRP1) in hepatocellular carcinoma (HCC) and explore the underlying mechanism of aberrant high expression of SSRP1 in cancers. In the present investigation, we validated that SSRP1 was upregulated in HCC samples. We also demonstrated that its upregulation was associated with several clinicopathologic features such as higher serum AFP level, larger tumor size, and higher T stage of HCC patients; and its high expression indicated shorter overall survival and faster recurrence. To investigate the role of SSRP1 in HCC progression, both loss- and gain-function models were established. We demonstrated that SSPR1 modulated both proliferation and metastasis of HCC cells in vitro and vivo. Furthermore, we demonstrated that SSRP1-modulated apoptosis process and its knockdown increased the sensitivity of HCC cells to doxorubicin, 5-Fluorouracil, and cisplatin. We also identified microRNA-497 (miR-497) as a posttranscriptional regulator of SSRP1. Ectopic expression of miR-497 inhibited 3'-untranslated-region-coupled luciferase activity and suppressed endogenous SSRP1 expression at both messenger RNA and protein levels. For the first time, we proved that SSRP1 upregulation contributed to HCC development and the tumor-suppressive miR-497 served as its negative regulator.

Histone deacetylase inhibitors reduce WB-F344 oval cell viability and migration capability by suppressing AKT/mTOR signaling in vitro.

Histone deacetylase (HDAC) can blockDNA replication and transcription and altered HDAC expression was associated with tumorigenesis. This study investigated the effects of HDAC inhibitors on hepatic oval cells and aimed to delineate the underlying molecular events. Hepatic oval cells were treated with two different HDAC inhibitors, suberoylanilidehydroxamic acid (SAHA) and trichostatin-A (TSA). Cells were subjected to cell morphology, cell viability, cell cycle, and wound healing assays. The expression of proteins related to both apoptosis and the cell cycle, and proteins of the AKT/mammalian target of rapamycin (mTOR) signaling pathway were analyzed by Western blot. The data showed that HDAC inhibitors reduced oval cell viability and migration capability, and arrested oval cells at the G0/G1 and S phases of the cell cycle, in a dose- and time-dependent manner. HDAC inhibitors altered cell morphology and reduced oval cell viability, and downregulated the expression of PCNA, cyclinD1, c-Myc and Bmi1 proteins, while also suppressing AKT/mTOR and its downstream target activity. In conclusion, this study demonstrates that HDAC inhibitors affect oval cells by suppressing AKT/mTOR signaling.

Interaction between microRNA-181a and TNFAIP1 regulates pancreatic cancer proliferation and migration.

We investigated the role of microRNA 181a (miR-181a) and its downstream target tumor necrosis factor, alpha-induced protein 1 (TNFAIP1) in pancreatic cancer regulation. Quantitative real-time PCR (qRT-PCR) was applied to evaluate the gene expression of miR-181a in seven pancreatic cancer cell lines. MiR-181a inhibitor lentivirus (miR-181a-IN) was used to down-regulate miR-181a in Capan-1 and AsPC-1 cells. The effects of miR-181a down-regulation on pancreatic cancer were evaluated by in vitro proliferation assay and migration assay. Targeting of miR-181a on TNFAIP1 in pancreatic cancer was evaluated by dual-luciferase reporter assay and western blot. TNFAIP1 was either upregulated by pcDNA3.1 (+) expression vector or down-regulated by siRNA in Capan-1 and AsPC-1 cells. The subsequent effects of TNFAIP1 upregulation or down-regulation on miR-181a mediated pancreatic cancer regulation were also evaluated through in vitro proliferation and migration assays. The in vivo effect of miR-181a down-regulation on pancreatic tumor growth was evaluated by a xenograft assay. MiR-181a was consistently upregulated in pancreatic cancer cell lines. MiR-181a down-regulation inhibited proliferation and migration in vitro, and upregulated TNFAIP1 in pancreatic cancer cells. Ectopic TNFAIP1 overexpression had similar tumor-suppressive effects on pancreatic cancer proliferation and migration as miR-181a down-regulation, whereas siRNA-mediated TNFAIP1 down-regulation had opposite or oncogenic effects on pancreatic cancer. In vivo pancreatic xenograft showed miR-181a recapitulated the in vitro anti-tumor effects and its regulation on TNFAIP1. MiR-181a played a critical role in regulating pancreatic cancer growth and migration, likely interacting with TNFAIP1.

