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ABSTRACT: INTRODUCTION: Insulin-like growth factor-II mRNA-binding protein 3 (IMP3), a newly identified oncofetal RNA-binding protein, plays a pivotal role in the regulation of cell growth and migration during early stages of embryogenesis, and is found to be expressed in various human cancers. In this study, we elucidated the clinicopathological significance of IMP3 expression in intrahepatic cholangiocarcinoma (ICC). METHODS: From March 1995 to December 2003, 61 surgically resected, unifocal primary ICCs were studied. IMP3 protein expression was detected by immunohistochemical staining. RESULTS: IMP3 protein was expressed in 25 of 61 ICCs (41.0%). In addition to correlating with tumor grade (p=0.0276), tumor stage (p=0.0059), lymphovascular invasion (p=0.0198), serum carbohydrate antigen 19-9 level (p=0.0146), IMP3 expression predicted early tumor recurrence (ETR) (p=0.0059) and was a strong indicator of worse disease-free survival (p=0.0001) and overall survival (p=0.0007). Even though we did not find that IMP3 expression exerted prognostic impact independent of tumor stage, multivariate analysis confirmed that IMP3 expression was an independent risk factor of high-stage tumor and ETR (p=0.0170, and p=0.0052, respectively), and thus it contributed to poor prognosis in ICC patients. CONCLUSIONS: IMP3 expression can serve as a novel maker for ETR and prognostic prediction, and may be a target for adjuvant therapy of patients with ICC after tumor resection.
International journal of surgery (London, England) 12/2012;
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ABSTRACT: Lin-41 is a stem cell-specific E3 ligase and a known target of the tumour suppressor microRNA (miRNA) let-7. Lin-41 was recently reported to mediate ubiquitylation and degradation of the miRNA pathway protein Ago2. We demonstrate that Lin-41 is overexpressed in hepatocellular carcinoma (HCC). Lin-41 overexpression correlates with high α-fetoprotein level, high tumour grade, high tumour stage, and predicts early tumour recurrence. Lin-41 is a strong predictor of poor long-term survival for patients with HCC. Lin-41 knockdown by RNA interference in HCC cell lines Huh7 and Hep3B suppressed proliferation in vitro and reduced in vivo tumour growth in NOD/SCID mice. On the other hand, overexpression of Lin-41 in the HCC cell line SK-Hep1 enhanced tumourigenicity. Overexpression and knockdown of Lin-41 led to inverse changes in the levels of Ago1 and Ago2 proteins. Overexpression of Ago1 and Ago2 reduced in vivo tumour growth. Lin-41 overexpression suppressed let-7 activity in HCC cell lines and expression of Lin-41 enhanced the expression of let-7-regulated oncogenes c-Myc, Lin-28B, HMGA2 and type 1 insulin-like growth factor receptor. Expression of Lin-28B and c-Myc enhanced the expression of Lin-41. Chromatin immunoprecipitation and reporter assays revealed direct association of Myc with the Lin-41 promoter, resulting in transcriptional transactivation. Our results indicate that Lin-41 plays an important role in the growth of HCC by regulating RISC complex proteins Ago1 and Ago2 to inhibit miRNA-mediated gene silencing and promote the expression of oncogenic proteins. Lin-41 is also a strong prognostic factor for patients with HCC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 10/2012; · 6.32 Impact Factor
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ABSTRACT: SIRT1 is a NAD+-dependent deacetylase that plays crucial roles in many biological processes, including stress response, apoptosis, cellular metabolism, adaptation to calorie restriction, aging, and tumorigenesis. The purpose of this study is to elucidate the clinicopathological and functional significance of SIRT1 expression in hepatocellular carcinoma (HCC).
SIRT1 expression in HCC was determined by immunohistochemical staining. The results were correlated with clinicopathological parameters. SIRT1 was overexpressed in HCC cell line SK-Hep1 to study its role in tumorigenesis and resistance to chemotherapy.
