[show abstract][hide abstract] ABSTRACT: 14-3-3ε is implicated in regulating tumor progression, including hepatocellular carcinoma (HCC). Our earlier study indicated that elevated 14-3-3ε expression is significantly associated with higher risk of metastasis and lower survival rates of HCC patients. However, the molecular mechanisms of how 14-3-3ε regulates HCC tumor metastasis are still unclear.
In this study, we show that increased 14-3-3ε expression induces HCC cell migration and promotes epithelial-mesenchymal transition (EMT), which is determined by the reduction of E-cadherin expression and induction of N-cadherin and vimentin expression. Knockdown with specific siRNA abolished 14-3-3ε-induced cell migration and EMT. Furthermore, 14-3-3ε selectively induced Zeb-1 and Snail expression, and 14-3-3ε-induced cell migration was abrogated by Zeb-1 or Snail siRNA. In addition, the effect of 14-3-3ε-reduced E-cadherin was specifically restored by Zeb-1 siRNA. Positive 14-3-3ε expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in HCC tumors. Analysis of 14-3-3ε/E-cadherin expression associated with clinicopathological characteristics revealed that the combination of positive 14-3-3ε and negative E-cadherin expression is significantly correlated with higher incidence of HCC metastasis and poor 5-year overall survival. In contrast, patients with positive 14-3-3ε and positive E-cadherin expression had better prognostic outcomes than did those with negative E-cadherin expression.
Our findings show for the first time that E-cadherin is one of the downstream targets of 14-3-3ε in modulating HCC tumor progression. Thus, 14-3-3ε may act as an important regulator in modulating tumor metastasis by promoting EMT as well as cell migration, and it may serve as a novel prognostic biomarker or therapeutic target for HCC.
PLoS ONE 01/2013; 8(3):e57968. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Partitioning defective 3 (Par-3), a crucial component of partitioning-defective complex proteins, controls cell polarity and contributes to cell migration and cancer cell epithelial-to-mesenchymal transition. However, the clinical relevance of Par-3 in tumor progression and metastasis has not been well elucidated. In this study, we investigated the impact and association of Par-3 expression and clinical outcomes with hepatocellular carcinoma (HCC). We first confirmed that Par-3 was abundantly expressed in HCC cell lines by Western blot analysis. We used immunohistochemistry to analyze the association of Par-3 expression and clinicopathological characteristics in primary and subsequent metastatic tumors of patients with HCC. Par-3 was overexpressed in 47 of 111 (42.3%) primary tumors. Increased expression of Par-3 in primary tumors predicted an increased five-year cumulative incidence of extrahepatic metastasis. In addition, multivariate analysis revealed that Par-3 overexpression was an independent risk factor of extrahepatic metastasis. Increased Par-3 expression in primary tumors was associated with poor five-year overall survival rates and was an independent prognostic factor on Cox regression analysis. In conclusion, we show for the first time that increased Par-3 expression is associated with distant metastasis and poor survival rates in patients with HCC. Par-3 may be a novel prognostic biomarker and therapeutic target for HCC.
International Journal of Molecular Sciences 01/2013; 14(1):1684-97. · 2.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Focal adhesion kinase (FAK) is implicated in cancer cell survival, proliferation and migration. Expression of FAK expression is elevated and associated with tumor progression and metastasis in various tumors, including hepatocellular carcinoma (HCC). Increased 14-3-3ε expression is shown to be a potential prognostic factor to predict higher risk of distant metastasis and worse overall survival in HCC. The aim of this study is to investigate whether FAK is associated or regulated by 14-3-3ε to modulate tumor progression in HCC. In this study, 114 primary HCC tumors including 34 matched metastatic tumors were subjected to immunohistochemistry analysis of FAK and 14-3-3ε expression. Overexpression of FAK was significantly associated with increased risk of extrahepatic metastasis (p=0.027) and reduced 5-year overall survival rate (p=0.017). A significant correlation of FAK and 14-3-3ε expression was observed in primary tumor (p<0.001) and also metastatic tumors. Furthermore, overexpression of 14-3-3ε induced FAK expression and promoter activity which were determined by Western blotting analysis and luciferase-reporter assay. Moreover, 14-3-3ε enhanced NFκB activation and increased nuclear translocation of NFκB. Results from chromatin immunoprecipitation assay revealed that 14-3-3ε induced NFκB binding on FAK promoter region. These findings suggest that FAK expression is correlated with and upregulated by 14-3-3ε via activation of NFκB. Target to suppress or inactivate FAK alone, or combine with 14-3-3ε is thus considered as the potential therapeutic strategy for preventing HCC tumor progression.
