AP-2α gene deregulation is associated with renal cell carcinoma patient survival.

BACKGROUND: Renal cell carcinoma (RCC), one of the most fatal urologic tumors, accounts for approximately 3% of all adult cancers and exhibits a high metastatic index at diagnosis and a high rate of relapse. Radical or partial nephrectomy is a curative option for nonmetastatic RCCs. Targeted therapy has been shown to improve the survival of patients with metastatic RCCs. However, the underlying cellular and molecular events associated with RCC pathogenesis are not well known. METHODS: To investigate the clinical role of the transcription factor activator protein (AP)-2α in RCC, methylated CpG island recovery assays and microarray analysis were employed. COBRA and RT‒qPCR assays were performed to assess AP-2α expression in RCC. RESULTS: A negative correlation was noted between AP-2α mRNA expression levels and methylation status. Multivariate analyses showed that AP-2α mRNA was a major risk factor not only for overall and disease-free survival in RCC but also for disease-free survival in clear cell RCC. CONCLUSIONS: Our results indicated that AP-2α expression was deregulated in RCC and associated with overall patient survival and disease-free survival. Such findings suggest that AP-2α might play an important role in the pathogenesis of RCC.

Should Patients with Renal Cell Carcinoma and Pathological Nodal Invasion Be Classified As Having Stage IV Disease?

BACKGROUND: Lymph node invasion is associated with poor outcome in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with RCC within a single center from 2001 to 2018 were retrospectively obtained from the Chang Gung Research Database. Patient gender, physical status, Charlson Comorbidity Index, tumor side, histology, age at diagnosis, and body mass index (BMI) were compared. The overall survival (OS) and cancer-specific survival (CSS) of each group were estimated using the Kaplan-Meier method. Log-rank tests were used to compare between the subgroups. RESULTS AND CONCLUSIONS: A total of 335 patients were enrolled, of whom 76 had pT3N0M0, 29 had pT1-3N1M0, 104 had T1-4N0M1, and 126 had T1-4N1M1 disease. Significant OS difference was noted between pT3N0M0 and pT1-3N1M0 groups with 12.08 years [95% confidence interval (CI), 8.33-15.84] versus 2.58 years (95% CI, 1.32-3.85), respectively (P < 0.005). No significant difference was observed in OS between pT1-3N1M0 and T1-4N0M1 groups with 2.58 years (95% CI, 1.32-3.85) versus 2.50 years (95% CI, 1.85-3.15, P = 0.72). The OS of N1M1 group was worse than that of N0M1 group with 1.00 year (95% CI, 0.74-1.26) versus 2.50 years (95% CI, 1.85-3.15, P < 0.05). Similar results were also observed in CSS. In summary, we claim that RCC with lymph node (LN) invasion should be reclassified as stage IV disease in terms of survival outcome.

High-Sensitivity Dual-Probe Detection of Urinary miR-141 in Cancer Patients via a Modified Screen-Printed Carbon Electrode-Based Electrochemical Biosensor.

The screening and diagnosis of cancer are hallmarks of medicine in the aging population. Recently, microRNAs have shown potential for use as biomarkers, which could advance the field of diagnostics. The presence of miRNA-141 in the serum has been well described in several malignancies. However, the invasive approach used for sampling represents the major limitation for its practical application and, hence, its notable absence as a method for screening the general population. In light of this, we aimed to develop a high-sensitivity microRNA (miR) biosensor for application in the diagnosis of all miR-141-associated cancers, such as colorectal cancer (CRC) and breast cancer (BC). The novelty lies in our dual-probe design, which is reliant on the hybridization of the fluorescein isothiocyanate (FITC) targeting probe onto an existing sample of urinary miR-141 in the first step, followed by complementary binding with a biotinylated probe that has been coated on a modified screen-printed carbon electrode (SPCE). The hybridization of the probe and sensor produces signals via the catalytic reduction of H2O2 at HRP-modified SPCEs in the presence of H2O, which was measured by either cyclic voltammetry or chronoamperometry (CA) currents. In our study, the detection and expression of miR-141 in a cohort of colorectal cancer (n = 6) and breast cancer (n = 4) samples showed that its levels were significantly higher than in a healthy cohort (n = 9) (p < 0.004). Moreover, our miR sensor demonstrated high stability, reliability, and sensitivity (p < 0.0001). This work hopefully provides new information for the detection and monitoring of de novo and existing cancers.

