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Haeryoung Kim,
Jeong Eun Yoo,
Jai Young Cho,
Bong-Kyeong Oh,
Yoo-Seok Yoon,
Ho-Seong Han,
Hye Seung Lee, Ja June Jang,
Sook Hyang Jeong,
Jin Wook Kim,
Young Nyun Park
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ABSTRACT: BACKGROUND& AIMS: Hepatocellular carcinomas (HCCs) expressing "stemness"-related markers have been associated with aggressive biological behavior and poor prognosis. We examined the relationship between "stemness"-related protein expression and telomere length, hTERT and shelterin complex protein expression and chromosomal instability. METHODS: Quantitative fluorescent in situ hybridization for telomere length, immunohistochemistry for K19, EpCAM, CD133, c-kit, HepPar1, hTERT, TRF1, TRF2, POT1, RAP1 and TPP1, and TUNEL assay were performed in 137 HCCs, and array comparative genomic hybridization was performed with 24 HCCs. RESULTS: Telomeres were significantly longer in HCCs expressing "stemness"-related proteins (K19: p<0.001, EpCAM: p=0.002, CD133: p=0.002). On analyzing different tumor cells within EpCAM-expressing HCCs, EpCAM-positive tumor cells showed longer telomeres (1.329±0.246) compared to EpCAM-negative tumor cells (0.996±0.381) within the same HCCs (p=0.031). Telomeres were significantly longer in HCCs expressing hTERT (p=0.048) and RAP1 proteins (p=0.031). K19-expressing HCCs expressed hTERT (p=0.002), TRF2 (p=0.001) and TPP1 (p=0.013) more frequently compared to K19-negative HCCs. EpCAM-positivity was associated with more frequent hTERT (p=0.028), TPP1 (p=0.017), TRF2 (p=0.027) and POT1 (p=0.004) expression. Copy number alterations were more frequent in K19 and EpCAM-expressing HCCs compared to HCCs without these markers (K19: p=0.038, EpCAM: p=0.009). HCCs with longer telomeres were associated with a shorter overall (p=0.019) and disease-free survivals (p=0.049), and decreased disease-free survivals were seen in TRF2-positive HCCs (p=0.018). CONCLUSIONS: HCCs expressing "stemness"-related proteins are characterized by increased telomere lengths, increased expression of hTERT and shelterin complex proteins, and increased chromosomal instability compared to conventional HCCs. Longer telomeres and TRF2 expression in HCCs are associated with poor patient outcomes.
Journal of Hepatology 05/2013; · 9.26 Impact Factor
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Kyubo Kim,
Hye Sook Min,
Eui Kyu Chie,
Jin-Young Jang,
Sun Whe Kim,
Sae-Won Han,
Do-Youn Oh,
Seock-Ah Im,
Tae-You Kim,
Yung-Jue Bang, Ja-June Jang,
Sung W Ha
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ABSTRACT: To evaluate the prognostic significance of CD24 expression in patients undergoing adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer.
Eighty-four patients with EHBD cancer who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled in this study. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to a median of 40 Gy (range: 40-56 Gy). All patients also received fluoropyrimidine chemotherapy for radiosensitization during radiotherapy. CD24 expression was assessed with immunohistochemical staining on tissue microarray. Clinicopathologic factors as well as CD24 expression were evaluated in multivariate analysis for clinical outcomes including loco-regional recurrence, distant metastasis-free and overall survival.
CD24 was expressed in 36 patients (42.9%). CD24 expression was associated with distant metastasis, but not with loco-regional recurrence nor with overall survival. The 5-year distant metastasis-free survival rates were 55.1% and 29.0% in patients with negative and positive expression, respectively (P = 0.0100). On multivariate analysis incorporating N stage, histologic differentiation and CD24 expression, N stage was the only significant factor predicting distant metastasis-free survival (P = 0.0089), while CD24 expression had borderline significance (P = 0.0733). In subgroup analysis, CD24 expression was significantly associated with 5-year distant metastasis-free survival in node-positive patients (38.4% with negative expression vs 0% with positive expression, P = 0.0110), but not in node-negative patients (62.0% with negative expression vs 64.0% with positive expression, P = 0.8599).