SIRT1 was overexpressed in 95 of 172 HCCs (55%). SIRT1 overexpression was associated with higher α-fetoprotein level, higher tumor grade, and absence of β-catenin mutation. SIRT1 expression predicted poor long-term survival for patients with resected HCC. The elevated SIRT1 protein level in HCC was not attributable to the elevation of mRNA level. The half-life of SIRT1 protein was longer in cell lines with higher expression of SIRT1. We further demonstrated that SIRT1 was degraded by the 26S proteasome in an ubiquitin-dependent manner. Overexpression of SIRT1 promoted tumorigenesis and resistance to chemotherapeutical agent and sorafenib.
SIRT1 is an oncogenic protein for HCC and is a predictor of worse outcome after surgical resection of HCC.
Annals of Surgical Oncology 12/2011; 19(6):2011-9. · 4.17 Impact Factor
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ABSTRACT: Viral hepatitis-associated intrahepatic cholangiocarcinoma is thought to have common disease processes with hepatocellular carcinoma, but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic cholangiocarcinoma is still unknown. From 2000 to 2010, 170 patients with intrahepatic cholangiocarcinoma who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected for this study. Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. These patients were younger, were more frequently male, and had elevated serum α-fetoprotein levels as compared with seronegative intrahepatic cholangiocarcinoma patients. Grossly these tumors were mostly of the mass-forming type, and histologically, cholangiolar differentiation was more frequently seen. We identified N-cadherin as an immunohistochemical marker strongly associated with hepatitis virus infection. The prevalence of viral hepatitis in patients with N-cadherin-positive intrahepatic cholangiocarcinoma was 75%, and that in N-cadherin-negative patients was only 37%. N-cadherin-positive patients were younger, had elevated α-fetoprotein, and had no hepatolithiasis. All N-cadherin-positive intrahepatic cholangiocarcinomas were of the mass-forming type. N-cadherin positivity was strongly associated with cholangiolar morphology and lack of carcinoembryonic antigen and MUC2 expression, whereas K-RAS mutations were less frequent. Our results indicate that a subgroup of intrahepatic cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.
Modern Pathology 03/2011; 24(6):810-9. · 4.79 Impact Factor
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Daw-Jen Tsuei,
Po-Huang Lee,
Hsiao-Yu Peng,
Hsiao-Ling Lu,
Shau-Lin Lu,
De-Shiuan Su,
Yung-Ming Jeng, Hey-Chi Hsu,
Shu-Hao Hsu,
Jia-Feng Wu,
Yen-Hsuan Ni,
Mei-Hwei Chang
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ABSTRACT: Male gender is a risk factor for the development of hepatocellular carcinoma (HCC) but the mechanisms are not fully understood. The RNA binding motif gene on the Y chromosome (RBMY), encoding a male germ cell-specific RNA splicing regulator during spermatogenesis, is aberrantly activated in human male liver cancers. This study investigated the in vitro oncogenic effect and the possible mechanism of RBMY in human hepatoma cell line HepG2 and its in vivo effect with regards to the livers of human and transgenic mice. RBMY expression in HepG2 cells was knocked down by RNA interference and the cancer cell phenotype was characterized by soft-agar colony formation and sensitivity to hydrogen-peroxide-induced apoptosis. The results revealed that RBMY knockdown reduced the transformation and anti-apoptotic efficiency of HepG2 cells. The expression of RBMY, androgen receptor (AR) and its inhibitory variant AR45, AR-targeted genes insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) was analyzed by quantitative RT-PCR. Up-regulation of AR45 variant and reduction of IGF-1 and IGFBP-3 expression was only detected in RBMY knockdown cells. Moreover, RBMY positive human male HCC expressed lower level of AR45 as compared to RBMY negative HCC tissues. The oncogenic properties of RBMY were further assessed in a transgenic mouse model. Liver-specific RBMY transgenic mice developed hepatic pre-cancerous lesions, adenoma, and HCC. RBMY also accelerated chemical carcinogen-induced hepatocarcinogenesis in transgenic mice. Collectively, these findings suggest that Y chromosome-specific RBMY is likely involved in the regulation of androgen receptor activity and contributes to male predominance of HCC.