Anti-cancer agents in medicinal chemistry 08/2012;
[show abstract][hide abstract] ABSTRACT: 14-3-3β is implicated in cell survival, proliferation, migration, and tumor growth; however, its clinical relevance in tumor progression and metastasis have never been elucidated. To evaluate the clinical significance of 14-3-3β, we analyzed the association of 14-3-3β expression and clinicopathologic characteristics in primary and subsequent metastatic tumors of hepatocellular carcinoma patients. 14-3-3β was expressed abundantly in 40 of 55 (70.7%) primary tumors. Increased 14-3-3β expression in primary tumors predicted a higher 5-year cumulative incidence of subsequent extrahepatic metastasis, and multivariate analysis revealed 14-3-3β overexpression was an independent risk factor for extrahepatic metastasis. Patients with increased 14-3-3β expression in primary tumors had worse 5-year overall survival rates, and 14-3-3β overexpression was an independent prognostic factor on Cox regression analysis. Furthermore, stably overexpressed 14-3-3β enhanced hepatocellular carcinoma cell migration and proliferation and increased anchorage-independent cell growth. In addition, in vivo study in a nude-mice model showed tumor formation significantly increased with 14-3-3β overexpression. In conclusion, this is the first report to show that increased 14-3-3β expression is associated with subsequent extrahepatic metastasis and worse survival rates, as well as cancer progression of hepatocellular carcinoma. Thus, 14-3-3β may be a novel prognostic biomarker and therapeutic target in hepatocellular carcinoma.
American Journal Of Pathology 09/2011; 179(6):2698-708. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: The results of our earlier studies suggested that 14-3-3ε is involved in cancer cell survival and growth. However, it is not clear whether 14-3-3ε plays a role in tumour metastasis and patient outcome. The aim of this study was to determine whether 14-3-3ε is a marker for predicting hepatocellular carcinoma (HCC) metastasis and survival.
One hundred and fourteen patients with tissue-diagnosed primary HCC were followed for an average of 58.6 months. 14-3-3ε in liver tissues was analysed by immunohistochemistry, and quantified by a Quick score system. Correlation of 14-3-3ε with patient survival and metastasis was analysed with a Wilcoxon signed rank test, Kaplan-Meier survival curves, and Cox proportional hazard regression. Seventy-one of 114 patients (62.3%) had a significant increase of 14-3-3ε expression in HCC tissues, whereas normal tissues expressed weak or undetectable 14-3-3ε. Elevated 14-3-3ε expression was significantly associated with shortened overall survival and progression-free survival. Furthermore, 14-3-3ε overexpression increased the risk of metastasis 4.6-fold.
Overexpression of 14-3-3ε in primary HCC tissues predicts a high risk of extrahepatic metastasis and worse survival, and is a potential therapeutic target.