Over-expression of TNNI3K is associated with early-stage carcinogenesis of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a devastating disease with very poor prognosis due to late diagnosis and resistance to traditional chemotherapies and radiotherapies. Herein, thioacetamide (TAA)-induced rat CCA model and CGCCA cell line were used; we aim to study the cytogenetic features during tumoral development of CCA and uncover the mystery regarding carcinogenesis of CCA. The Array comparative genomic hybridization analysis, in silico method, gene knockdown, Western blot, cell count proliferation assay, clonogenecity assay, and IHC staining were applied in this study. Array comparative genomic hybridization analysis was performed on all different TAA-induced phases of rat tissues to reveal the certain pattern, +2q45, +Xq22, -12p12, have been identified for the tumor early stage, where involve the gene TNNI3K. In addition, 16 genes and 3 loci were associated with rapid tumor progression; JAK-STAT signaling pathway was highly correlated to late stage of CCA. In silico database was used to observe TNNI3K was highly express at tumor part compared with normal adjacent tissue in CCA patients from TCGA dataset. Furthermore, the growth of TNNI3K-knockdown SNU308 and HuCCT1 cells decreased when compared with cells transfected with an empty vector cell demonstrated by proliferation and colonogenecity assay. Besides, over expression of TNNI3K was especially confirmed on human CCA tumors and compared with the intrahepatic duct stone bile duct tissues and normal bile duct tissues (P < 0.001). Our findings might uncover the mystery regarding carcinogenesis of CCA, and provide the potential genetic mechanism to the clinicians some ideas for the patients' treatment.

Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma.

UNLABELLED: Intrahepatic metastasis is the primary cause of the high recurrence and poor prognosis of human hepatocellular carcinoma (HCC). However, neither its molecular mechanisms nor markers for its prediction before hepatectomy have been identified. We recently revealed up-regulation of erythroblastic leukemia viral oncogene homolog 3 (ERBB3) in human HCC. Here we examined the clinical and biological significance of ERBB3 in HCC. Up-regulation of ERBB3 in HCC was strongly associated with male gender (P < 0.001), chronic hepatitis B (P = 0.002), microscopic vascular invasion (P = 0.034), early recurrence (P = 0.003), and worse prognosis (P = 0.004). Phosphorylated ERBB3 and its ligands [neuregulins (NRGs)] were detected in both HCC tissues and cells. Phosphorylation of ERBB3 could be induced by conditioned media of HCC cells and abolished by the pretreatment of conditioned media with anti-NRG antibodies or by the silencing of the endogenous NRG expression of the donor HCC cells. Human epidermal growth factor receptor 2 was required for ERBB3 phosphorylation. The downstream phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene homolog pathways were primarily elicited by NRG1/ERBB3 signaling, whereas the mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were elicited by both epidermal growth factor/epidermal growth factor receptor and NRG1/ERBB3 signaling. The activation and silencing of ERBB3-dependent signaling had potent effects on both the migration and invasion of HCC cells, but neither had significant effects on the proliferation of HCC cells, tumor formation, or tumor growth in vitro and in vivo. CONCLUSION: The constitutive activation of ERBB3-dependent signaling via the NRG1/ERBB3 autocrine loop plays a crucial role in the regulation of cell motility and invasion, which contribute to intrahepatic metastasis and early recurrence of HCC. ERBB3 is a marker for the prediction of intrahepatic metastasis and early recurrence. ERBB3-dependent signaling is a candidate target for the treatment of microscopic vascular invasion and for the prevention of HCC recurrence.

Establishment of a novel MALT lymphoma cell line, ma-1, from a patient with t(14;18)(q32;q21)-positive Helicobacter pylori-independent gastric MALT lymphoma.

Although t(11;18)(q21;q21), t(1;14)(p22;q32), and a few other genetic mutations are specific markers for the Helicobacter pylori (HP)-independent status of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the molecular mechanisms responsible for HP-independence of gastric MALT lymphoma without such translocations and mutations remain uncharacterized. In the present study, we describe the establishment and characterization of a novel MALT lymphoma cell line, MA-1, which was derived from a gastric MALT lymphoma which was negative for both t(11;18)(q21;q21) and t(1;14)(p22;q32); the patient had failed HP eradication therapy and chemotherapy. The cell morphology and the immunophenotype of this cell line were similar to that of the original gastric MALT lymphoma. Comparative genomic hybridization analysis showed no significant gene copy number changes. Spectral karyotyping displayed a near-diploid chromosome content (48 < 2n>XY), with at least 13 chromosome structural abnormalities. Furthermore, fluorescence in situ hybridization analyses disclosed the existence of three sub-clones, characterized by t(14;18)(q32;q21)/IGH-BCL2, t(14;18)(q32;q21)/IGH-MALT1, and the presence of both chromosomal translocations in the same cell, respectively; whereas amplification of the genes CRAD9, TRAF2, and BCL10 were not found. In conclusion, we have established the first human gastric MALT lymphoma cell line, which is characterized by unusual and complex chromosome translocations and will be useful to explore further the molecular mechanisms of HP-independence in gastric MALT lymphoma.

