-
Gastroenterology 03/2013; · 11.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Catheter-based intra-arterial therapies provided effective tumour control for unresectable hepatocellular carcinoma without distant metastasis. There was a renewed interest in the advancement of yttrium-90 radio-embolization.
An extensive search on the MEDLINE databases identified seven case series and two comparative studies regarding yttrium-90 radio-embolization.
Case series on yttrium-90 radio-embolization indicated a tumour response rate that ranged from 20% to 70%, and median survival that ranged from 7.7 to 26.6 months. Two comparative studies did not demonstrate significant difference in terms of tumour response rate and survival. One of these comparative studies demonstrated a statistically significant reduction in treatment-related neutropaenia.
The current use of yttrium-90 radio-embolization was mainly based on small case series. Yttrium-90 radio-embolization seemed equivalent to conventional chemo-embolization in terms of tumour response rate and survival benefit. Emerging evidence suggested that yttrium-90 radio-embolization may have a more favourable side effects profile, in particular in reducing the chance of neutropaenia. Cost and logistics arrangement were two important considerations in generalizing the application of yttrium-90 radio-embolization.
ANZ Journal of Surgery 07/2012; 82(7-8):505-9. · 1.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In management of intrahepatic recurrence of hepatocellular carcinoma (HCC), controversy exists over the efficacy of re-resection for patients with preserved liver function. This study aimed to determine the long-term outcomes of re-resection in these patients.
Prospectively collected data of 47 patients having re-resection (Group R) with curative intent for metachronous primary HCC between December 1989 and December 2007 were compared with those of 863 patients having primary resection (Group P) in the same period. There was no overlap of patient. All patients had gross tumour-free resection margin.
The two groups had comparable demographics. Group R had a median age of 58 years (range, 48-67 years), and had almost all patients belonging to Child-Pugh class A (46/47). Median blood loss was 0.66 L (range, 0.3-1.28 L) for Group P and 0.37 L (range, 0.13-0.92 L) for Group R. Both groups had median blood transfusion rate at 0. Median operative time was 365 min (range, 240-490 min) for Group P and 270 min (range, 193-360 min) for Group R. Group R had significantly fewer tumour nodules and the only one operative death. Median follow-up was 41 months for Group P and 37 months for Group R (P= 0.133). The two groups displayed no significant differences in disease-free survival and overall survival. Univariate analysis showed that re-resection was not a significant risk factor in overall survival.
Re-resection for metachronous primary HCC for patients with preserved liver function can achieve favourable survival outcome.
ANZ Journal of Surgery 01/2012; 82(1-2):63-7. · 1.25 Impact Factor
-
International Journal of Colorectal Disease 08/2011; 27(7):987-8. · 2.38 Impact Factor
-
Edmund Kwok-Kwan Tung,
Carmen Ka-Man Mak,
Sarwat Fatima,
Regina Cheuk-Lam Lo,
Heng Zhao,
Chunsheng Zhang,
Hongyue Dai, Ronnie Tung-Ping Poon,
Man-Fung Yuen,
Ching-Lung Lai,
Jin-jun Li,
John Moon-Ching Luk,
Irene Oi-Lin Ng
[show abstract]
[hide abstract]
ABSTRACT: Although Dickkopf-1 (DKK1) is known to be a negative regulator of the Wnt/β-catenin pathway, it has been recently found to be upregulated in cancers.
We investigated the clinical and prognostic significance of both serum and transcript DKK1 and its functional roles in human hepatocellular carcinoma (HCC).
We evaluated the expression level of DKK1 in both tissue and serum samples from patients with HCC using GeneChip microarray and real-time-quantitative PCR and sandwich ELISA system respectively. The clinicopathological and prognostic significance of serum and tissue DKK1 levels was examined. Functional characterization of DKK1 with regard to cell migration, invasion and tumour growth was performed.