[show abstract][hide abstract] ABSTRACT: Although The Bethesda System 2001 attempted to standardize the criteria for specimen adequacy, much confusion still exists, which includes the significance of unsatisfactory smears, the causes and clinical conditions related to unsatisfactory smears, and the appropriate management of unsatisfactory smears. The aim of this study is to find out the clinical factors associated with unsatisfactory cervical smears. We reviewed the medical charts of patients who received conventional Pap smears between March 2006 and August 2006 in a tertiary care center. After excluding 378 cases with incomplete demographic data, the clinical data of 7,059 cases were processed for analysis. Clinical parameters retrieved included: history of pelvic malignancy, pelvic irradiation, conization, hysterectomy, pregnancy status, within 3-months postpartum. Vaginal bleeding, abnormal vaginal discharge, intrauterine device, and cervical polyps found during pelvic examinations were also documented. The 1,397 cases with history of pelvic irradiation, pelvic malignancy, and hysterectomy were excluded. Finally, 5,662 cases were enrolled for data analysis. The relationship between clinical parameters and unsatisfactory smears were analyzed by Pearson's chi-square test with Yates' continuity correction and multivariate binary logistic regression test. The incidence of unsatisfactory smears was 4.5% (252/5,662). Clinical parameters correlated with unsatisfactory smears were postpartum status (OR = 1.92, 95% CI = 1.23-3.01, P = 0.004), vaginal bleeding (OR = 2.02, 95% CI = 1.30-3.16, P = 0.002), and endocervical polyps (OR = 2.62, 95% CI = 1.39-4.947, P = 0.003). In conclusion, if any of these parameters are noted prior to obtaining a Pap smear, optimal collecting devices, better sampling techniques, and liquid-based cytology should be considered to decrease the incidence of unsatisfactory smears.
[show abstract][hide abstract] ABSTRACT: The 14-3-3γ protein is an important regulator of various cellular and physiologic functions. Overexpression promotes cell proliferation and induces cancer cell polyploidization. Production is up-regulated in human hepatocellular carcinoma. However, the clinical significance of 14-3-3γ for human hepatocellular carcinoma metastasis and survival has not been clarified. In this study, 55 patients with human hepatocellular carcinoma were enrolled; and 18 of them were identified as having extrahepatic metastases. Expression of 14-3-3γ in these primary and metastatic samples was measured with semiquantitative immunohistochemistry analysis. Overexpression of 14-3-3γ was observed in 38 (69.1%) of the primary tumors, correlated significantly with a high α-fetoprotein concentration (P = .003), and predicted a higher probability of extrahepatic metastasis (cumulative probabilities at 5 years: 42.2% ± 8.0% versus 5.9% ± 5.7%, 14-3-3γ positive versus negative; P = .012). Furthermore, 14-3-3γ overexpression was associated with a worse 5-year overall survival rate (81.6% ± 9.6% versus 59.5% ± 8.1%, respectively) and a worse 5-year progression-free survival rate (75.6% ± 10.6% versus 48.6% ± 8.2%, respectively). Elevated expression of 14-3-3γ in human hepatocellular carcinoma predicts extrahepatic metastasis and worse survival. The protein thus is a candidate biomarker and a potential target for novel therapies against human hepatocellular carcinoma progression and metastasis.
Human pathology 01/2011; 42(1):129-35. · 3.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: Focal nodular hyperplasia of the liver is a benign tumor that usually affects young women. Traditionally, its treatment in children has been conservative. As a result of its rarity in childhood, its differential diagnosis with other liver tumors is challenging. We present the case of a 5-year-old girl with a 1-week history of fever and abdominal pain. No definite diagnosis could be obtained after serial imaging and liver biopsy. As a result of uncertainty in the imaging and needle biopsy results, the patient underwent complete tumor resection. Pathology showed focal nodular hyperplasia that affected the right lobe of the liver. After surgery, the child was doing well at 24 months of follow-up.