CD24 expression was a significant predictor of distant metastasis for patients undergoing curative resection followed by adjuvant chemoradiotherapy especially for node-positive EHBD cancer.
World Journal of Gastroenterology 03/2013; 19(9):1438-43. · 2.47 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) participate in diverse biological functions and carcinogenesis by inhibiting specific gene expression. We previously reported that suppression of adenine nucleotide translocase 2 (ANT2) by using the short hairpin RNA (shRNA) approach has an antitumor effect in several cancer cells. We here examined the influence of ANT2 on expression of miRNAs in hepatocellular carcinoma (HCC) to further elucidate the tumor-suppressive mechanism of ANT2 shRNA. We first carried out screening for miRNAs, whose expression is regulated by ANT2 suppression in the Hep3B HCC cell line using miRNA microarrays. Validation of candidate miRNAs was done by incorporating clinical samples, and their effects on the tumorigenesis of HCC were studied in vitro and in vivo. miR-636 was one of the miRNAs whose expression was highly upregulated by ANT2 suppression in miRNA microarray analysis, as confirmed by real-time reverse transcription-polymerase chain reaction. Notably, miR-636 was markedly downregulated in HCC tissues compared with matched non-neoplastic liver in clinical samples. Restoration of miR-636 in Hep3B cells led to significant reduction of cell proliferation and colony formation. miR-636 restoration resulted in a decreased level of Ras, one of the putative targets of miR-636, and inactivation of its signaling pathway. Moreover, tumorigenesis was efficiently suppressed by miR-636 in an in vivo tumor xenograft model of HCC. The data suggest that miR-636 might function as a tumor suppressor miRNA affecting HCC tumorigenesis via downregulation of Ras, and that ANT2 suppression by shRNA could exert an anticancer effect by restoring miR-636 expression in HCC.
Experimental & molecular medicine. 01/2013; 45:e3.
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Han Suk Ryu,
Jin-Haeng Chung,
Kyoungbun Lee,
Eun Shin,
Jin Jing,
Gheeyoung Choe,
Haeryoung Kim,
Xianhua Xu,
Hee Eun Lee,
Dae-Ghon Kim,
Hyebin Lee, Ja-June Jang
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ABSTRACT: Although increased evidence has suggested that epithelial-mesenchymal transition has been implicated in cancer invasion and is associated with poor prognosis, its significance in cholangiocarcinoma remains unclear. We evaluated the levels of expression of epithelial-mesenchymal transition-related genes and proteins in 2 established human cholangiocarcinoma cell lines with different morphological characteristics and performed transwell cell invasion assays. Furthermore, we investigated the association between altered expression of 6 epithelial-mesenchymal transition-related proteins and clinical outcomes in human cholangiocarcinoma patients (n = 119) by immunohistochemistry using a tissue microarray approach. Comparative analysis of protein and messenger RNA expression revealed that the cell line with less differentiation (JCK) showed increased expression of mesenchymal markers and zinc-finger proteins and decreased expression of epithelial markers. The invasion activity of JCK cells was significantly higher than that of cells from OZ cell lines. Tissue microarray analysis revealed that the combined expression pattern of 6 epithelial-mesenchymal transition-related proteins predicted shortened disease-free survival (13.0 versus 22.0 months, P = .033) and overall survival (23.0 versus 63.0 months, P = .003) and was confirmed as an independent unfavorable prognostic factor for survival in multivariate survival analysis (disease-free survival, P = .028 for the 3 epithelial-mesenchymal transition-related markers; overall survival, P = .010 for the 6 epithelial-mesenchymal transition-related markers). In conclusion, our results suggest that altered expression of a number of epithelial-mesenchymal transition-related genes in tumor cells with poor differentiation may explain their increased invasive ability. Our results also suggest that altered expression of a suite of epithelial-mesenchymal transition-related proteins could be used as a tool to predict poor outcomes in human cholangiocarcinoma patients.
Human pathology 10/2012; · 3.03 Impact Factor
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ABSTRACT: The molecular profile of peritumoral non-neoplastic liver parenchyma (PNLP) has recently been suggested as predictive factor of early and late recurrence of hepatocellular carcinoma (HCC). However, there is no definite cut-off point for tumor-free PNLP in terms of either histological or molecular changes. Therefore, our aim is to determine the numerical cut-off point for separating adjacent PNLP and remote PNLP in histopathologic perspective.