Both DKK1 transcript and serum protein were upregulated in a stepwise manner in human HCCs. Its transcript levels were associated with more aggressive tumour behaviour, in terms of venous invasion (P = 0.003), advanced tumour stage (P = 0.003). DKK1 transcript correlated with shorter overall (P = 0.006) and disease-free survival (P = 0.012), and higher serum DKK1 levels correlated with shorter disease-free survival (P = 0.046). Knockdown of DKK1 significantly reduced both migratory and invasive abilities of HCC cells, whereas overexpression of DKK1 enhanced the tumour formation efficiency and tumour growth in vivo.
Serum and tissue DKK1 levels increased in a stepwise manner in multistep hepatocarcinogenesis and had prognostic significance. DKK1 plays a functional role in cell migration, invasion and tumour growth.
Liver international: official journal of the International Association for the Study of the Liver 08/2011; 31(10):1494-504. · 3.82 Impact Factor
-
Edmund Kwok‐Kwan Tung,
Carmen Ka‐Man Mak,
Sarwat Fatima,
Regina Cheuk‐Lam Lo,
Heng Zhao,
Chunsheng Zhang,
Hongyue Dai, Ronnie Tung‐Ping Poon,
Man‐Fung Yuen,
Ching‐Lung Lai,
Jin‐jun Li,
John Moon‐Ching Luk,
Irene Oi‐Lin Ng
[show abstract]
[hide abstract]
ABSTRACT: Background:Although Dickkopf-1 (DKK1) is known to be a negative regulator of the Wnt/β-catenin pathway, it has been recently found to be upregulated in cancers.Aims:We investigated the clinical and prognostic significance of both serum and transcript DKK1 and its functional roles in human hepatocellular carcinoma (HCC).Methods:We evaluated the expression level of DKK1 in both tissue and serum samples from patients with HCC using GeneChip microarray and real-time-quantitative PCR and sandwich ELISA system respectively. The clinicopathological and prognostic significance of serum and tissue DKK1 levels was examined. Functional characterization of DKK1 with regard to cell migration, invasion and tumour growth was performed.Results:Both DKK1 transcript and serum protein were upregulated in a stepwise manner in human HCCs. Its transcript levels were associated with more aggressive tumour behaviour, in terms of venous invasion (P = 0.003), advanced tumour stage (P = 0.003). DKK1 transcript correlated with shorter overall (P = 0.006) and disease-free survival (P = 0.012), and higher serum DKK1 levels correlated with shorter disease-free survival (P = 0.046). Knockdown of DKK1 significantly reduced both migratory and invasive abilities of HCC cells, whereas overexpression of DKK1 enhanced the tumour formation efficiency and tumour growth in vivo.Conclusions:Serum and tissue DKK1 levels increased in a stepwise manner in multistep hepatocarcinogenesis and had prognostic significance. DKK1 plays a functional role in cell migration, invasion and tumour growth.
Liver international: official journal of the International Association for the Study of the Liver 08/2011; 31(10):1494 - 1504. · 3.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We aimed to investigate the incidence of occult hepatitis B infection (OBI) in patients with "cryptogenic" hepatocellular carcinoma (HCC) and to study the HBV replicative activity in these patients. Tumorous and adjacent nontumorous liver tissues were obtained from 33 cryptogenic HCC patients and 28 HCC patients with identifiable causes (13 with chronic hepatitis B [CHB], six with chronic hepatitis C, and nine alcohol-related). OBI was identified by nested polymerase chain reaction (PCR). Intrahepatic HBV DNA, covalently closed circular DNA (cccDNA), and pregenomic RNA (pgRNA) were quantified by real-time PCR and reverse-transcription PCR (RT-PCR), respectively. OBI was identified in 24 (73%) cryptogenic HCC patients, one (17%) HCC patient with HCV, and five (56%) patients with alcohol-related HCC. In HCC patients with OBI, HBV DNA were detected in ≥2 HBV genomic regions more often in nontumorous tissues than in tumorous tissues (90% versus 57%, respectively; P = 0.007). Cryptogenic HCC patients with OBI had lower intrahepatic total HBV DNA levels than HCC patients with CHB (median: 0.010 versus 3.19 copies/cell, respectively; P < 0.0001). Only six (26%) cryptogenic HCC patients with OBI had detectable cccDNA (median: <0.0002 copies/cell), which was significantly lower than that of the CHB patients (median: 0.005 copies/cell; P < 0.0001). HBV pgRNA were detectable in 12 (52%) cryptogenic HCC patients with OBI (median: 0.0001 copies/cell), which was significantly lower than that of the CHB patients (median: 2.90 copies/cell; P < 0.001). Conclusion: 73% of patients with apparently unidentifiable causes for HCC were HBV-related. The detection rate was higher in nontumorous tissues than tumorous tissues. The low intrahepatic HBV DNA and pgRNA levels indicated that persistent viral replication and possibly HBV integration are the likely causes of HCC in OBI patients.