ABO-incompatible liver transplantation for severe hepatitis B patients.

Effect of ABO-incompatible liver transplantation on patients with severe hepatitis B (SHB) remains unclear. Herein, we summarized 22 cases with SHB in whom were performed emergency liver transplantation from ABO-incompatible donors. The immunosuppressive protocol consisted basiliximab, tacrolimus, steroids and mycophenolate mofetil. The mean MELD score was 35.2 ± 7.1. Major complications included rejection, infections, biliary complications, hepatic artery thrombosis or stenosis and portal vein thrombosis. Patient survival rates were 40.9%, 78.9% and 82.3% in 1 year, 29.2%, 66.8% and 72.9% in 3 years, and 21.9%, 60.1% and 62.5% in 5 years for ABO-incompatible, ABO-compatible and ABO-identical groups. Graft survival rates were 39%, 78.9% and 82.3% in 1 year, 27.8%, 66.4% and 71.1% in 3 years, and 20.9%, 57.9% and 61.0% in 5 years for incompatible, compatible and identical ABO graft-recipient match. The 1-, 3-, 5-year graft and patient survival rates of ABO-incompatible were distinctly lower than that of ABO-compatible group (P < 0.05). Our results suggested that ABO-incompatible liver transplantation might be a life-saving procedure for patients with SHB as a promising alternative operation when ABO-compatible donors are not available and at least bridges the second opportunity for liver retransplantation.

Upregulated plasma and urinary levels of nucleosides as biological markers in the diagnosis of primary gallbladder cancer.

We first detected aberrant nucleoside levels in the plasma, urine, bile, and tissues from cases and controls to explore them as biomarkers in the diagnosis of gallbladder cancer. Reversed-phase high-performance liquid chromatography was used to assess the levels of ten nucleosides in these samples from gallbladder cancer patients, gallstone patients, and healthy controls. Plasma and urine samples were collected from patients with gallbladder cancer (n = 202), patients with gallstones (n = 203), and healthy controls (n = 205); bile and tissue samples were collected from 91 gallbladder cancer patients, 93 gallstone patients; and 90 were donated after cardiac death. Of the ten nucleosides analyzed, eight urinary nucleosides, five plasma nucleosides, three bile nucleosides, and one tissue nucleoside were significantly upregulated in the gallbladder cancer patients compared to control groups (p < 0.05). Among these upregulated nucleosides, the sensitivity, specificity, and accuracy of urinary nucleosides in the diagnosis of gallbladder cancer patients were 89.4, 97.1, and 95.7%, respectively, those of plasma nucleosides were 91.2, 95.6, and 94.2%, respectively, those of bile nucleosides were 95.3, 96.4, and 95.1%, respectively, and those of tissue nucleosides were 86.2, 93.8, and 92.6%, respectively. These results suggest that nucleosides may be as useful as biological markers for gallbladder cancer.

Liver transplantation using organs from deceased organ donors: a single organ transplant center experience.