Urinary MicroRNA Sensing Using Electrochemical Biosensor to Evaluate Colorectal Cancer Progression.

Research in cancer diagnostics has recently established its footing and significance in the biosensor sphere, emphasizing the idea of a unique probe design used as a sensor and actuator, to identify the presence of protein, DNA, RNA, or miRNA. The fluorescein isothiocyanate (FITC) probe and biotinylated probe are designed for a two-pronged approach to the detection of the urinary miR-21 and miR-141, both of which have demonstrated significance in the development and progression of colorectal cancer, a leading cause of mortality and morbidity. The remainder of the apparatus is composed of a modified screen-printed carbon electrode (SPCE), to which the probes adhere, that transduces signals via the redox reaction between H2O2 and HRP, measured with chronoamperometry and cyclic voltammetry. The precise nature of our ultra-non-invasive biosensor makes for a highly sensitive and practical cancer detector, concluded by the significance when establishing disease presence (miR-21 p-value = 0.0176, miR-141 p-value = 0.0032), disease follow-up (miR-21 p-value = 0.00154, miR141 p-value < 0.0005), and even disease severity. This article hopes to emphasize the potential of an additional clinical tool for the management of colorectal cancer.

A Highly Sensitive Urinary Exosomal miRNAs Biosensor Applied to Evaluation of Prostate Cancer Progression.

Prostate cancer is the most common cancer in the male population, carrying a significant disease burden. PSA is a widely available screening tools for this disease. Current screen-printed carbon electrode (SPCE)-based biosensors use a two-pronged probe approach to capture urinary miRNA. We were able to successfully detect specific exosomal miRNAs (exomiRs) in the urine of patients with prostate cancer, including exomiR-451 and exomiR-21, and used electrochemistry for measurement and analysis. Our results significantly reaffirmed the presence of exomiR-451 in urine and that a CV value higher than 220 nA is capable of identifying the presence of disease (p-value = 0.005). Similar results were further proven by a PAS greater than 4 (p-value = 0.001). Moreover, a higher urinary exomiR-21 was observed in the high-T3b stage; this significantly decreased following tumor removal (p-values were 0.016 and 0.907, respectively). According to analysis of the correlation with tumor metastasis, a higher exomiR-21 was associated with lymphatic metastasis (p-value 0.042), and higher exomiR-461 expression was correlated with tumor stage (p-value 0.031), demonstrating that the present exomiR biosensor can usefully predict tumor progression. In conclusion, this biosensor represents an easy-to-use, non-invasive screening tool that is both sensitive and specific. We strongly believe that this can be used in conjunction with PSA for the screening of prostate cancer.

A Comparative Study of Stone Re-Treatment after Lithotripsy.

The high recurrence rate has always been a problem associated with urolithiasis. This study aimed to explore the effectiveness of single interventions, combined therapies, and surgical and nonsurgical interventions. Herein, three lithotripsy procedures­extracorporeal shock wave lithotripsy (ESWL), percutaneous nephrolithotomy (PCNL), and ureteroscopic lithotripsy (URSL)­were assessed and a retrospective cohort was selected in order to further analyze the association with several risk factors. Firstly, a population-based cohort from the Taiwan National Health Insurance Research Database (NHIRD) from 1997 to 2010 was selected. In this study, 350 lithotripsy patients who underwent re-treatment were followed up for at least six years to compare re-treatment rates, with 1400 patients without any lithotripsy treatment being used as the comparison cohort. A Cox proportional hazards regression model was applied. Our results indicate that the risk of repeat urolithiasis treatment was 1.71-fold higher in patients that received lithotripsy when compared to patients that were not treated with lithotripsy (hazard ratio (HR) 1.71; 95% confidence interval (CI) = 1.427−2.048; p < 0.001). Furthermore, a high percentage of repeated treatment was observed in the ESWL group (HR 1.60; 95% CI = 1.292−1.978; p < 0.001). Similarly, the PCNL group was also independently associated with a high chance of repeated treatment (HR 2.32; 95% CI = 1.616−3.329; p < 0.001). Furthermore, age, season, level of care, and Charlson comorbidities index (CCI) should always be taken into consideration as effect factors that are highly correlated with repeated treatment rates.