Hepatology 07/2011; 54(3):829-36. · 11.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Microvascular invasion is a poor prognostic indicator of the recurrence of hepatocellular carcinoma (HCC) after surgical treatment. Positron emission tomography (PET) with [(18) F]fludeoxyglucose ([(18) F]FDG) as a tracer has been employed to predict the prognosis before surgery for various kinds of tumors, but it has not been found to be sensitive enough for HCC. Thus, [(11) C]acetate has been adopted as an additional tracer. This study was designed to evaluate the ability of dual-tracer PET ([(18) F]FDG and [(11) C]acetate) to predict microvascular invasion before liver resection or transplantation. Fifty-eight HCC patients who were preoperatively examined with whole-body dual-tracer PET were studied. Twenty-five patients were [(18) F]FDG-positive, and 56 were [(11) C]acetate-positive. The sensitivity of [(18) F]FDG in detecting primary HCC was 43%, and the sensitivity of [(11) C]acetate was 93%. Twenty-nine patients had HCC with microvascular invasion according to the final pathological examination. The sensitivity, specificity, positive predictive value, and negative predictive value of [(18) F]FDG PET in predicting microvascular invasion were 55.2%, 69%, 64%, and 60.6%, respectively; the corresponding rates for [(11) C]acetate PET were 93.1%, 0%, 48.2%, and 0%. The factors associated with HCC recurrence, which included multifocal involvement, a large tumor size, microsatellite lesions, poor HCC differentiation, and an advanced stage of disease, were analyzed and compared with positive PET results. A tumor size greater than 5 cm was significantly associated with positive [(18) F]FDG PET results; [(11) C]acetate was not associated with poor prognostic indicators. Preoperative [(18) F]FDG PET may predict microvascular invasion. The addition of [(11) C]acetate improves the overall sensitivity of PET, but it has no incremental value in predicting microvascular invasion.
Liver Transplantation 06/2011; 17(10):1218-25. · 3.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tumour recurrence and metastasis are pressing issues of hepatocellular carcinoma (HCC) patients who receive surgical treatments. Matrix metalloproteinase-12 (MMP-12), previously identified from our animal model, is involved in tumour invasiveness of rat hepatoma. We aimed to investigate the significance and prognostic value of MMP-12 expression in human HCC. MMP-12 mRNA level of 139 pairs of tumour and non-tumour liver tissues of HCC patients after hepatectomy were investigated by quantitative real-time RT-PCR. MMP-12 mRNA was significantly elevated in tumour liver tissues of HCC patients compared to non-tumour and normal liver tissues. By comparing paired tumour and non-tumour liver tissues, MMP-12 mRNA was overexpressed in 58% of tumour tissue of HCC patients. Overexpression of MMP-12 mRNA was significantly correlated with presence of venous infiltration (p=0.004), high serum AFP level (p=0.012), early tumour recurrence (p=0.018) and poor overall survival (p=0.02) of HCC patients. Moreover, MMP-12 mRNA was an independent factor in predicting the 1- and 3-year overall survival of HCC patients after hepatectomy. Our data demonstrated that MMP-12 mRNA may be a valuable prognostic marker for both overall survival and tumour recurrence of HCC patients after liver resection.