BACKGROUND: In 2011, a pilot program for deceased organ donation was initiated in China. We describe the first successful series of liver transplants in the pilot program. METHODS: From July 2011 to August 2012, our center performed 26 liver transplants from a pool of 29 deceased donors. All organ donation and allograft procurement were conducted according to the national protocol. The clinical data of donors and recipients were collected and summarized retrospectively. RESULTS: Among the 29 donors, 24 were China Category II donors (organ donation after cardiac death), and five were China Category III donors (organ donation after brain death followed by cardiac death). The recipients were mainly the patients with hepatocellular carcinoma. The one-year patient survival rate was 80.8% with a median follow-up of 422 (2-696) days. Among the five mortalities during the follow-up, three died of tumor recurrence. In terms of post-transplant complications, 9 recipients (34.6%) experienced early allograft dysfunction, 1 (3.8%) had non-anastomotic biliary stricture, and 1 (3.8%) was complicated with hepatic arterial thrombosis. None of these complications resulted in patient death. Notably, primary non-function was not observed in any of the grafts. CONCLUSION: With careful donor selection, liver transplant from deceased donors can be performed safely and plays a critical role in overcoming the extreme organ shortage in China.

Cuproptosis-related genes score and its hub gene GCSH: A novel predictor for cholangiocarcinomas prognosis based on RNA seq and experimental analyses.

Background: Recent researches have demonstrated that cuproptosis, a copper-dependent cell death mechanism, is related to tumorigenesis, progression, clinical prognosis, tumor microenvironment, and drug sensitivity. Nevertheless, the function and impact of cuproptosis in cholangiocarcinoma (CCA), remain elusive. Methods: Utilizing data obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA-CHOL) datasets, we conducted subgroup typing of CCA according to cuproptosis-related genes (CRGs) and explored functional differences and prognostic value between groups. A CRG score was established considering clinical prognosis and gene expression. Furthermore, differences in the immune microenvironment, response to immunotherapy, metabolic patterns, and cancer progression characteristics between high- and low-risk groups were examined on the basis of these scores. In vitro experiments validated the function of the key gene glycine cleavage system protein H (GCSH) in cellular and tissues, respectively. Results: Prognostic models established on the basis of subgroup genetic differences achieved satisfactory results in validation. Metabolic-related gene expression levels and tumor microenvironment distribution were significantly different between the high and low CRG groups. GCSH was revealed as the singular prognostic CRG in CCA (HR =6.04; 95% CI: 1.15-31.80). Moreover, inhibition of the cupcoptosis key gene GCSH attenuated the malignant ability of CCA cell lines in vitro, including cell proliferation, migration and invasion, and this function of GCSH may be achieved via JAK-STAT signaling in CCA. Conclusion: The CRG scoring system accurately predicts prognosis and opens up new possibilities for cuproptosis-related therapy for CCA. The cuproptosis key gene GCSH has been preliminarily confirmed as a reliable therapeutic target or prognostic marker for CCA patients.

[Transforming growth factor ß1 cooperates with stromal cell derived factor 1 to affect the proliferation of hepatic oval cells via ß-catenin inactivation].

OBJECTIVE: To investigate the role of stromal cell derived factor 1 (SDF-1) on the proliferation of hepatic oval cells, and the influencing factors. METHODS: Flow cytometry was used to detect the expression of CXCR4 on the cell surface when WB-F344 cells were growing in the culture medium with and without transforming growth factor ß1 (TGF-ß1) respectively. Western bolt was used to detect the expression of ß-catenin and its phosphorylation level. The translocation of ß-catenin was shown by confocal microscopy analysis. Q-RT-PCR was used in detecting the ß-catenin downstream gene expression such as Ccnd1 and c-Myc. MTT was used to detect the proliferation of WB-F344 cells which were treated by SDF-1 + TGF-ß1 and those cells exposed to SDF-1 or TGF-ß1 only, as well as of the negative control group. RESULT: WB-F344 cells rarely express CXCR4 under conventional circumstance, but this receptor can be up-regulated when the culture medium contain a modest amount of TGF-ß1 (the rate of CXCR4 positive cell increased by 39.5%). The bond of SDF-1 to CXCR4 results in the phosphorylation of ß-catenin, and its inactivation. SDF-1 alone didn't affect the proliferation of WB-F344 cells (0.512 ± 0.010 vs. 0.513 ± 0.008, t = 0.337, P > 0.05), while TGF-ß1 group show a slight decrease of cell population (0.393 ± 0.007,t = 28.001, P < 0.05). But when TGF-ß1 combined with SDF-1, the proliferation of WB-F344 was more weakened than TGF-ß1 group, and the difference was statistically significant (0.272 ± 0.009,t = 32.204, P < 0.05). CONCLUSIONS: TGF-ß1 can up-regulate the expression of CXCR4 in hepatic oval cells, and then inhibit the proliferation of hepatic oval cells via inactivating ß-catenin in vitro.