Peritumoral tissues from 20 resected HCC patients were sampled from 0 to 40 mm distance from the tumor border (divided into 5-mm columns). Histopathologic parameters such as necroinflammatory activity, fibrosis, bile ductular reaction, hepatic venulitis, peliosis, and steatosis were compared between each column.
The morphologic changes just adjacent to the tumor were notably severe and faded with distance. The parenchyma within 10 mm of the tumor showed significantly severe inflammation, fibrosis, peliosis and hepatic venulitis compared with those from farther areas. The histopathologic changes of the parenchyma became stable beyond 20 mm.
Results of this study revealed that the parenchyma within 10 mm distance from the tumor, or adjacent PNLP, has histopathologic changes that are directly affected by the tumor, and the parenchyma beyond 20 mm as the remote PNLP without tumor effect.
Korean journal of pathology. 08/2012; 46(4):349-58.
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ABSTRACT: Aims and background. Differential diagnosis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma is sometimes difficult to accurately perform. Methods. Eight markers including cytokeratin 7 (CK7), cytokeratin 19 (CK19), MOC31, CD10, glypican 3 (GPC3), claudin 4, biglycan and high mobility group A1 (HMGA1) were immunohistochemically stained in samples from 179 surgically resected hepatocellular carcinomas and 127 intrahepatic cholangiocarcinomas, and the rates of marker expression were statistically compared. Results. With the exception of biglycan, 7 of the 8 markers were found to have significantly different expression patterns when comparing the two types of cancer (P <0.05). In intrahepatic cholangiocarcinomas, the expression rates of CK7, CK19, MOC31, claudin 4 and HMGA1 were 83.4%, 89.0%, 88.2%, 69.2%, and 31.5%, respectively. These rates of expression in intrahepatic cholangiocarcinomas were all higher than in those in hepatocellular carcinomas (CK7, 31.3%; CK19, 10.1%; MOC31, 34.0%; claudin 4, 11.2%; and HMGA1, 19.5%). The expression rates of GPC3, CD10, and biglycan were 72.6%, 39.7% and 10.0%, respectively, in hepatocellular carcinoma. These were higher than the rates found in intrahepatic cholangiocarcinomas (GPC3, 7.0%; CD10, 18.1%; and biglycan, 7.0%). In a multivariate logistic regression analysis, GPC3, CK19, MOC31 and claudin 4 were found to be independent markers for differentially diagnosing intrahepatic cholangiocarcinoma. Conclusions. Based on our results, GPC3 and CK19 can be used as first-line markers for differential diagnoses of hepatocellular carcinoma and intrahepatic cholangiocarcinoma (accuracy rate, 73.5%), and additional combined screening for claudin 4 and MOC31 markers in GPC3(-) and CK19(-) tumors might increase the accuracy rate for distinguishing hepatocellular carcinoma from intrahepatic cholangiocarcinoma to 88.5%.
Tumori. 07/2012; 98(4):478-84.
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Jin Sil Chung,
Sunhoo Park,
Seon Ho Park,
Eun-Ran Park,
Pu-Hyeon Cha,
Bu-Yeo Kim,
Young Min Chung,
Seon Rang Woo,
Chul Ju Han,
Sang-Bum Kim, [......],
Dong Wook Choi,
Sora Lee,
Gi Young Lee,
Ki Baik Hahm,
Jung Ar Shin,
Byung Soo Kim,
Kyung Hee Noh,
Tae Woo Kim,
Kee-Ho Lee,
Young Do Yoo
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ABSTRACT: Chronic oxidative stress from reactive oxygen species (ROS) produced by the mitochondria promotes hepatocarcinogenesis and tumor progression. However, the exact mechanism by which mitochondrial ROS contributes to tumor cell invasion is not known. We investigated the role of ROS modulator 1 (Romo1) in hepatocellular carcinoma (HCC) development and tumor cell invasiveness.
We performed real-time, semi-quantitative, reverse transcriptase polymerase chain reaction; invasion and luciferase assays; and immunofluorescence and immunohistochemical analyses. The formation of pulmonary metastatic nodules after tumor cell injection was tested in severe combined immunodeficient mice. We analyzed Romo1 expression in HCC cell lines and tissues (n = 95).