European journal of cancer (Oxford, England: 1990) 06/2011; 47(15):2299-305. · 4.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: One of the most relevant risk factors for hepatocellular carcinoma (HCC) development is chronic hepatitis B virus (HBV) infection, but only a fraction of chronic HBV carriers develop HCC, indicating that complex interactions among viral, environmental and genetic factors lead to HCC in HBV-infected patients. So far, host genetic factors have incompletely been characterized. Therefore, we performed a genome-wide association (GWA) study in a Southern Chinese cohort consisting of 95 HBV-infected HCC patients (cases) and 97 HBV-infected patients without HCC (controls) using the Illumina Human610-Quad BeadChips. The top single nucleotide polymorphisms (SNPs) were then validated in an independent cohort of 500 cases and 728 controls. 4 SNPs (rs12682266, rs7821974, rs2275959, rs1573266) at chromosome 8p12 showed consistent association in both the GWA and replication phases (OR(combined) = 1.31-1.39; p(combined) = 2.71 × 10(-5)-5.19 × 10(-4); PAR(combined) = 26-31%). We found a 2.3-kb expressed sequence tag (EST) in the region using in-silico data mining and verified the existence of the full-length EST experimentally. The expression level of the EST was significantly reduced in human HCC tumors in comparison to the corresponding non-tumorous liver tissues (P<0.001). Results from sequence analysis and in-vitro protein translation study suggest that the transcript might function as a long non-coding RNA. In summary, our study suggests that variations at chromosome 8p12 may promote HCC in patients with HBV. Further functional studies of this region may help understand HBV-associated hepatocarcinogenesis.
PLoS ONE 01/2011; 6(12):e28798. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We investigated mechanisms of hepatocellular carcinoma (HCC) metastasis and identified an antimetastatic microRNA (miRNA), miR-139, that is down-regulated in human HCC samples.
Effects of stable and transient expression of miRNA-139 and its inhibitors were studied in the human HCC cell lines SMMC-7721 and BEL7402; cells were analyzed for migration and invasion. Liver samples from patients with metastatic HCC were analyzed for levels of miRNA-139; data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. Tumor formation and metastasis from human HCC MHCC97L cells that did or did not express miR-139 were analyzed in mice.
Down-regulation of miR-139 in HCC was associated significantly with poor prognosis of patients and features of metastatic tumors, including venous invasion, microsatellite formation, absence of tumor encapsulation, and reduced differentiation. miR-139 expression was reduced in metastatic HCC tumors compared with primary tumors. Overexpression of miR-139 in HCC cells significantly reduced cell migration and invasion in vitro and the incidence and severity of lung metastasis from orthotopic liver tumors in mice. miR-139 interacted with the 3' untranslated region of Rho-kinase 2 (ROCK2) and reduced its expression in HCC cells. Levels of miR-139 were correlated inversely with ROCK2 protein in human HCC samples. Overexpression of miR-139 did not inhibit HCC cell motility when ROCK2 was knocked down.
The microRNA miR-139 interacts with ROCK2 and reduces its expression in HCC cells. Down-regulation of miR-139 increased the invasive abilities of HCC cells in vitro and HCC metastasis in vivo. Expression of miR-139 is reduced in human metastatic HCC samples and correlates with prognosis.
Gastroenterology 10/2010; 140(1):322-31. · 11.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Conventional hepatectomy is an effective way to treat hepatocellular carcinoma. However, it is invasive and stressful. The use of laparoscopy in hepatectomy, while technically demanding, reduces surgical invasiveness and stressfulness but still achieves complete resection with adequate margins. Compared with conventional hepatectomy, laparoscopic hepatectomy provides a better chance and situation for further surgery in the case of recurrence of hepatocellular carcinoma. Even aged patients can successfully endure repeated hepatectomy using laparoscopy, as shown in the present report. This report presents a case of repeated laparoscopic hepatectomy treating hepatocellular carcinoma and its recurrence in an aged patient having cirrhosis, a disease causing extra difficulty for performing laparoscopic hepatectomy. The report also describes techniques of the operation and displays characteristic results of laparoscopic hepatectomy such as smaller wounds, less blood loss, less pain, less scars and adhesion, shorter postoperative hospital stay, and faster recovery.