PLoS ONE 01/2011; 6(11):e26948. · 4.09 Impact Factor
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ABSTRACT: Annexin A10 (ANXA10) and its liver-specific short isoform (ANXA10S) had tissue-restricted expression. The downregulation of ANXA10S is correlated with tumor progression and poor prognosis in hepatocellular carcinoma. The aim of the present study was to validate the tissue distribution and explore the role of the ANXA10 protein expression in gastric carcinoma.
We examined the ANXA10 protein expression in human and animal tissues and 356 resected primary gastric carcinomas, using specific mouse and rabbit polyclonal antibodies, by immunohistochemical staining.
The ANXA10 protein is a nuclear protein specifically expressed in fetal and adult gastric mucosa and Brunner's gland across species, including humans, minipigs, woodchucks, and mice, and is commonly lost in gastric mucosa with intestinal metaplasia. The ANXA10 protein was expressed in 43.5% (155 cases) of gastric carcinomas; 74.2% (98/132) in the diffuse-type gastric carcinoma (DGC), 73.7% (28/38) in the mixed-type gastric carcinoma, and significantly lower in the intestinal-type gastric carcinoma (IGC) and indeterminate groups, 16.8% (28/167) and 5.3% (1/19), respectively (P<1×10(-8)). IGC with ANXA10 expression was correlated with a higher stage (P=0.049), particularly higher in stage IIIA/IIIB/IV IGC than lower-stage (IA/IB/II) tumors (P=0.005), but was not correlated with age, sex, and nodal status. In contrast, DGC with ANXA10 expression was associated with younger age, female patients, and importantly, lower tumor stage and lymph node metastasis (P=0.007, P=0.065, P=0.024, and P=0.0014, respectively). Moreover, DGC with ANXA10 expression had a better 5-year patient survival (P=0.0048), whereas IGC with ANXA10 expression had a lower 5-year survival (P=0.034).
The ANXA10 protein expression is a novel marker of gastric differentiation, and is differentially expressed in IGC and DGC, with opposite prognostic significance.
Journal of Gastroenterology and Hepatology 01/2011; 26(1):90-7. · 2.87 Impact Factor
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ABSTRACT: Cytokeratin 19 (CK19), a molecular marker of hepatic progenitor cells and cholangiocytes, is expressed in hepatocellular carcinomas (HCC), but not in normal hepatocytes. However, role of CK19 in HCC progression, especially when interacted with p53 and β-catenin mutations, remained largely unknown.
From January 1983 to December 1997, 210 surgically resected, unifocal, primary HCCs were studied retrospectively. CK19 protein expression was detected by immunohistochemistry while mutations of p53 and β-catenin genes were detected by direct DNA sequencing.
CK19 protein expression was detected in 35.7% (75/210), p53 mutation in 47.2% (83/176) and β-catenin mutation in 14.5% (27/186). The tumor size (p=0.0023), grade (p = 0.00093), tumor stage (p = 4 x 10-7), high α-fetoprotein (p=0.0004), p53 mutation (p = 0.024), absence of β-catenin mutation (p = 0.0013), and CK19 expression (p = 3 x 10-5) were markers predictive of early tumor recurrence (ETR). CK19 expression, stage, and ETR were strong indicators of poor prognosis (all p < 0.0001). Importantly, combination analysis showed an additive unfavorable prognostic interaction of CK19 expression and p53 mutation. On the contrary, concurrent CK19 expression and β-catenin mutation was rare and CK19 expression abolished the suppression effect of β-catenin mutation on HCC progression.
CK19 expression is associated with more aggressive HCC. CK19 cooperates with p53 mutation towards advanced disease. In contrast, CK19 expression and β-catenin mutation play dramatic opposite roles in vascular invasion, ETR and the prognosis of HCC.
