10 research outputs found
Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90
No full text10.1159/000348325Oncology (Switzerland)845311-318ONCO
Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma
No full textCadherin is an important cell adhesion molecule that plays paramount roles in organ development and the maintenance of tissue integrity. Dysregulation of cadherin expression is often associated with disease pathology including tissue dysplasia, tumor formation, and metastasis. Cadherin-17 (CDH17), belonging to a subclass of 7D-cadherin superfamily, is present in fetal liver and gastrointestinal tract during embryogenesis, but the gene becomes silenced in healthy adult liver and stomach tissues. It functions as a peptide transporter and a cell adhesion molecule to maintain tissue integrity in epithelia. However, recent findings from our group and others have reported aberrant expression of CDH17 in major gastrointestinal malignancies including hepatocellular carcinoma (HCC), stomach and colorectal cancers, and its clinical association with tumor metastasis and advanced tumor stages. Furthermore, alternative splice isoforms and genetic polymorphisms of CDH17 gene have been identified in HCC and linked to an increased risk of HCC. CDH17 is an attractive target for HCC therapy. Targeting CDH17 in HCC can inhibit tumor growth and inactivate Wnt signaling pathway in concomitance with activation of tumor suppressor genes. Further investigation on CDH17-mediated oncogenic signaling and cognate molecular mechanisms would shed light on new targeting therapy on HCC and potentially other gastrointestinal malignancies. © 2010 Elsevier B.V.link_to_subscribed_fulltex
Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: A retrospective cohort study
No full textObjective: Serum α-fetoprotein (AFP) is the most commonly used biomarker for screening hepatocellular carcinoma (HCC) but fails to detect about half of the patients. Thus, we investigated if circulating microRNAs (miRNAs) could outperform AFP for HCC detection. Design: A retrospective cohort study. Setting: Two clinical centres in China. Participants: The exploration phase included 96 patients with HCC who received primary curative hepatectomy, and the validation phase included 29 hepatitis B carriers, 57 patients with HCC and 30 healthy controls. Main outcome measures: Expression of miRNAs was measured by real-time quantitative reverse transcription-PCR. Areas under receiver operating characteristic curves were used to determine the feasibility of using serum miRNA concentration as a diagnostic marker for defining HCC. A multivariate logistic regression analysis was used to evaluate performances of combined serum miRNAs. Results: In the exploration phase, miRNA profiling on resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study, combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP. Conclusion: The combined miR-15b and miR-130b classifier is a serum biomarker with clinical value for HCC screening.published_or_final_versio
Proteomics of hepatocellular carcinoma: Serum vimentin as a surrogate marker for small tumors (≤2 cm)
No full textSmall hepatocellular carcinomas (HCCs) can be effectively cured by surgery with good clinical outcomes. However, the conventional AFP marker is ineffective in detecting small tumors. Here we employed a proteomic profiling approach to identify a candidate marker for HCC (≤2 cm) in tumor tissues and then evaluate its clinical feasibility in patients? sera. The study was divided into 2 phases. (i) Biomarker discovery: we collected 76 frozen liver tissues (40 HCC and 36 controls) for proteomics profiling. Candidate protein markers were identified by MALDI-TOF/TOF and confirmed by immunoblot and qPCR. (ii) Clinical evaluation: Selected biomarker was tested by ELISA for sensitivity and specificity using serum samples from a separate cohort of 152 subjects (88 HCC and 64 controls). Vimentin was found significantly overexpressed in HCC, in particular the small-size subgroup (≤2 cm) with p < 0.01. When tested in the serum samples, vimentin level was significantly higher in small tumors than the non-neoplastic controls (AUC = 0.69 and p < 0.01). Further analysis suggested that elevated circulating vimentin level could detect small HCC at 40.91% sensitivity and 87.50% specificity. Moreover, vimentin was found to be superior to serum AFP assayed at different cut-offs in detecting small tumors. When combined with AFP, the detection sensitivity and specificity could be further enhanced to 58.77 and 98.15%, respectively. In conclusion, serum vimentin is a potential surrogate marker, either alone or in combination with AFP, for detection of small HCCs. © 2010 American Chemical Society.link_to_subscribed_fulltex
Enhanced detection of early hepatocellular carcinoma by serum SELDI-TOF proteomic signature combined with alpha-fetoprotein marker
No full textBackground: Biomarkers for accurate diagnosis of early hepatocellular carcinoma (HCC) are limited in number and clinical validation. We applied SELDI-TOF-MS ProteinChip technology to identify serum profile for distinguishing HCC and liver cirrhosis (LC) and to compare the accuracy of SELDI-TOF-MS profile and alpha-fetoprotein (AFP) level in HCC diagnosis. Patients and Methods: Serum samples were obtained from 120 HCC and 120 LC patients for biomarker discovery and validation studies. ProteinChip technology was employed for generating SELDI-TOF proteomic features and analyzing serum proteins/peptides. Results: A diagnostic model was established by CART algorithm, which is based on 5 proteomic peaks with m/z values at 3324, 3994, 4665, 4795, and 5152. In the training set, the CART algorithm could differentiate HCC from LC subjects with a sensitivity and specificity of 98% and 95%, respectively. The results were assessed in blind validation using separate cohorts of 60 HCC and 60 LC patients, with an accuracy of 83% for HCC and 92% for LC patients. The diagnostic odd ratio (DOR) indicated that SELDI-TOF proteomic signature could achieve better diagnostic performance than serum AFP level at a cutoff of 20 ng/mL (AFP 20) (92.72 vs 9.11), particularly superior for early-stage HCC (87% vs 54%). Importantly, a combined use of both tests could enhance the detection of HCC (sensitivity, 95%; specificity, 98%; DOR, 931). Conclusion: Serum SELDI-TOF proteomic signature, alone or in combination with AFP marker, promises to be a good tool for early diagnosis and/screening of HCC in at-risk population with liver cirrhosis. © 2010 Society of Surgical Oncology.published_or_final_versionSpringer Open Choice, 01 Dec 201