The Role of Caspase-11 and Pyroptosis in the Regulation of Inflammation in Peri-Implantitis.

Peri-implantitis is an important cause of oral implant failure. In the past, TLR4 and TLR2 in the Toll-like family were generally considered as the key immune recognition receptors regulating peri-implantitis. However, under the guidance of this theory, there are still some unexplainable peri-implantitis symptoms. With the discovery of novel intracellular LPS receptor Caspase-11, a new understanding of inflammatory signaling and immune regulation in the development of peri-implantitis has been gained. However, the regulatory role of Caspase-11 in peri-implantitis and its crosstalk with the TLR4 pathway remain unclear. The therapeutic effect of drugs targeting Caspase-11 on peri-implantitis is still in its early stages. In view of this situation, this paper reviews the possible role of Caspase-11 in peri-implant inflammation, elaborated the entry process of LPS and the activation mechanism of Caspase-11, and analyzes the differences in Caspase-11 between commonly studied animals, mice and humans. The current research hotspots and challenges are also analyzed to provide new insights and ideas for researchers.

Low MARCO Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma Following Liver Transplantation.

Background: Macrophage receptor with collagenous structure (MARCO) reportedly plays a crucial role in the occurrence and development of several cancers. However, the association between MARCO and the prognosis of hepatocellular carcinoma (HCC) post-liver transplantation remains poorly elucidated. Methods: We examined MARCO expression at mRNA and protein level in 145 HCC samples and adjacent nontumor tissues using quantitative reverse transcription PCR, Western blot and immunohistochemistry. Furthermore, we analyzed the correlation of MARCO expression with clinicopathologic features and prognosis. Results: We assessed the association between MARCO expression and clinicopathologic features and used the Cox proportional hazards regression model to explore the association between MARCO expression and clinical prognosis of patients with HCC post-liver transplantation. We observed that the expression of MARCO at mRNA and protein level in adjacent nontumor tissues was higher than that in the HCC tissues. Low MARCO expression in HCC tissues was correlated with higher alpha-fetoprotein levels, higher incidence of microvascular invasion, and a higher number of patients beyond Milan criteria. Kaplan-Meier survival curves showed that patients with HCC with low MARCO expression exhibited poor overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analysis revealed that MARCO expression was an independent prognostic factor for OS (hazard ratio [HR] 2.696, 95% confidence interval [CI] 1.335-5.444, P=0.006) and DFS (HR 2.867, 95% CI 1.665-4.936, P<0.001) in patients with HCC post-liver transplantation. Based on immunofluorescence analysis, MARCO expression was primarily localized to macrophages and might be associated with M2-like macrophage polarization during HCC. Conclusion: MARCO expression was downregulated in HCC and associated with poor prognosis of patients with HCC post-liver transplantation. Moreover, it could be a potential prognostic marker and therapeutic target in post-liver transplantation HCC.

Ala499Val (C>T) and Lys939Gln (A>C) polymorphisms of the XPC gene: their correlation with the risk of primary gallbladder adenocarcinoma--a case-control study in China.