Journal of Gastrointestinal Surgery 11/2010; 15(2):321-9. · 2.83 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) play critical roles in embryonic development and are frequently deregulated in human cancers. The let-7 family members are tumor-suppressing miRNAs and are frequently downregulated in cancer cells. Lin-28 and Lin-28B are RNA-binding proteins highly expressed in embryonic tissues. Lin-28 proteins block let-7 precursors from being processed to mature miRNAs by inducing terminal uridylation and degradation of let-7 precursors. Here, we report that Lin-28B, but not Lin-28, is highly expressed in hepatocellular carcinoma (HCC). Lin-28B expression was more frequently noted in high-grade HCCs with high alpha-fetoprotein levels. Knockdown of Lin-28B by RNA interference in the HCC cell line HCC36 suppressed proliferation in vitro and reduced in vivo tumor growth in NOD/SCID mice. In contrast, overexpression of Lin-28B in the HCC cell line HA22T enhanced tumorigenicity. Overexpression of Lin-28B also induced epithelial-mesenchymal transition in HA22T cells and hence, invasion capacity. Large-scale real-time PCR array analysis revealed that, among 380 miRNAs, only let-7/mir-98 family members were regulated by Lin-28B. Lin-28B overexpression enhanced the expression of the known let-7 targets c-myc and HMGA2. It was also found that Lin-28B enhanced the expression of type 1 insulin-like growth factor receptor in a let-7-dependent manner. These results indicate that Lin-28B regulates tumor formation and invasion in HCC through coordinated repression of the let-7/mir-98 family and induction of multiple oncogenic pathways.
Carcinogenesis 09/2010; 31(9):1516-22. · 5.70 Impact Factor
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ABSTRACT: To investigate the significance of Aurora B expression in hepatocellular carcinoma (HCC).
The Aurora B and Aurora A mRNA level was measured in 160 HCCs and the paired nontumorous liver tissues by reverse transcription-polymerase chain reaction. Mutations of the p53 and β-catenin genes were analyzed in 134 and 150 tumors, respectively, by direct sequencing of exon 2 to exon 11 of p53 and exon 3 of β-catenin. Anticancer effects of AZD1152-HQPA, an Aurora B kinase selective inhibitor, were examined in Huh-7 and Hep3B cell lines.
Aurora B was overexpressed in 98 (61%) of 160 HCCs and in all 7 HCC cell lines examined. The overexpression of Aurora B was associated with Aurora A overexpression (P = 0.0003) and p53 mutation (P = 0.002) and was inversely associated with β-catenin mutation (P = 0.002). Aurora B overexpression correlated with worse clinicopathologic characteristics. Multivariate analysis confirmed that Aurora B overexpression was an independent poor prognostic factor, despite its interaction with Aurora A overexpression and mutations of p53 and β-catenin. In Huh-7 and Hep3B cells, AZD1152-HQPA induced proliferation blockade, histone H3 (Ser10) dephosphorylation, cell cycle disturbance, and apoptosis.
Aurora B overexpression is an independent molecular marker predicting tumor invasiveness and poor prognosis of HCC. Aurora B kinase selective inhibitors are potential therapeutic agents for HCC treatment.
BMC Cancer 01/2010; 10:461. · 3.01 Impact Factor
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ABSTRACT: Stathmin, an important cytosolic phosphoprotein, is involved in cell proliferation and motility. This study was performed to elucidate the role of stathmin in the progression of medulloblastoma.
The expression of stathmin protein was examined by immunohistochemical staining of tumor sections obtained in 17 consecutive patients with medulloblastoma who underwent resection between 1995 and 2005. Four patients were excluded because they were either lost to follow-up or underwent biopsy sampling only, leaving a total of 13 patients in the study. The stathmin expression was scored according to the immunoreactive fraction of tumor cells, and the level was correlated with various clinicopathological factors.
The expression level of stathmin protein was < or = 10% in 9 patients, 11-50% in 1, and > 50% in 3. No staining was seen in the tissues adjacent to the tumors. For comparison, the authors grouped the expression level of stathmin into high (> 50%) and low (< or = 50%). It was found that patients with high expression of stathmin had more frequent tumor dissemination at the time of resection or soon after total excision of the tumor (p = 0.0035), and hence experienced a fulminant course with lower patient survival (p < 0.0001), with an average survival period of 6.7 months (range 2-10 months). The expression level of stathmin did not correlate with patient age, sex, CSF cytological findings, use of adjuvant therapies, Ki 67 index, or risk classification of the tumors according to previously described categories in the literature.