Journal of the Chinese Medical Association 11/2010; 73(11):611-4. · 0.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Precursor B lymphoblastic neoplasm usually presented as childhood leukemia. Most precursor lymphoblastic lymphoma are T-cell lineage and precursor B lymphoblastic lymphoma constitutes only about 10% of cases according to the WHO Classification of Tumours of Haematologic and Lymphoid Tissues. The most frequent sites of involvement in precursor B lymphoblastic lymphoma are the skin, soft tissue, bone and lymph nodes. Primary appendiceal involvement is an uncommon condition. We present an unusual case of primary appendiceal precursor B lymphoblastic lymphoma in an 11-year-old boy with peculiar histological morphology mimicking diffuse large B cell lymphoma. Histologically, the tumor was composed of diffusely infiltrated large cells from mucosa and extended to the subserosal area. The tumor cells were positive to CD79a, CD20, PAX5, BCL2, CD10, TdT, p53 but not to CD3, BCL6 and CD34 by immunohistochemical studies. The response to conventional treatment regimen for lymphoblastic lymphoma was not good, with early relapse within three months. Partial remission was achieved by adding rituximab. Unfortunately, the patient died in ten months due to uncontrolled relapsed disease with generalized lymphadenopathy and massive pleural effusion. The special morphologic changes and poor response to chemotherapy may be related to the overexpression of p53.
Pathology International 10/2010; 60(10):690-3. · 1.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various cancers; however, it remains unclear how FAK participates in tumor malignancy in vivo. This study seeks to understand the role of FAK activation in gastric cancer progression. Using immunohistochemical staining and Western blotting, we found that pY397 FAK, an autophosphorylation site on FAK activation, was abundant in the cancerous tissues of 21 of 59 patients with gastric carcinomas. We attempted to correlate clinicopathological parameters, including histological types, TNM staging, and cancer recurrence, with the expression of FAK and pY397 FAK in cancerous tissues. Intriguingly, patients with higher levels of pY397 FAK displayed higher incidences of gastric cancer recurrence after surgery and poor 5-year recurrence-free survival. Furthermore, multivariate analyses showed that pY397 FAK was an independent predictor of gastric cancer recurrence. As a result, expression of pY397 FAK is a significant prognostic factor for the recurrence of gastric cancer. Additionally, in vitro studies showed that overexpression of Y397F, a dominant-negative mutant of FAK, in AGS human gastric carcinoma cells impaired cell migration, invasion, and proliferation compared with cells overexpressing wild-type FAK. Thus, activation of FAK through autophosphorylation at Tyr397 leads to the progression of gastric carcinomas by promoting cell migration, invasion, and proliferation. Collectively, our results have provided valuable insights for the development of novel diagnoses and therapeutic targets for gastric cancer treatments.
American Journal Of Pathology 10/2010; 177(4):1629-37. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: We report a unique case of combined primary neuroendocrine carcinoma (NEC) and hepatocellular carcinoma (HCC) of the liver in a 65-year-old male patient. The patient underwent segmental resection of the liver and regional lymph node dissection for a tumor mass that measured 7.5 cm in diameter in the right lobe, with regional lymphadenopathy. Histologically, the hepatic tumor was composed of predominantly small-cell NEC, but admixed with a small island of moderately differentiated HCC. We speculate that the NEC originated from a poorly differentiated tumor clone of an HCC that underwent neuroendocrine differentiation, and that this tumor was now at the end stage of the transitional period from HCC to NEC, based on the small amount of disappearing HCC. Ki-67 and p53 expression were higher in the NEC than in the HCC, and the lymph nodes showed only metastatic NEC. Therefore, this kind of tumor had a more aggressive clinical course in accordance with being an NEC rather than a conventional HCC. Three months after operation, the patient had multiple recurrent tumor nodules within the liver, spreading the metastasis to the adrenal glands and para-aortic lymph nodes. The patient died 1 year after operation.
Journal of the Chinese Medical Association 09/2009; 72(8):430-3. · 0.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Focal adhesion kinase plays a critical role in cancer progression, invasion, and metastasis. Although focal adhesion kinase overexpression indicates poor prognoses for hepatocellular carcinoma, its role in hepatocellular carcinoma metastasis has not been well investigated. In this study, 55 hepatocellular carcinoma patients were enrolled, and their primary liver tumors as well as 18 matched metastases were subjected to semiquantitative immunohistochemistry analysis of focal adhesion kinase expression. Overexpression of focal adhesion kinase was observed in 34 (61.8%) of 55 primary tumors and significantly predicted subsequent extrahepatic metastases (P = .04). Metastatic tumors expressed higher focal adhesion kinase than their matched primaries (P = .010). Focal adhesion kinase overexpression indicated both worse overall 5-year survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .004) and 5-year progression-free survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .041). Taken together, we demonstrated here that focal adhesion kinase expression is significantly related to subsequent hepatocellular carcinoma metastasis. Focal adhesion kinase is thus considered as a reasonable target for novel therapies against hepatocellular carcinoma progression and metastasis.