World Journal of Gastroenterology 01/2010; 16(4):526-30. · 2.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Deleted in liver cancer (DLC) is a family of tumour suppressors that plays a critical role in hepatocellular carcinoma (HCC).
This study aimed to document the expression profiles of the three known DLC1 isoforms (alpha, beta and gamma) in normal human tissues and human HCCs and address their functional and regulatory differences. We also aimed to determine the clinicopathological and prognostic significance of the DLC1 dominant isoform in human HCCs.
Quantitative polymerase chain reaction was performed to determine the expressions of DLC1 isoforms in different normal human tissues and human HCCs. The clinicopathological and prognostic significance of DLC1 expression in HCC samples was also analysed. In addition, the functional roles of DLC1 isoforms were addressed using HCC cell lines to examine their abilities to suppress stress fibre formation and HCC cell growth.
DLC1alpha was the most predominant of the three isoforms in the normal human tissues examined, except the heart. The DLC1alpha promoter, but not the DLC1beta and gamma promoter, was hypermethylated and epigenetically silenced in HCC cells. Underexpression of DLC1alpha at the mRNA level was frequently (52.5%, n=52) observed in the 99 HCCs as compared with the corresponding nontumorous liver tissues. DLC1alpha underexpression correlated with poorer tumour cellular differentiation (P=0.010). Functionally, DLC1alpha and beta, but not DLC1gamma, were localized at focal adhesions of cells and able to inhibit stress fibre formation and suppress HCC cell growth.
The results suggested that DLC1 isoforms are differentially expressed in human tissues, have different epigenetic transcriptional regulations and are functionally different. DLC1alpha was underexpressed and clinically relevant in human HCCs.
Liver international: official journal of the International Association for the Study of the Liver 10/2009; 30(1):139-48. · 3.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The authors evaluated and compared the treatment outcomes of transarterial chemoembolization (TACE) between young (<or=70 years) and elderly (>70 years) patients at their institute over an 18-year period.
Advanced hepatocellular carcinoma (HCC) patients who received TACE at the authors' center were analyzed retrospectively. The demographic data, TACE-related morbidities, and survival outcome were compared between these 2 age groups.
Between 1989 and 2006, 843 patients who were <or=70 years old and 197 patients who were >70 years old received TACE treatment for advanced HCC. There were significantly more comorbid illnesses associated with the elderly patients than the young patients (64 % vs 33%, P < .01). Moreover, elderly patients who received TACE treatment for HCC were at earlier stages of disease (P < .01). Both the overall median survival (14.0 months vs 8.1 months, P < .003) and disease-specific survival (15.2 months vs 8.7 months, P < .001) were significantly higher in elderly than young patients. The most commonly encountered TACE-related morbidity in both age groups was liver function derangement. Young patients had a significantly higher rate of developing liver derangement after TACE than elderly patients (21% vs 11%, P < .01). Conversely, the elderly patients had a significantly higher rate of developing peptic ulcer disease with TACE treatment than young patients (2.5% vs 0.5%, P = .01). Overall, there was no significant difference in TACE-related mortality between the young and elderly patients (3% vs 4%, P = .49).
This study has confirmed the comparable efficacy and tolerability in using TACE for the treatment of advanced HCC in young and elderly patient populations.