High stathmin expression correlates with tumor dissemination, is an important prognostic factor of medulloblastoma, and may serve as a useful marker for more intensive adjuvant therapies.
Journal of Neurosurgery Pediatrics 08/2009; 4(1):74-80. · 1.53 Impact Factor
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Zhong-Zhe Lin, Hey-Chi Hsu,
Chih-Hung Hsu,
Pei-Yen Yeh,
Chi-Ying F Huang,
Yung-Feng Huang,
Te-Jung Chen,
Sung-Hsin Kuo,
Chiun Hsu,
Fu-Chang Hu,
Yung-Ming Jeng,
Ying Chung,
Ann-Lii Cheng
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and novel therapies are urgently needed. Recently, aberrant expression of Aurora kinases has been reported in various human cancers including HCC. We sought to investigate the potential of a potent and selective Aurora kinase inhibitor, VE-465, for targeted therapy of HCC.
Cytotoxicity effects of VE-465 were tested in Huh-7 and HepG2 cell lines. Inhibition of Aurora kinase activity was demonstrated by Western blotting and immunofluorescence staining. Mitotic perturbation was visualized by confocal microscopy. Cell cycle profiles and apoptosis were assessed by flow cytometry. In vivo efficacy was determined in nude mice with human HCC xenografts.
We demonstrated that VE-465 induced proliferation blockade, histone H3 (Ser10) dephosphorylation, mitotic disturbance, endoreduplication, and apoptosis in Huh-7 and HepG2 cells. We also found that VE-465 suppressed Aurora kinase activity, prevented tumor growth, and induced apoptosis in a Huh-7 xenograft model.
These findings show that VE-465 has potent anticancer effects in human HCC. Inhibitors of Aurora kinases may deserve further exploration as molecular targeted agents against HCC.
Journal of Hepatology 01/2009; 50(3):518-27. · 9.26 Impact Factor
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ABSTRACT: Background: Adenomatous polyposis coli (APC) gene mutations have been demonstrated not only in colorectal tumors but also in a variety of human cancers.Methods: To elucidate the possible roles of APC gene mutations in oral squamous cell carcinomas (OSCCs), we examined 40 untreated human primary OSCCs using polymerase chain reaction–single strand conformation polymorphism (PCR–SSCP) and DNA sequencing assays.Results: By screening nearly one-half of the coding region (codons 279–1673, including the MCR) of the APC gene, five missense mutations and a 1-base pair deletion were detected in five (12.5%) tumors, resulting in five amino-acid substitutions or a truncation of the APC protein. All patients with APC mutations were both areca quid chewers and tobacco smokers (P = 0.049).Conclusions: These results suggest that APC mutations may also contribute to the carcinogenesis of at least some OSCCs in Taiwan, especially for the users of areca quid and tobacco.
Journal of Oral Pathology and Medicine 10/2008; 31(7):395 - 401. · 1.63 Impact Factor
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ABSTRACT: Abnormal spindle-like microcephaly associated (ASPM) plays an important role in neurogenesis and cell proliferation. This study is to elucidate its role in hepatocellular carcinoma (HCC), particularly early tumor recurrence (ETR) and prognosis.
We used reverse transcription-PCR assays to measure the ASPM mRNA levels in 247 HCC and correlated with clinicopathologic and molecular features.