Expression of Romo1 was increased in HCC cells, compared with normal human lung fibroblast cells. Exogenous expression of Romo1 in HCC cells increased their invasive activity, compared with control cells. Knockdown of Romo1 in Hep3B and Huh-7 HCC cells reduced their invasive activity in response to stimulation with 12-O-tetradecanoylphorbol-13-acetate. Levels of Romo1 were increased compared with normal liver tissues in 63 of 95 HCC samples from patients. In HCC samples from patients, there was an inverse correlation between Romo1 overexpression and patient survival times. Increased levels of Romo1 also correlated with vascular invasion by the tumors, reduced differentiation, and larger tumor size.
Romo1 is a biomarker of HCC progression that might be used in diagnosis. Reagents that inhibit activity of Romo1 and suppress mitochondrial ROS production, rather than eliminate up-regulated intracellular ROS, might be developed as cancer therapies.
Gastroenterology 06/2012; 143(4):1084-1094.e7. · 11.68 Impact Factor
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ABSTRACT: DNA methylation is one of the main epigenetic mechanisms and hypermethylation of CpG islands at tumor suppressor genes switches off these genes. To find novel DNA methylation markers in hepatocellular carcinoma (HCC), we performed pharmacological unmasking (treatment with 5-aza-2'-deoxycytidine or trichostatin A) followed by microarray analysis in HCC cell lines. Of the 239 promoter CpG island loci hypermethylated in HCC cell lines (as revealed by methylation-specific PCR), 221 loci were found to be hypermethylated in HCC or nonneoplastic liver tissues. Thirty-three loci showed a 20% higher methylation frequency in tumors than in adjacent nonneoplastic tissues. Correlation of individual cancer-related methylation markers with clinicopathological features of HCC patients (n = 95) revealed that the number of hypermethylated genes in HCC tumors was higher in older than in younger patients. Univariate and multivariate survival analysis revealed that the HIST1H2AE methylation status is closely correlated with the patient's overall survival (P = 0.022 and P = 0.010, respectively). In conclusion, we identified 221 novel DNA methylation markers for HCC. One promising prognostic marker, HIST1H2AE, should be further validated in the prognostication of HCC patients.
Journal of Korean medical science 06/2012; 27(6):594-604. · 0.84 Impact Factor
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ABSTRACT: The S-phase kinase-associated protein 2 (Skp2), which ubiquitinates the cell cycle inhibitor p27(Kip1) and targets it for degradation, is commonly overexpressed in human cancers and is associated with poor prognosis in several cancers. The aim of this study was to investigate Skp2 expression and its clinicopathologic significance in surgically resected hepatocellular carcinomas. We collected 359 hepatocellular carcinoma samples and evaluated Skp2 protein expression in cytoplasmic and nuclear fractions by immunohistochemistry using a tissue microarray method. Among the 359 patients, nuclear expression of Skp2 was observed in 41 (10.38%), and cytoplasmic expression of Skp2 was observed in 195 (49.37%). Of the several clinicopathologic variables examined, high Edmonson-Steiner grade and early recurrence correlated with nuclear expression of Skp2 (p = 0.000 and 0.022, respectively). Cytoplasmic expression of Skp2 correlated negatively with microvascular and macrovascular invasion, tumor size, histologic grade, and overall survival. Multivariate analysis revealed that nuclear expression of Skp2 correlated with short disease-free survival. Our findings suggest that nuclear expression of Skp2 may be used as an independent predictor of poor prognosis for hepatocellular carcinoma, whereas cytoplasmic expression of Skp2 may indicate less aggressive disease.