Genetic variations in the gene XPC may be associated with increased risk for gallbladder cancer (GBC). In this study, we detected two non-synonymous polymorphisms in XPC (Ala499Val and Lys939Gln) in 334 cases of GBC and 329 subjects of hospital-based age- and sex frequency-matched controls in China using a polymerase chain reaction-restriction fragment length polymorphism assay. Allelic association analysis for the two single-nucleotide polymorphisms (SNPs) showed that the risk allele T of Ala499Val was significantly associated with GBC [odds ratio (OR)=1.40, 95% confidence interval (CI): 1.11-1.76, P=0.005), with a population attributive risk of 5.3%. Logistic regression analysis revealed that Ala499Val CT heterozygote (OR=1.56, 95% CI: 1.13-2.14, P=0.002) and TT homozygote (OR=1.93, 95% CI: 1.04-3.55, P=0.048) had a significantly increased risk compared with CC homozygotes. Genetic analysis suggested that either the SNPs directly exert an effect or the linked functional gene impact of the disease trait likely follows an additive or dominant model. Gene interaction analysis demonstrated that the effects of XPC diplotypes (defined as the number of risk genotypes at the two SNP loci) were highly dependent on gallstone. The data from this case-control study indicated that XPC exonic variants contributed to the risk of GBC in this Chinese population.

LDH and GGT/ALT Ratio as Novel Prognostic Biomarkers in Hepatocellular Carcinoma Patients after Liver Transplantation.

BACKGROUND: Liver inflammation indices reflect its inflammatory microenvironment, which may play a role in the proliferation, invasion, and migration of carcinoma. This study is aimed at exploring the prognostic significance of serum lactate dehydrogenase (LDH) levels and gamma-glutamyl transferase (GGT)/alanine aminotransferase (ALT) ratio in hepatocellular carcinoma after liver transplant (LT). METHODS: We retrospectively analyzed data from 155 patients with a pathologically confirmed diagnosis of hepatocellular carcinoma who received LT between January 2013 and September 2017. We used receiver operating characteristics (ROC) curves to determine the optimal LDH and GGT/ALT ratio cut-off values. The Kaplan-Meier method and the logarithmic rank test were used to compare the survival curves without recurrence (RFS) and overall survival (OS). Univariate and multivariate analyses were used to identify factors associated with survival. RESULTS: Serum LDH levels were significantly associated with the Child-Pugh score (P = 0.037), largest tumor size (<50 vs. ≥50 mm) (P = 0.017), tumor count (<3 vs. ≥3) (P = 0.009), microvascular invasion (P = 0.006), and the Milan criteria (P ≤ 0.001). The serum GGT/ALT ratio was significantly correlated with alpha-fetoprotein (AFP) levels (of <400 vs. ≥400 ng/ml) (P ≤ 0.001), largest tumor size (of <50 vs. ≥50 mm) (P ≤ 0.001), the Edmondson grade (I-II vs. III-IV) (P = 0.028), microvascular invasion (P ≤ 0.001), and the Milan (P = 0.002) and Hangzhou criteria (P = 0.018). The survival curves showed that the patients with high LDH and the GGT/ALT ratio were associated with poor RFS and OS (P < 0.05). Univariate and multivariate analyses showed that AFP levels of ≥400 ng/ml, largest tumor size of ≥50 mm, microvascular invasion, LDH levels of ≥213.5 U/l, and the GGT/ALT ratio of ≥3.1338 were factors independently associated with RFS. CONCLUSION: Elevated LDH levels and the GGT/ALT ratio before LT were associated with poor OS and RFS in the present study. These factors could be used in the prognostication of patients with hepatocellular carcinoma undergoing LT.

Cell nucleus as endogenous biological micropump.

