[Show abstract][Hide abstract] ABSTRACT: 14-3-3ε is overexpressed in hepatocellular carcinoma (HCC) and its expression significantly associates with a poor prognostic outcome. To uncover how 14-3-3ε contributes to the tumor progression of HCC, we investigated the potential downstream targets regulated by 14-3-3ε. We found that 14-3-3ε increases expression and nuclear translocation of β-catenin and that 14-3-3ε-induced cell proliferation is attenuated by β-catenin silencing in HCC cells. Moreover, 14-3-3ε induces aldo-keto reductase family 1 member B10 (AKR1B10) expression through the activation of β-catenin signaling. Knockdown of AKR1B10 by siRNAs abolished 14-3-3ε-induced in vitro cell proliferation, anchorage-independent growth as well as in vivo tumor growth. Furthermore, AKR1B10 silencing increased retinoic acid (RA) levels in the serum of tumor-bearing mice and RA treatment attenuated 14-3-3ε-induced HCC cell proliferation. We further examined 14-3-3ε and AKR1B10 expression and clinicopathological characteristics of HCC tumors. Although the expression of AKR1B10 was significantly correlated with 14-3-3ε, an increase of AKR1B10 expression in 14-3-3ε positive patients paradoxically had better overall survival and disease-free survival rates as well as lower metastatic incidence than those without an AKR1B10 increase. Finally, we found a loss of AKR1B10 expression in cells exhibiting a high capacity of invasiveness. Silencing of AKR1B10 resulted in inducing snail and vimentin expression in HCC cells. These results indicate that AKR1B10 may play a dual role during HCC tumor progression. Our results also indicate that 14-3-3ε regulates AKR1B10 expression by activating β-catenin signaling. A combination of 14-3-3ε with AKR1B10 is a potential therapeutic target and novel prognostic biomarker of HCC.
[Show abstract][Hide abstract] ABSTRACT: The qRT-PCR analysis of 139 clinical samples and analysis of 150 on-line database clinical samples indicated that AKT3 mRNA expression level was elevated in primary prostate tumors. Immunohistochemical staining of 65 clinical samples revealed that AKT3 protein expression was higher in prostate tumors of stage I, II, III as compared to nearby normal tissues. Plasmid overexpression of AKT3 promoted cell proliferation of LNCaP, PC-3, DU-145, and CA-HPV-10 human prostate cancer (PCa) cells, while knockdown of AKT3 by siRNA reduced cell proliferation. Overexpression of AKT3 increased the protein expression of total AKT, phospho-AKT S473, phospho-AKT T308, B-Raf, c-Myc, Skp2, cyclin E, GSK3β, phospho-GSK3β S9, phospho-mTOR S2448, and phospho-p70S6K T421/S424, but decreased TSC1 (tuberous sclerosis 1) and TSC2 (tuberous Sclerosis Complex 2) proteins in PC-3 PCa cells. Overexpression of AKT3 also increased protein abundance of phospho-AKT S473, phospho-AKT T308, and B-Raf but decreased expression of TSC1 and TSC2 proteins in LNCaP, DU-145, and CA-HPV-10 PCa cells. Oncomine datasets analysis suggested that AKT3 mRNA level was positively correlated to BRAF. Knockdown of AKT3 in DU-145 cells with siRNA increased the sensitivity of DU-145 cells to B-Raf inhibitor treatment. Knockdown of TSC1 or TSC2 promoted the proliferation of PCa cells. Our observations implied that AKT3 may be a potential therapeutic target for PCa treatment.
[Show abstract][Hide abstract] ABSTRACT: There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners. Increased expression of 14-3-3 proteins contributes to tumor progression of various malignancies. Several isoforms of 14-3-3 are overexpressed and associate with higher metastatic risks and poorer survival rates of hepatocellular carcinoma (HCC). 14-3-3β and 14-3-3ζ regulate HCC cell proliferation, tumor growth and chemosensitivity via modulating mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 signal pathways. Moreover, 14-3-3ε suppresses E-cadherin and induces focal adhesion kinase (FAK) expression, thereby enhancing epithelial-mesenchymal transition (EMT) and HCC cell migration. 14-3-3ζ forms complexes with αB-crystallin, which induces EMT and is the cause of sorafenib resistance in HCC. Finally, a recent study has indicated that 14-3-3σ induces heat shock protein 70 (HSP70) expression, which increases HCC cell migration. These results suggest that selective 14-3-3 isoforms contribute to cell proliferation, EMT and cell migration of HCC by regulating distinct targets and signal pathways. Targeting 14-3-3 proteins together with specific downstream effectors therefore has potential to be therapeutic and prognostic factors of HCC. In this article, we will overview 14-3-3's regulation of its downstream factors and contributions to HCC EMT, cell migration and proliferation.