Apmis 05/2012; 120(5):349-57. · 1.99 Impact Factor
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ABSTRACT: Extrahepatic cholangiocarcinoma (EHC) is usually difficult to diagnose by bile cytology because of cellular disintegration. However, DNA samples from bile fluid can provide sufficient materials to screen for the presence of EHC. We developed DNA methylation marker panels that can be used for MethyLight assay-based detection of EHC in bile fluid specimens. The methylation status of 59 DNA methylation markers was investigated in 20 EHC and 20 non-neoplastic gallbladder tissue samples with MethyLight assay to determine cancer-specific DNA methylation markers. Through assaying cancer-specific DNA methylation markers in a training set (n = 40) and validation set (n = 45) of bile fluid specimens from patients with EHC or those without cancer, we selected suitable marker panels that were assessed for their performance in a third set (test set; n = 40). Four marker panels showed a sensitivity of 60% or more and a specificity of 100% in both the training and validation sets, whereas bile cytology displayed a sensitivity of 40% to 46% and a specificity of 100%. In an independent test set of bile fluid samples, a five-gene panel (CCND2, CDH13, GRIN2B, RUNX3, and TWIST1) detected EHC at a sensitivity of 83%, which was far higher than that of bile cytology (46%, P = 0.004). Using bile fluids, a methylation assay consisting of a five-gene panel may be useful for detecting EHC and in helping to increase the sensitivity of preoperative diagnoses.
The Journal of molecular diagnostics: JMD 03/2012; 14(3):256-63. · 3.48 Impact Factor
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ABSTRACT: Although chemotherapy-related hepatic injury has been reported in colorectal cancer liver metastasis (CRLM) patients, the morphologic changes caused by chemotherapeutic agents and the effect of chemotherapy on postoperative outcome remain ill-defined. A comprehensive review of the morphologic changes in the post-chemotherapy non-neoplastic liver was performed and the clinical effect of preoperative chemotherapy in CRLM patients was analyzed.
Hematoxylin-eosin, Masson's trichrome and reticulin-stained slides from non-neoplastic livers obtained from 89 CRLM patients were analyzed, and the clinicopathologic features were correlated with the status of chemotherapy exposure.
Histopathologic features of sinusoidal injury (sinusoidal dilatation, centrilobular perivenular fibrosis, parenchymal extinction lesions, small vessel obliteration, and hepatocyte plate disruption) were significantly more frequent in oxaliplatin-exposed livers (p<0.05). The extent of sinusoidal dilatation was positively correlated with increasing numbers of chemotherapy cycles (p=0.022). Abnormal preoperative liver function tests were more frequently seen (p<0.05) and postoperative total bilirubin was higher in the chemotherapy group (p=0.008). Postoperative morbidity was more common in the chemotherapy group (p=0.044).
Sinusoidal injury is frequently seen in oxaliplatin-treated livers, and its presence, especially when extensive, should be documented in surgical pathology practice. The recognition of sinusoidal injury may provide helpful guidelines for surgeons in deciding the extent of hepatic resection.
Korean journal of pathology. 02/2012; 46(1):22-9.
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ABSTRACT: Many risk factors affect survival after liver resection for hepatocellular carcinoma (HCC), but these lack specificity for the prognosis. Studies of gene expression profiles successfully predicted the survival of HCC. To date, few studies have focused on HBV-associated HCC. Therefore, we investigated the genes involved in tumor prognosis in patients with HBV-associated HCC.
We analyzed clinical data and microarray test results in 51 patients who underwent liver resection for HBV-associated HCC between August 1998 and December 2002. We used Kaplan-Meier plots to analyze survival rates and some well-known clinical staging systems. In addition, we performed microarray survival analysis using Cox univariate regression. Then, we devised a scoring system that adds the survival-associated gene expression signature to one or two independent clinical risk factors for survival.
The mean follow-up period was 61.4 mo. Thirty-six patients had recurrence during this period, and 22 died. The 5-y survival rate was 58.0%. Multivariate analysis showed that tumor size was an independent risk factor for survival. We identified 194 spots on the microarray in survival analysis. These genes were clustered into two groups and showed a statistically significant difference in the survival rates. In the clinical analysis, the CLIP and Okuda staging systems showed statistically significant relationships. When we added the survival-associated gene expression signature to tumor size, our new method showed a more statistically significant relationship between stage and survival.
We propose that adding the results of microarray survival analysis to the staging system predicts survival more precisely.
Journal of Surgical Research 12/2011; 171(2):524-31. · 2.25 Impact Factor
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ABSTRACT: To retrospectively assess feasibility of dual-source dual-energy (DSDE) computed tomography (CT) for evaluation of hepatic iron accumulation in a liver phantom and liver transplantation candidates and to compare its accuracy with that of 3-T magnetic resonance (MR) imaging.