Micropumps can generate directional microflows in blood vessels or bio-capillaries for targeted transport of nanoparticles and cells in vivo, which is highly significant for biomedical applications from active drug delivery to precision clinical therapy. Meanwhile, they have been extensively used in the biosensing fields with their unique features of autonomous motion, easy surface functionalization, dynamic capture and effective isolation of analytes in complex biological media. However, synthetic devices for actuating microflows, including pumps and motors, generally exhibit poor or limited biocompatibility with living organisms as a result of the invasive implantation of exogenous materials into blood vessels. Here we demonstrate a method of constructing endogenous micropumps by extracting nuclei from red blood cells, thus making them intrinsically and completely biocompatible. The nuclei are extracted and then driven by a scanning optical tweezing system. By a precise actuation of the microflows, nanoparticles and cells are navigated to target destinations, and the transport velocity and direction is controlled by the multifunctional dynamics of the micropumps. With the targeted transport of functionalized micro/nanoparticles followed by a dynamic mixing in microliter blood samples, the micropumps provide considerable promises to enhance the target binding efficiency and improve the sensitivity and speed of biological assays in vivo. Furthermore, multiplexing by simultaneously driving an array of multiple nuclei is demonstrated, thus confirming that the micropumps could provide a bio-friendly high-throughput in vivo platform for the treatment of blood diseases, microenvironment monitoring, and biomedical analysis.

Correction: JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells.

[This corrects the article DOI: 10.18632/oncotarget.3713.].

Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARgamma signaling pathway.

AIM: Resistance to 5-fluorouracil (5-FU) is a major cause of chemotherapy failure in advanced hepatocellular carcinoma (HCC). Rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has a crucial role in growth inhibition and induction of apoptosis in several carcinoma cell lines. In this study, we examine rosiglitazone-induced sensitization of HCC cell lines (BEL-7402 and Huh-7 cells) to 5-FU. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate cell viability. Western blotting analysis was performed to detect the protein expression (PPARgamma, PTEN, and COX-2) in BEL-7402 cells. Immunohistochemistry staining was used to examine the expression of PTEN in 100 advanced HCC tissues and paracancerous tissues. In addition, small interfering RNA was used to suppress PPARgamma, PTEN, and COX-2 expression. RESULTS: Rosiglitazone facilitates the anti-tumor effect of 5-FU in HCC cell lines, which is mediated by the PPARgamma signaling pathway. Activation of PPARgamma by rosiglitazone increases PTEN expression and decreases COX-2 expression. Since distribution of PTEN in HCC tissues is significantly decreased compared with the paracancerous tissue, over-expression of PTEN by rosiglitazone enhances 5-FU-inhibited cell growth of HCC. Moreover, down-regulation of COX-2 is implicated in the synergistic effect of 5-FU. CONCLUSION: Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-FU antitumor activity through the activation of PPARgamma. The results suggest potential novel therapies for the treatment of advanced liver cancer.

Outcome of the use of paediatric donor livers in adult recipients: A single Chinese centre experience.

BACKGROUND: Paediatric liver allografts sometimes are allocated to adult recipients when there are no suitable paediatric recipients on the waiting list. However, debate exits regarding the reported outcomes of liver transplants using such small grafts. METHODS: Records from adult patients undergoing liver transplantation between February 2010 and January 2016 who received whole grafts from paediatric (≤ 13 years) donors or ideal deceased adult (18-35 years) donors were reviewed. Patient and graft survival, post-transplant liver function, and complications between the two groups were compared. RESULTS: The baseline characteristics were comparable, except that the paediatric donor allografts had smaller size. The 3-month, 1-year, and 3-year rates of patient survival were 91.3%, 85.2%, and 85.2% in the paediatric donor group and 93.4%, 88.9%, and 85.0% in the adult donor group (P = 0.947), respectively. One patient receiving a paediatric allograft developed small-for-size liver syndrome post-transplantation. There was no difference in primary non-function, early allograft dysfunction, biliary complications, vascular complications, or infection between the two groups. CONCLUSION: Our study indicates that using paediatric donor livers in well-selected adult recipients is a safe procedure, considering there was no suitable paediatric recipient. However, the risk of portal hyperperfusion should be considered in clinical cases such as size-mismatched transplants.