ASPM mRNA levels were high in fetal tissues but very low in most adult tissues. ASPM mRNA was overexpressed in 162 HCC (66%) but not in benign liver tumors. ASPM overexpression correlated with high alpha-fetoprotein (P = 1 x 10(-8)), high-grade (grade II-IV) HCC (P = 2 x 10(-6)), high-stage (stage IIIA-IV) HCC (P = 1 x 10(-8)), and importantly ETR (P = 1 x 10(-8)). ETR is the most critical unfavorable clinical prognostic factor. Among the various independent histopathologic (tumor size, tumor grade and tumor stage) and molecular factors (p53 mutation, high alpha-fetoprotein, and ASPM overexpression), tumor stage was the most crucial histologic factor (odds ratio, 14.7; 95% confidence interval, 6.65-33.0; P = 1 x 10(-8)), whereas ASPM overexpression (odds ratio, 6.49; P = 1 x 10(-8)) is the most important molecular factor associated with ETR. ASPM overexpression was associated with vascular invasion and ETR in both p53-mutated (all P values = 1 x 10(-8)) and non-p53-mutated HCC (P = 1 x 10(-8) and 0.00088, respectively). Hence, patients with APSM-overexpressing HCC had lower 5-year survival (P = 0.000001) in both p53-mutated (P = 0.00008) and non-p53-mutated HCC (P = 0.0027). In low-stage (stage II) HCC, ASPM overexpression also correlated with higher ETR (P = 0.008).
ASPM overexpression is a molecular marker predicting enhanced invasive/metastatic potential of HCC, higher risk of ETR regardless of p53 mutation status and tumor stage, and hence poor prognosis.
Clinical Cancer Research 09/2008; 14(15):4814-20. · 7.74 Impact Factor
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ABSTRACT: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an RNA-binding protein expressed in embryonic tissues and multiple cancers. To investigate the role of IMP3 in hepatocellular carcinoma (HCC), its protein expression in the surgically resected unifocal tumors of 377 HCC patients (296 men and 81 women) with ages ranging from 7 to 88 years (mean, 55.49 years) was analyzed by immunohistochemistry. IMP3 was expressed in 255 (67.6%) of 377 resected unifocal primary HCCs. IMP3 protein was predominantly expressed in tumor border and invasive front, and it was more abundant in the satellite nodules and tumor thrombi than in the main tumors. The expression correlated with high alpha-fetoprotein (>200 ng/mL, P < 1 x 10(-7)), larger tumor size (>5 cm, P = 0.006), high tumor grade (P < 1 x 10(-7)), and high tumor stage with vascular invasion and various degrees of intrahepatic metastasis (P < 1 x 10(-7)). IMP3 expression predicted early tumor recurrence (P < 1 x 10(-7)) and was a strong indicator of poor prognosis (P < 0.0001). Depletion of IMP3 with RNA interference in HCC cell line HA22T caused a decrease in cell motility, invasion, and transendothelial migration. Microarray analysis revealed that IMP3 depletion was associated with downregulation of multiple genes involved in tumor invasion. CONCLUSION: Our results indicate that IMP3 plays an important role in tumor invasion and metastasis and is a strong prognostic factor for patients with HCC.
Hepatology 07/2008; 48(4):1118-27. · 11.66 Impact Factor
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ABSTRACT: To investigate whether annexin A1 (ANXA1) expression is a marker in predicting the prognosis of oral cancer patients.
We immunohistochemically examined the expression of ANXA1 in 66 cases of oral epithelial dysplasia (OED) and 115 cases of oral squamous cell carcinoma (OSCC). The results were correlated with the clinicopathological parameters of tumors and overall patient survival.
In normal oral mucosa, ANXA1 staining was predominantly located on the cell membrane. In OED and OSCC specimens, membranous staining decreased, whereas nuclear staining increased. Positive nuclear staining was observed in 9 of 66 (13.64%) OED cases and 63 of 115 (54.8%) OSCCs. Kaplan-Meier curves showed that OSCC patients with ANXA1 nuclear staining had significantly shorter overall lengths of survival (P = 0.00036 by the log-rank test). Multivariate analysis showed that ANXA1 nuclear staining is a significant predictor of poor overall survival. And oral cancer SAS cells treated with hepatocyte growth factor (HGF) can induce ANXA1 protein translocation from cytoplasm to nucleus. Cells pretreated with LY294002 (PI3K inhibitor) almost completely inhibited (88.3% inhibition) HGF-mediated ANXA1 nuclear translocation.