Cancer 08/2009; 115(23):5507-15. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Systemic chemotherapy has had a disappointing track record in the management of advanced hepatocellular carcinoma (HCC). Single-agent doxorubicin produces a response rate of 10-15%, but without any survival benefit, and combination chemotherapy has also yielded unimpressive results. With recent advances in the knowledge of hepato-carcinogenesis, there has been encouraging development in the systemic therapy of advanced HCC patients, and particularly in the targeted therapy of advanced HCC. Among the newly identified targets, exciting results have been shown in targeting the anti-angiogenic pathway and the Raf/mitogen-activated protein kinase pathways. Bevacizumab, both as a single agent and in combination with other agents, has shown initial encouraging activity in treating advanced HCC. More recently, single-agent sorafenib, a putative multitargeted kinase inhibitor, has shown to prolong the overall survival of patients with advanced HCC in the pivotal phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Oriental study. Currently, sorafenib is the only approved targeted therapy for patients with advanced HCC. In addition, however, promising early results have been reported for other molecular-targeted drugs including erlotinib and sunitinib. Future progress seems likely to depend on using controlled clinical trials to optimize synergistic combination treatments.
Liver international: official journal of the International Association for the Study of the Liver 02/2009; 29(1):10-7. · 3.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: p27(Kip1) (p27) is a member of the Cip/Kip family of cyclin/cyclin-dependent kinase inhibitors (CKIs), and its CKI-independent function regarding cell motility modulation has been discovered. However, it is controversial whether p27 promotes or inhibits cell migration. This study investigates the migration regulatory role of p27 in metastatic hepatocellular carcinoma (HCC) cells.
RNA interference, RhoA-GTP pull-down assay, Western blots, immunostaining, transwell and wound-healing assays were used.
High levels of p27 and phosphorylated p27 (Ser10) were detected in metastatic HCC cells, MHCC97L and MHCC97H, when compared with nonmetastatic HCC cells, PLC and Hep3B. We hypothesized that p27 is responsible for metastasis-related migration in HCC cells and tested the hypothesis by using the p27 RNA interference approach. Increased RhoA activity was observed when p27 was knocked down in MHCC97L cells, which further led to stress fiber formation and decreased cell migration and wound healing. Moreover, high p27 and low stathmin expression of metastatic HCC cells indicated that migration inhibition by p27-stathmin interaction might not be the major regulatory pathway in metastatic HCC cells.
p27 promotes cell migration in metastatic HCC cells through the regulation of RhoA activity.
Tumor Biology 10/2008; 29(4):217-23. · 1.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hepatic resection is not applicable to a certain proportion of hepatocellular carcinoma patients owing to an insufficient liver function reserve. The present study was designed to investigate the effects of cardiotrophin-1 (CT-1) on improving the function of CCl(4)-induced cirrhotic liver remnant after major hepatectomy.
CT-1 was administered to rats after hepatectomy according to different protocols.
A double-dose CT-1 protocol improved liver function, enlarged the volume of liver remnant, upregulated the expression of von Willebrand factor and increased the number of BrdU(+) or Ki-67(+) hepatocytes. Administration of CT-1 enhanced the expression of nuclear factor-kappaB (P65), vascular endothelial growth factor (VEGF), CyclinD1 and p42/44 in the liver remnant. However, the effects of CT-1 were blocked by a VEGF receptor blocker, PTK787. Although the expression of gp130, a receptor of CT-1, was downregulated in the diseased hepatocytes isolated from the cirrhotic liver, CT-1 could still stimulate the cell proliferation. CT-1 administration enhanced the expression of P65 and VEGF in the diseased hepatocytes, but the augmented P65 and VEGF expression was blocked by PTK787 administration.
Short-term administration of CT-1 could improve the function of cirrhotic liver remnant and stimulate liver regeneration through promotion of angiogenesis and cell proliferation.