Human pathology 06/2009; 40(10):1384-90. · 3.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: Lipoastrocytomas are rare and only four cases have been reported previously. Our case is in the fourth ventricle of a 32 year-old man.Many areas showed tumor cells with a signet-ring appearance and focally formed perivascular arrangements. Eosinophilic granular bodies were frequent. There was strong positive immunoreactivity to GFAP and S-100 protein, even in those vacuolated tumor cells.The proliferation index was less than 10%. Ultrastructural studies showed that the signet-ring cells had large lipid droplets as well as intermediate filaments. Ultrastructural features characteristic of ependymomas were not seen. These findings confirm that the vacuoles were lipid droplets in astrocytic tumor cells. The features noted are suggestive of a probable better prognosis in this variant of low-grade astrocytoma.
[show abstract][hide abstract] ABSTRACT: A 55-year-old male who presented with obstructive jaundice and radiographically documented extrahepatic biliary tract obstruction is reported. Eosinophilic infiltration of the gallbladder, common bile duct, intrahepatic bile ducts, and bone marrow was observed. Eosinophilic cholangitis, a rare inflammatory condition that clinically resembles a biliary malignancy, should be taken into consideration in the differential diagnosis in the evaluation of presumed neoplasm of the bile ducts.
Journal of Hepato-Biliary-Pancreatic Surgery 03/2009; 16(2):242-5. · 1.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in renal fibrosis. We conducted this study to examine whether serum PAI-1 has a role in predicting chronic allograft nephropathy (CAN).
Fifty kidney transplant recipients receiving graft biopsies were enrolled. The pathologic diagnoses were acute tubular necrosis (ATN; n = 12), borderline rejection (BR; n = 7), acute rejection (ACR; n = 12), CAN (n = 11), polyomavirus nephropathy (PVN; n = 3) and others (n = 5; glomerulopathy, n = 4; calcineurin inhibitor nephropathy, n = 1). The serum level of PAI-1 and chronic allograft damage index (CADI) score of each patient were determined.
The CADI score of all patients was 4 (0-10) (median and range) and in each group was ATN 0.5 (0-4), BR 2.0 (1-4), ACR 4.0 (2-8), CAN 5.0 (4-10), PVN 7 (4-8) and others 2 (0-8). The serum PAI-1 level of each group was ATN 9.38 (2.35-14.52) ng/mL, BR 10.09 (0.61-18.06) ng/mL, ACR 11.08 (2.32-20.68) ng/mL, CAN 14.51 (3.66-21.12), PVN 14.79 (13.94-21.94) and others 16.35 (4.05-21.01) ng/mL. CADI score is associated with serum PAI-1 activity (r = 0.405, p = 0.003) and is inversely associated with serum creatinine (r = -0.348, p = 0.011), but not with estimated glomerular filtration rate (p = 0.124).
Serum PAI-1 level has the potential to be a marker to predict CADI score, the quantitative score of CAN.
[show abstract][hide abstract] ABSTRACT: Liquid-based cytology (LBC) has achieved great success in cytological diagnosis of various cancers when compared with conventional smear methods. However, its application in diagnosing nasopharyngeal carcinoma (NPC) has never been studied.
Eighty-four consecutive patients who underwent nasopharyngeal biopsy for suspicious NPC or a nasopharyngeal mass under nasopharyngoscopy were enrolled in this prospective study. Brush samples were taken from the same site before punch biopsy and processed with the Thin Prep test.