The nuclear localization of ANXA1 protein is a frequent event and could be used as a prognostic factor in OSCC.
Journal of Surgical Oncology 06/2008; 97(6):544-50. · 2.10 Impact Factor
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ABSTRACT: Glypican-3 (gpc3) is the gene responsible for Simpson-Golabi-Behmel overgrowth syndrome. Previously, we have shown that GPC3 is overexpressed in hepatocellular carcinoma (HCC). In this study, we demonstrated the mechanisms for GPC3-mediated oncogenesis. Firstly, GPC3 overexpression in NIH3T3 cells gave to cancer cell phenotypes including growing in serum-free medium and forming colonies in soft agar, or on the other way, GPC3 knockdown in HuH-7 cells decreased oncogenecity. We further demonstrated that GPC3 bound specifically through its N-terminal proline-rich region to both Insulin-like growth factor (IGF)-II and IGF-1R. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule extracellular signal-regulated kinase (ERK) in an IGF-II-dependent way. Also, GPC3 knockdown in HCC cells decreased the phosphorylation of both IGF-1R and ERK. Therefore, GPC3 confers oncogenecity through the interaction between IGF-II and its receptor, and the subsequent activation of the IGF-signaling pathway. This data are novel to the current understanding of the role of GPC3 in HCC and will be important in future developments of cancer therapy.
Carcinogenesis 05/2008; 29(7):1319-26. · 5.70 Impact Factor
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ABSTRACT: Cancer cells with a high glycolytic rate have an advantage in tumor growth. Hepatocellular carcinoma (HCC) often exhibits an aberrant expression of glycolytic enzymes, particularly type II hexokinase (HKII) and aldolase B (ALDOB). This study examined the aberrant expression of HKII and ALDOB in 203 surgically resected HCCs. A dramatic down-regulation of ALDOB was found in 116 HCCs (57%), while 43% of HCCs maintained the expression. HKII mRNA was overexpressed in 70 (35%) primary HCCs. The ALDOB down-regulation and HKII overexpression correlated with high-grade (grade II-IV) HCC (all ps<0.0001), portal vein invasion (stage IIIB-IV) (ps<1x10(-6)), early tumor recurrence (ETR) (p<0.001 and p<0.01, respectively) and a lower 5-year survival (p=0.000001 and p=0.0062, respectively). Notably, in stage II HCC which had no vascular invasion, the ALDOB down-regulation was associated with ETR (p<0.05) and a lower 5-year survival (p=0.015). The down-regulation of ALDOB correlated with a high AFP (p=1x10(-8)), whereas the overexpression of HKII, which has two functional motifs for the mutant p53, correlated with the p53 mutation, p<0.01. The three factors (ALDOB down-regulation, HKII overexpression and p53 mutation) not only correlated with tumor progression, but also interacted with one another, leading to a more aggressive HCC with a portal vein invasion and various extent of intrahepatic metastasis by more than four-fold (ps<1x10(-6)) and frequent ETR by more than two-fold (ps<0.0001) compared with HCCs without the events. In conclusion, the aberrant expression of ALDOB and HKII is associated with advanced disease, ETR and poor prognosis, and ALDOB down-regulation in stage II HCC is a predictive marker of ETR and an unfavorable outcome.
Oncology Reports 04/2008; 19(4):1045-53. · 1.84 Impact Factor
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ABSTRACT: To clarify the natural history of hepatitis B virus (HBV)-associated liver cirrhosis, the clinical, laboratory and histological features of 174 untreated hepatitis B surface antigen (HBsAg)-positive cirrhotics were analysed, with a mean follow-up period of 34 months (range 8–135 months) after liver biopsy. Male patients were predominant (86.8%) and the mean age of the whole group was 45 years, s.d. = 12 (range 15–82 years). Serum HBeAg and HBV-DNA positivity were 38.9% and 31.8%, respectively. The calculated annual rate of spontaneous HBeAg seroconversion was 6.4% which was significantly lower than that (12%) of patients with HBeAg-positive chronic active hepatitis (CAH). Superinfection by δ-agent was rare, and anti-δ antibody was detected in only 1.7% of them. The occurrence rate of hepatocellular carcinoma in the whole group was 5.7%/year which was not higher than that of HBsAg-negative cirrhotics (6.2%/year). Serial liver biopsy showed that in the late evolution of cirrhosis, hepatitic activity tended to decline. Active cirrhosis may represent the intermediate stage between CAH and inactive liver cirrhosis. The 5-year survival probability rate of the patients belonging to Child's functional classes A, B and C was 83.4% (s.d. = 5.7), 79.2% (s.d. = 9.4) and 30.9% (s.d. = 14.3), respectively. Most patients were in a well-compensated state on entry into the study and remained stable for several years after diagnosis. Major causes of death include massive variceal bleeding, hepatic failure and/or hepatorenal syndrome, infection and hepatocellular carcinoma.