Liver international: official journal of the International Association for the Study of the Liver 06/2008; 28(5):622-31. · 3.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study investigated the effect of YC-1, a novel anti-cancer agent, on the chemo-sensitivity of hepatocellular carcinoma (HCC). YC-1 was administered with chemo-cytotoxic drug, cisplatin, both in vitro and in vivo. YC-1 alone downregulated the expression of phosphorylated form of signal transducers and activators of transcription 3 (P-Stat3[705]), a key mediator in chemo-resistance. When combined with cisplatin, YC-1 further promoted tumor cell apoptosis, decreased the expression of P-Stat3(705), Bcl-xL, CyclinD1 and survivin, and induced the cleavage of caspase 9 and PARP. Overexpression of Stat3 reversed YC-1 induced cell death. YC-1 inhibited Stat3 activity by enhancing the polyubiquitination of P-Stat3(705) induced by cisplatin. In the in vivo setting, YC-1 combined with cisplatin remarkably suppressed tumor growth in a HCC xenograft model, and this effect was also accompanied by YC-1 mediated downregulation of P-Stat3(705), Bcl-xL, Cyclin D1 and survivin, and induction of cleaved caspase 9 and PARP in the tumor tissues. In conclusion, the present study demonstrated a novel anti-cancer effect of YC-1 in enhancing chemo-sensitivity of HCC cells to cisplatin through a Stat3 dependent manner. This finding provides insight into design of a new therapeutic strategy to improve efficacy of chemotherapy in HCC patients.
Cancer biology & therapy 01/2008; 6(12):1900-7. · 2.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study aims to investigate the potential therapeutic role of interleukin-10 (IL-10) in small-for-size liver transplantation. A syngenic rat orthotopic liver transplantation model was performed using either whole or 40% liver volume of Lewis rats as grafts according to the experimental design. IL-10 was given to the 40% grafts right after reperfusion, and also at 24 and 48 hours after transplantation. When no treatment was given, less than 40% of the small-for-size grafts survived indefinitely, whereas IL-10 treatment could increase the long-term survival rate of the small-for-size grafts to 80%. The 40% grafts presented with extensive areas of necrosis and increased number of apoptotic cells at the early phases after reperfusion. In addition, upregulation of plasma protein carbonyl content (PCC) levels was also detected in the 40% graft group. IL-10 treatment suppressed the upregulation of allograft inflammatory factor-1 (AIF-1) on macrophages in the 40% grafts, and at the same time, decreased the levels of plasma PCC, and improved the histology and function of the 40% grafts. The expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-alpha, and caspase 9 in the 40% grafts were upregulated after reperfusion, whereas the augmentation could be suppressed by the administration of IL-10. Finally, IL-10 culture could block AIF-1-mediated NO production and downregulate the expression of iNOS and TNF-alpha in a macrophage cell line. In conclusion, IL-10 rescued the small-for-size liver grafts by its antiinflammatory properties, through inhibition of AIF-1 mediated proinflammatory and proapoptotic activities of the macrophages during the early period after ischemia/reperfusion.
Liver Transplantation 04/2007; 13(4):558-65. · 3.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Inhibition of HIF-1alpha activity provides an important strategy for the treatment of cancer. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) has been identified as an anti-HIF-1alpha drug in cancer therapy with unclear molecular mechanism. In the present study, we aimed to investigate the effect and mechanism of YC-1 on HIF-1alpha in a hepatocellular carcinoma cell line under hypoxic condition, which was generated by incubating cells with 0.1% O(2). The phenotypic and molecular changes of cells were determined by cell proliferation assay, apoptosis assay, luciferase promoter assay, and Western blot analysis. YC-1 arrested tumor cell growth in a dose-dependent manner, whereas it did not induce cell apoptosis. Hypoxia-induced upregulation of HIF-1alpha was suppressed by YC-1 administration. YC-1 inhibited HIF-1alpha protein synthesis under normoxia and affected protein stability under hypoxia. YC-1 suppressed the expression of total and phosphorylated forms of murine double minute 2 (Mdm2), whereas this inhibitory effect was blocked by overexpression of Mdm2. In conclusion, YC-1 suppressed both protein synthesis and stability of HIF-1alpha in HCC cells, and its inhibitory effects on HIF-1alpha were dependent on Mdm2.
Biochemical and Biophysical Research Communications 11/2006; 348(4):1443-8. · 2.48 Impact Factor