This study was approved by the institutional review board; informed consent was waived. A liver agar phantom containing six tubes of iron (concentrations, 100-5000 mg of iron per 100 mL of solution) was scanned at 80 and 140 kVp with both DSDE mode and single-source dual-energy (SSDE) CT with sequential scanning mode. Difference of averaged attenuation between 80 and 140 kVp at CT (ΔH) was measured and correlated with iron concentration. Thirty-two liver transplant recipients and 55 donors who underwent DSDE CT at 80 and 140 kVp were included. Twenty-three underwent 3-T liver MR with dual-echo in-phase and opposed-phase T1-weighted and spin-echo T2-weighted imaging. Hepatic ΔH was measured at CT. On T1- and T2-weighted MR images, iron indexes were calculated. Degree of iron accumulation and macrosteatosis were determined at histologic examination (reference). Diagnostic performance of ΔH at CT and iron indexes at MR for diagnosing clinically important iron accumulation was evaluated (receiver operating characteristic [ROC] analysis).
For phantom study, ΔH obtained from both DSDE mode and SSDE CT with sequential scanning mode was correlated with iron concentration (correlation coefficient, 1.00 and 0.943, respectively; P = .173). ΔH (13.53) in 10 patients with clinically important (≥ 10%) iron accumulation was significantly higher than that (7.39) in 77 patients with normal or mild iron deposition (P < .001). ΔH was significantly correlated with degree of iron accumulation (correlation coefficient, 0.430; P < .001) but not with degree of hepatic macrosteatosis (P = .216). Area under the ROC curve for diagnosing clinically important iron accumulation was 0.881 and 0.897 with CT and MR, respectively (P = .851).
DSDE CT is accurate for diagnosing clinically important hepatic iron accumulation without confounding influence of hepatic steatosis, with diagnostic performance on par with MR.
Radiology 11/2011; 262(1):126-35. · 5.73 Impact Factor
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ABSTRACT: Liver fibrosis and its end-stage disease, cirrhosis, are major worldwide healthcare burdens. In this study, we evaluated the inhibitory effects of nicotinamide (NA) on rat hepatic fibrogenesis and investigated its underlying mechanism. We examined the inhibitory effects of NA in vivo by using F344 rats in a thioacetamide (TAA)-induced fibrogenesis model and assessed the inhibitory effects in vitro by using the rat hepatic stellate cell line THSC-Cl6. In vivo, NA significantly attenuated liver fibrosis in TAA-treated rats as assessed by histological analysis using hematoxylin-eosin and Masson's trichrome staining. In vitro, NA inhibited viability of THSC-Cl6 cells in a dose- and time-dependent manner, suppressed DNA synthesis, and induced apoptosis. Transcription of collagen mRNA and expression of alpha smooth muscle actin (the hallmark of activated hepatic stellate cells) were reduced by NA. Expression of the cell cycle-related proteins cyclin E, cyclin D1, and cyclin-dependent kinase (cdk)4, was reduced by NA treatment, but expression of cyclin A and cdk2 was not. Expression of the cdk inhibitors p16 and p21 was decreased by NA treatment, whereas expression of p27 was increased. It appears that NA inhibits rat hepatic fibrogenesis by suppressing DNA synthesis and enhancing apoptosis of hepatic stellate cells.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2011; 458(6):689-96. · 2.49 Impact Factor
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ABSTRACT: Cluster differentiation 44 standard isoform (CD44s) is a transmembrane glycoprotein. CD44s is a known prognostic factor in various cancers, due to its involvement in tumor cell growth, invasion and metastasis. Its prognostic role, however, is debated because it can be a positive or negative prognostic factor depending on tumor type and is still an ambiguous prognostic indicator in other cancers, especially hepatocellular carcinoma (HCC). We investigated the relationship between CD44s expression and survival in HCC patients.
A total of 260 HCC samples were collected to generate a tissue microarray. Staining of the arrays with a primary mouse CD44s monoclonal antibody was followed by evaluation of the relationship between CD44s expression and tumor differentiation. The effect of CD44s expression on patient survival was analyzed.