[Show abstract][Hide abstract] ABSTRACT: Background
14-3-3σ is implicated in promoting tumor development of various malignancies. However, the clinical relevance of 14-3-3σ in hepatocellular carcinoma (HCC) tumor progression and modulation and pathway elucidation remain unclear.
We investigated 14-3-3σ expression in 109 HCC tissues by immunohistochemistry. Overexpression and knockdown experiments were performed by transfection with cDNA or siRNA. Protein expression and cell migration were determined by Western blot and Boyden chamber assay.
In this study, we found that 14-3-3σ is abundantly expressed in HCC tumors. Stable or transient overexpression of 14-3-3σ induces the expression of heat shock factor-1α (HSF-1α) and heat shock protein 70 (HSP70) in HCC cells. Moreover, expression of 14-3-3σ significantly correlates with HSF-1α/HSP70 in HCC tumors and both 14-3-3σ and HSP70 overexpression are associated with micro-vascular thrombi in HCC patients, suggesting that 14-3-3σ/HSP70 expression is potentially involved in cell migration/invasion. Results of an in vitro migration assay indicate that 14-3-3σ promotes cell migration and that 14-3-3σ-induced cell migration is impaired by siRNA knockdown of HSP70. Finally, 14-3-3σ-induced HSF-1α/HSP70 expression is abolished by the knockdown of β-catenin or activation of GSK-3β.
Our findings indicate that 14-3-3σ participates in promoting HCC cell migration and tumor development via β-catenin/HSF-1α/HSP70 pathway regulation. Thus, 14-3-3σ alone or combined with HSP70 are potential prognostic biomarkers for HCC.
[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.
[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.
Full-text · Article · Jan 2013 · International Journal of Molecular Sciences
[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.
No preview · Article · Aug 2012 · Anti-cancer agents in medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: A 54-year-old female had a 9-cm left renal mass with a 12-cm aorto-caval mass lesion mimicking an enlarged lymph node. Retroperitoneal dissection and left radical nephrectomy were performed, and pathology revealed a left renal mucinous tubular and spindle cell carcinoma combined with a retroperitoneal ganglioneuroma. The patient has had no local recurrence or distant metastasis after 3 years' follow-up. A misdiagnosis of metastatic renal cell carcinoma may be upheld by the primary imaging studies. Even in the targeted therapy era, cytoreductive nephrectomy is still an important step in the diagnosis and treatment of suspicious metastatic renal cell carcinomas.
Full-text · Article · May 2012 · Journal of the Chinese Medical Association
[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.
Full-text · Article · Sep 2011 · American Journal Of Pathology
[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.
Full-text · Article · Feb 2011 · Diagnostic Cytopathology
[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.
[Show abstract][Hide abstract] ABSTRACT: Prostatic biopsies provide the information for the determined diagnosis of prostatic cancer. Computer-aid investigation of
biopsies can reduce the loading of pathologists and also inter- and intra-observer variability as well. In this paper, we
proposed a two stages approach for prostatic cancer grading according to Gleason grading system. The first stage classifies
biopsy images into clusters based on their Skeleton-set (SK-set), so that images in the same cluster consist of the similar
two-tone texture. In the second stage, we analyzed the fractal dimension of sub-bands derived from the images of prostatic
biopsies. We adopted the Support Vector Machines as the classifier and using the leaving-one-out approach to estimate error
rate. The present experimental results demonstrated that 92.1% of accuracy for a set of 1000 pathological prostatic biopsy
[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.
Full-text · Article · Nov 2010 · Journal of the Chinese Medical Association
[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.
No preview · Article · Oct 2010 · Pathology International
[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.
Full-text · Article · Oct 2010 · American Journal Of Pathology
[Show abstract][Hide abstract] ABSTRACT: Prostatic biopsies provide the information for the determined diagnosis of prostatic cancer. Computer-aid investigation of biopsies can reduce the loading of pathologists and also inter- and intra-observer variability as well. In this paper, we proposed a novel method to classify prostatic biopsies according to the Gleason Grading System. This method analyzes the fractal dimension of sub-bands derived from the images of prostatic biopsies. In the experiments, we adopted Support vector machine as the classifier and the leave-one-out approach to estimate error rate. The present experimental results demonstrated that 86.3% of accuracy for a set of 1000 pathological images. These images are randomly selected from 50 cases which were prepared within last five years.