Journal of Gastroenterology and Hepatology 03/2008; 3(6):583 - 592. · 2.87 Impact Factor
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ABSTRACT: This study examined the virologic profiles and pathologic features in 10 infants with fulminant hepatitis and aged 2–7 months. Nine male infants were related to hepatitis B virus infection: as evidenced by positive anti-HBc IgM (4 cases); positive serum HBsAg, and/or liver HBcAg (4 cases); or born to an HBsAg carrier mother (1 case). Only one female infant had presumed non-A non-B fulminant hepatitis, but none had hepatitis A. The mothers of eight infants with HBV-ralated fulminant hepatitis were all positive for serum HBsAg, and most (5/6) were negative for HBeAg but positive for anti-HBe. These findings suggest that infants born to HBsAg carrier mothers, particularly those who are negative for HBeAg, may contract fulminant hepatitis B in infancy in Taiwan. Six infants studied had massive hepatic necrosis and all died, whereas four had submassive or bridging hepatic necrosis and all survived, suggesting a close correlation between the extent of liver necrosis and the patient's outcome. None of the infants had hepatocyte HBsAg, although four had cytoplasmic HBcAg. Anti-HBc IgM was commonly detected (4/6), in sharp contrast to the constant negativity in infants who had contracted an asymptomatic HBV infection. These findings suggest that cytoplasmic HBcAg and anti-HBc IgM may be related to the occurrence of severe liver disease.
Journal of Gastroenterology and Hepatology 03/2008; 3(1):1 - 7. · 2.87 Impact Factor
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ABSTRACT: Based on observations of a limited number of patients, delta (δ) infection has been reported to be infrequent in Taiwan. To further evaluate the role of δ-infection in patients with hepatitis B virus (HBV) infection, serum samples of 493 subjects with acute and chronic HBV infections collected in 1976–85 were studied for anti-δ by radioimmunoassay. Intrahepatic δ-antigen was also studied by immunofluorescence in 12 anti-δ-positive patients. The overall prevalence of δ-infection was 4.7%, consistent with previous studies. δ-Infection had an even yearly distribution in the last decade. However, there were four groups with significantly higher frequencies: (i) 24% of 41 anti-HBe-positive patients with chronic active hepatitis (CAH); (ii) 21% of 14 HBsAg carriers with prominent lobular hepatitis; (iii) two of three HBsAg carriers with intravenous drug abuse; and (iv) two of seven with fulminant hepatitis. On the other hand, δ-infection was uncommon in patients with chronic persistent hepatitis, cirrhosis, hepatocellular carcinoma, classical type B hepatitis, submassive necrosis and asymptomatic HBsAg carriers. δ-Antigen was found in only two patients with CAH; one progressed to cirrhosis, and the other had disease regression on follow-up. Overall, at least half of the δ-superinfected HBsAg-positive patients had a non-progressive course on follow-up.It was concluded that δ-agent was introduced to Taiwan before 1976. Although it has played a role in some clinical settings of HBV infections, it is generally infrequent in Taiwan. The δ-superinfection apparent in half the patients studied seems to have a non-progressive course.
Journal of Gastroenterology and Hepatology 03/2008; 2(1):1 - 8. · 2.87 Impact Factor