CD44s protein expression correlated with histological grade (most and worst Edmondson grade) of the HCC (p=0.029 and p=0.039, respectively) and adversely affected the disease free survival period based on univariate and multivariate analyses (p=0.038 and p=0.077, respectively).
High CD44s protein expression correlates with shorter disease free survival and poorly differentiated HCC. CD44s-targeted therapy may be efficacious for HCC treatment in the future.
Gut and liver 06/2011; 5(2):204-9. · 0.83 Impact Factor
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Goh Eun Chung,
Jeong-Hoon Lee,
Jung-Hwan Yoon,
Sun Jung Myung,
Kyoungbun Lee, Ja June Jang,
Jeong Min Lee,
Se-Hyung Kim,
Kyung-Suk Suh,
Yoon Jun Kim,
Hyo-Suk Lee
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ABSTRACT: Although hepatocellular carcinoma (HCC) demonstrates characteristic hypervascularity, some HCCs have a hypovascular pattern on computed tomography (CT). Cytokeratin 19 (CK19) is a marker for the biliary phenotype reflecting a poor prognosis. We assessed the prognostic implications of tumor vascularity and its association with CK19 expression in HCC.
Patients that underwent surgical resection for HCC were included. Tumor vascularity was evaluated according to the arterial enhancement patterns on CT scans and CK19 expression was evaluated by using tissue microarray methods.
One hundred and forty patients were included. Their median follow-up duration was 55.0 months, and 92 (65.7%) patients had tumor recurrence. Forty-five patients (30.6%) had hypovascular HCC at the time of diagnosis, and they showed a significantly higher CK19 expression rate (32.5% vs. 8.2%, P = 0.001) and earlier recurrence rate within 6 months (hazard ratio (HR), 2.301; P = 0.025) compared to the patients with hypervascular HCCs. Hypovascularity (HR, 1.694; P = 0.045) was an independent risk factor for short overall survival.
Hypovascular HCCs were associated with early recurrence and short overall survival, and CK19 was more frequently expressed in hypovascular HCC than in hypervascular tumors. Therefore, tumor vascularity on CT images might be utilized in determining the prognosis of patients with HCCs.
Abdominal Imaging 05/2011; 37(3):439-46. · 1.73 Impact Factor
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Sang Geon Kim,
Young Mi Kim,
Jong Young Choi,
Joon-Yeol Han,
Jeong Won Jang,
Se-Hyun Cho,
Soon Ho Um,
Chae Yoon Chon,
Dong Hoo Lee, Ja-June Jang,
Eunsil Yu,
Young Sok Lee
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ABSTRACT: Oltipraz, a cancer chemopreventive agent, has an anticirrhotic effect in animals. A phase II trial was designed to investigate the preliminary efficacy of oltipraz therapy in liver fibrosis or cirrhosis.
Of 83 patients who were randomized to receive placebo, oltipraz 60 mg bid or oltipraz 90 mg qd for 24 weeks, 68 completed the study without any major protocol violation. Pre- and post-treatment liver biopsies, and blood fibrosis markers were assessed.
Twenty-four weeks of oltipraz treatment showed no significant differences in the proportions of patients showing an improvement in histological outcomes, including Ishak fibrosis score. In the oltipraz 60 mg bid group, there was a trend of decreases in hepatic collagen area and plasma transforming growth factor-β1 (TGF-β1, a blood fibrosis marker) levels from baseline to week 24. In the per-protocol population (n = 68), decreases in plasma TGF-β1 correlated with those in the Ishak fibrosis score, suggesting that circulating TGF-β1 serves a possible indicator for fibrosis treatment.
No significant differences in liver histological outcomes were seen among the three treatment groups in this 24-week pilot study. Our finding indicates an association between TGF-β1 repression and improvement in the histological index of fibrosis.
The Journal of pharmacy and pharmacology. 05/2011; 63(5):627-35.
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Bu-Yeo Kim,
Kyung-Suk Suh,
Je-Geun Lee,
Seon Rang Woo,
In-Chul Park,
Sun-Hoo Park,
Chul Ju Han,
Sang-Bum Kim,
Sook-Hyang Jeong,
Young Il Yeom,
Suk-Jin Yang,
Chang-Min Kim,
Su Jin Cho,
Young Do Yoo,
Myung-Haing Cho, Ja June Jang,
Dong Wook Choi,
Kee-Ho Lee
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ABSTRACT: The tissue environment in the region of hepatocellular carcinoma (HCC) influences both vascular invasion and recurrence. Thus, HCC patient prognosis depends on the characteristics not only of the tumor but also those of adjacent surrounding liver tissue.