Anti-Cadherin-17 Antibody Modulates Beta-Catenin Signaling and Tumorigenicity of Hepatocellular Carcinoma
No full text10.1371/journal.pone.0072386PLoS ONE89e7238
Gene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma
No full textBiomarkers derived from gene expression profiling data may have a high false-positive rate and must be rigorously validated using independent clinical data sets, which are not always available. Although animal model systems could provide alternative data sets to formulate hypotheses and limit the number of signatures to be tested in clinical samples, the predictive power of such an approach is not yet proven. The present study aims to analyze the molecular signatures of liver cancer in a c-MET-transgenic mouse model and investigate its prognostic relevance to human hepatocellular carcinoma (HCC). Tissue samples were obtained from tumor (TU), adjacent non-tumor (AN) and distant normal (DN) liver in Tet-operator regulated (TRE) human c-MET transgenic mice (n = 21) as well as from a Chinese cohort of 272 HBV- and 9 HCV-associated HCC patients. Whole genome microarray expression profiling was conducted in Affymetrix gene expression chips, and prognostic significances of gene expression signatures were evaluated across the two species. Our data revealed parallels between mouse and human liver tumors, including down-regulation of metabolic pathways and up-regulation of cell cycle processes. The mouse tumors were most similar to a subset of patient samples characterized by activation of the Wnt pathway, but distinctive in the p53 pathway signals. Of potential clinical utility, we identified a set of genes that were down regulated in both mouse tumors and human HCC having significant predictive power on overall and disease-free survival, which were highly enriched for metabolic functions. In conclusions, this study provides evidence that a disease model can serve as a possible platform for generating hypotheses to be tested in human tissues and highlights an efficient method for generating biomarker signatures before extensive clinical trials have been initiated. © 2011 Ivanovska et al.published_or_final_versio
MicroRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma
No full textTumorigenesis involves multistep genetic alterations. To elucidate the microRNA (miRNA)-gene interaction network in carcinogenesis, we examined their genome-wide expression profiles in 96 pairs of tumor/non-tumor tissues from hepatocellular carcinoma (HCC). Comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-122 is under-expressed in HCC and that increased expression of miR-122 seed-matched genes leads to a loss of mitochondrial metabolic function. Furthermore, the miR-122 secondary targets, which decrease in expression, are good prognostic markers for HCC. Transcriptome profiling data from additional 180 HCC and 40 liver cirrhotic patients in the same cohort were used to confirm the anti-correlation of miR-122 primary and secondary target gene sets. The HCC findings can be recapitulated in mouse liver by silencing miR-122 with antagomir treatment followed by gene-expression microarray analysis. In vitro miR-122 data further provided a direct link between induction of miR-122-controlled genes and impairment of mitochondrial metabolism. In conclusion, miR-122 regulates mitochondrial metabolism and its loss may be detrimental to sustaining critical liver function and contribute to morbidity and mortality of liver cancer patients. © 2010 EMBO and Macmillan Publishers Limited.published_or_final_versio
Asian pacific association for the study of the liver consensus recommendations on hepatocellular carcinoma
No full textIntroduction: The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. Methods: The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. Results: Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference. © 2010 Asian Pacific Association for the Study of the Liver.link_to_OA_fulltex
Nitrogen removal and the fate of Nitrate in Riparian buffer zones
No full textRiparian buffer zones, adjacent to waterways, may protect water quality by intercepting and removing nitrogen in runoff from agricultural land. This research comprised four parts: (1) a field study of nitrogen buffering by differently vegetated riparian zones in a United Kingdom (UK) sheep-grazed pastoral catchment; (2) a field study of surface and subsurface runoff hydrology, and nitrogen flux, in a UK riparian wetland; (3) a laboratory study ((^15)N tracer-isotope dilution) of microbial inorganic nitrogen production and removal processes in the UK riparian wetland soil; and (4) a laboratory microcosm study ((^15)tracer) of nitrate removal processes in bare and plant-inhabited (Glyceria declinata) New Zealand (NZ) riparian wetland soil. Dissolved organic nitrogen and ammonium were generally more important components of subsurface runoff than nitrate in the three UK riparian zones. All riparian zones were poor buffers having minimal effect on the nitrogen concentration of subsurface runoff. In the UK riparian wetland site subsurface (saturated zone) and surface 'preferential flow paths' typically conveyed large quantities of catchment runoff rapidly into, and across the site, and hindered nitrogen buffering. However, under low flow conditions, runoff-riparian soil contact increased and the wetland decreased the catchment nitrogen flux by 27%. In the UK riparian wetland soil most nitrate removal was attributable to denitrification (87- 100%) as opposed to dissimilatory nitrate reduction to ammonium (DNRA) (0-13%) and immobilisation (0-10%). Total ((^14)N+(^15)N) transformation rates for these processes were 1.3-47, 0.5-1.5 and 0.6-2.5 μg N g soil(^-1) hr(^-1) respectively. In the NZ riparian wetland soil Glyceria declinata assimilated 11-15% of nitrate but, more importantly, increased soil oxidation and altered the proportions of nitrate removal attributable to denitrification (from 29% to 61-63%) and DNRA (from 49 to <1%), but not immobilisation (22-26%). Denitrification and, thus, nitrogen buffering might be enhanced, in some riparian zones by increasing the extent of moderately anoxic soil with plants that release oxygen from their roots or with water table management