The adequacy, accuracy, sensitivity, specificity, false-negative rate, and false-positive rate of LBC in diagnosing NPC were 92.9% (78 of 84), 93.6% (73 of 78), 84.2% (16 of 19), 96.6% (57 of 59), 15.8% (three of 19), and 3.4% (two of 25), respectively. There were four inadequate specimens from patients with NPC and two inadequate ones from those without NPC.
Our study showed that the adequacy, accuracy, sensitivity, specificity, and diagnostic rate of LBC were equivalent to those using conventional smear methods. Although the diagnostic rate of NPC was lower using brush cytology than by punch biopsy, further improvements in the sampling technique could make brushing cytology a potential tool for NPC screening.
American journal of rhinology & allergy 01/2009; 23(4):422-5. · 1.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Site-dependent profiles of chromosome imbalances (CIs) have been reported in gastrointestinal stromal tumors (GISTs). However, the role of specific CIs in association with metastasis is not clear.
Thirteen resected liver metastatic GISTs, including seven from the stomach and six from the small intestine, were analyzed using comparative genomic hybridization (CGH). The CIs associated with metastatic risk were assessed by comparing them with those identified in our previous study of 25 primary GISTs, including 14 from the stomach and 11 from the small intestine.
Synchronous detection of liver metastasis was found more often in patients with intestinal than gastric GIST (5/6 vs. 2/7, p = 0.048). When compared with the primary tumors, the CI profile of liver metastases was similar in the intestinal group, but became more complex in the gastric group. Deletions of chromosomes 1p and 15q were very common (> 80%) in primary and metastatic tumors of the intestinal group, and exhibited a trend towards increase in the metastatic tumors of the gastric group. Both groups had a doubling in the frequency of 22q deletion in the liver metastases, which was not significantly different. Other CIs, including 9p deletion, increased significantly in the liver metastases of the gastric group, but not in the intestinal group.
Our results, together with clinical findings, indicated a CGH profile associated with the intrinsic aggressiveness of the GISTs. Deletion of 1p and 15q play a critical role in the acquisition of aggressiveness during early GIST development.
Journal of the Formosan Medical Association 01/2009; 108(1):28-37. · 1.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Most female genital tract sarcomas are highly malignant and fatal. Their aggressive growth pattern and poor response to chemotherapy are the major causes of death. Deregulation of the apoptosis pathway is related to tumorigenesis and chemodrug resistance. The purpose of this study was to investigate the expression status and relationship of the apoptosis-related markers TP53, BCL-2, BAX and c-MYC in this group of tumors. In addition, correlations of these markers with clinicopathologic findings and their prognostic significance were also examined.
Paraffin blocks of female genital tract sarcoma tissue from 54 patients were obtained after pathology review. Protein expression of TP53, BCL-2, BAX and c-MYC was examined using immunohistochemical staining with standard procedures. A semiquantitative method was used to assess the staining result where scoring 1-3 was negative and 4-9 was positive for expression. The mutual relationships between TP53, BCL-2, BAX and c-MYC were examined. Associations between expression of the apoptotic markers and tumor stage as well as outcome were also analyzed.
We found that all 4 of the apoptosis-related markers were frequently expressed in female genital tract sarcomas. Of the 54 cases, 24 (44%) were positive for TP53, 23 (43%) for BCL-2, 25 (46%) for BAX, and 30 (56%) for c-MYC. A significant positive association was observed between BAX and c-MYC (p < 0.001). There was no significant difference for the expression status of the 4 markers in early and late stage tumors. In prognostic analysis, overexpression of TP53, late stage, and age were significant prognostic factors in both univariate and multivariate analyses.
Since changes in TP53, BCL-2, BAX and c-MYC frequently occur in female genital tract sarcomas, deregulation of apoptosis appears to be involved in the pathogenesis of this group of tumors. This mechanism may occur early in tumorigenesis and include the c-MYC/BAX apoptotic pathway or BCL-2. However, TP53 mutation may play a crucial role in this process, and clinically, it could be used as a prognostic indicator.
Journal of the Chinese Medical Association 01/2009; 71(12):628-34. · 0.75 Impact Factor