Expression profiles of both tumor and adjacent liver tissue following curative resection were measured to discriminate 56 hepatitis B virus-positive HCC patients into subgroups based on survival risk. This approach was further tested in 40 patients.
Expression profiles of both tumor and adjacent liver tissue successfully discriminated 56 training samples into 2 subgroups, those at low- or high-risk for survival and recurrence. However, the prognostic gene set selected for tumor tissue was quite different from that for adjacent tissues. This variation in prognostic genes resulted in a change in allocation of patients within each low- or high-risk group. Combination of survival subgroups from tumor and adjacent liver tissue significantly improved the prediction of prognostic outcome. This integrative approach was confirmed to be effective in a further 40 test patients. A clinicopathological study showed that survival subgroups divided by tumor and adjacent liver tissue gene expression were also statistically associated with UICC stage and extent of cell differentiation, respectively.
Variation in gene expression during the nontumor stage as well as the tumor stage may affect the prognosis of HCC patients, and integration of the gene expression profiles of HCC and adjacent liver tissue increases discriminatory effectiveness between patient groups, predicting clinical outcomes with enhanced statistical reliability.
Annals of Surgical Oncology 04/2011; 19 Suppl 3:S328-38. · 4.17 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) can cause severe complications, resulting in a high incidence of recurrence after treatment of the primary tumor. Recently, we have shown that nicotinamide effectively inhibits the growth and progression of bladder tumors by up-regulating RUNX3 and p300 expression. Therefore, in this study, the efficacy and inhibitory mechanisms of nicotinamide against HCC were investigated in mice and HCC cell lines, respectively. To evaluate the inhibitory effects of nicotinamide on HCC development, mice were injected with diethylnitrosamine (DEN) and simultaneously treated with 1% nicotinamide. Also, the effect of nicotinamide on human HCC cell lines was assessed by measuring caspase activity, cell proliferation, and DNA content using immunoblot analysis and reverse-transcriptase polymerase chain reaction. It was found that nicotinamide significantly inhibited the development of pre-neoplastic lesions (foci and adenomas) during the early stages of HCC. Furthermore, nicotinamide inhibited cell proliferation and induced mitochondria-mediated apoptosis in HCC cell lines. It also increased the expression of p21, and the expression and acetylation of p53. These results strongly suggest that nicotinamide inhibits the progression of early-stage HCC and may contribute to the induction of apoptosis and the inhibition of proliferation of HCC cells. Taken together, the results of this study indicate that nicotinamide is a potential chemopreventive agent, i.e., it may prevent the progression of early HCC development and/or the recurrence of HCC after primary treatment.
Journal of Cellular Physiology 04/2011; 227(3):899-908. · 3.87 Impact Factor
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ABSTRACT: We elucidated the genetic profile of hepatoblastomas (HBLs) to identify diagnostic and prognostic markers. RNA was extracted from 32 formalin-fixed, paraffin-embedded HBLs and corresponding nonneoplastic liver (NNL) tissues, and cDNA-mediated annealing, selection, extension, and ligation (DASL) chip assays were performed. Immunohistochemistry was performed to confirm the expression of Yin Yang 1 (YY1) protein in HBL. Twenty-four genes that were associated with signal transduction, cell-cell adhesion, cell cycle regulation, and apoptosis were differentially expressed in HBL and NNL tissues. Two apoptosis-associated genes, MYCN and BIRC5, were highly upregulated in HBL. Eight genes, including YY1 and IGF1, were upregulated in HBL cases that had a poor prognosis. Thirty-eight genes, including YY1, were differentially expressed according to histologic differentiation of HBL, and the immunohistochemical expression of YY1 was correlated with poor HBL differentiation. Thus, using DASL chip assays, we report the gene expression profiles of HBL, which suggest new candidate prognostic and diagnostic genetic markers and putative therapeutic targets for HBL.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2011; 458(4):453-65. · 2.49 Impact Factor