Gold Nanocluster-Based Fluorometric Banoxantrone Assay Enabled by Photoinduced Electron Transfer.

Monitoring the blood concentration of banoxantrone (AQ4N) is important to evaluate the therapeutic efficacy and side effects of this new anticancer prodrug during its clinical applications. Herein, we report a fluorescence method for AQ4N detection through the modulation of the molecule-like photoinduced electron transfer (PET) behavior of gold nanoclusters (AuNCs). AQ4N can electrostatically bind to the surface of carboxylated chitosan (CC) and dithiothreitol (DTT) co-stabilized AuNCs and quench their fluorescence via a Coulomb interaction-accelerated PET process. Under optimized experimental conditions, the linear range of AQ4N is from 25 to 200 nM and the limit of detection is as low as 5 nM. In addition, this assay is confirmed to be reliable based on its successful use in AQ4N determination in mouse plasma samples. This work offers an effective strategy for AQ4N sensing based on fluorescent AuNCs and widens the application of AuNCs in clinical diagnosis and pharmaceutical analysis.

Micro-RNA378a-3p Induces Apoptosis in Sarcomatoid Renal Cell Carcinoma and Regulates POLR2A and RUNX2 Expression.

BACKGROUND/AIM: Sarcomatoid renal cell carcinoma (sRCC) is an aggressive subtype of RCC. In the current study, we investigated whether the POLR2A and RUNX2 genes are involved in RCC-related signaling pathway and associated with miR-378. MATERIALS AND METHODS: Thirteen formalin-fixed and paraffin-embedded RCC samples were collected. Three software programs were used to predict the potential gene regulation in RCC by miR-378 and immunohistochemistry analysis was applied to confirm the expression of targeted proteins in FFPE samples. MicroRNA-378 transfection, analysis of mRNA and protein expression via Western Blotting and cell apoptosis analysis via flow cytometry for POLR2A and RUNX2 were further studied in four renal cell carcinoma cell lines. RESULTS: Both the mRNA and protein expression levels of POLR2A and RUNX2 in sRCC cell lines and were significantly higher than those in other subtypes of RCC, and similar results were obtained in clinical samples (p<0.01). Second, overexpression of miR-378 significantly suppressed the expression of POLR2A and RUNX2 in sRCC cells (p<0.01) and enhanced apoptosis (p<0.05). CONCLUSION: miR-378 significantly inhibits the expression of POLR2A and RUNX2 in sRCC and further promotes apoptosis of sRCC cells. We speculated that the apoptosis mechanism in sRCC occurs via regulation of the ERK2 and PI3K/AKT pathways, which might distinguish it from other subtypes of RCC.

EPA Modulates KLK Genes via miR-378: A Potential Therapy in Prostate Cancer.

It is known that miRNA-378a-3p (miR-378) could be induced by eicosapentaenoic acid (EPA), an omega-3 fatty acid. Herein, we first demonstrated how miR-378 exerts anti-prostate cancer (PCa) actions by influencing multiple target genes, including KLK2, KLK4, KLK6, and KLK14, which are implicated in PCa development, cell proliferation, and cell survival. Furthermore, these genes also correlate with androgen and mTOR signaling transduction, and are considered pivotal pathways for the onset and progression of PCa. In total, four PCa cell lines and eight pairing tissues (tumor vs. normal) from clinical PCa patients were included in the current study. The results showed high significance after EPA induced tumor cells containing higher expression levels of miR-378, and led the PCa cells having low cell viabilities, and they progressed to apoptosis when compared with normal prostate cells (p < 0.001). The findings indicated that EPA might become a potential therapy for PCa, especially because it is derived from the components of natural fish oil; it may prove to be a great help for solving the problem of castration-resistant prostate cancer (CRPC).

Identification of genetic alterations in upper urinary tract urothelial carcinoma in end-stage renal disease patients.

Clinical presentations of end-stage renal disease (ESRD) patients on dialysis with upper urinary tract urothelial carcinoma (UUT-UC) are different from those with normal renal function. The pathogenesis remains unknown. We investigated the pathogenetic influence of chromosomal aberrations in patient on dialysis with UUT-UC. The chromosomal aberrations of UUT-UC specimens from seven dialysis patients were assessed by conventional comparative genomic hybridization (cCGH). Subsequently, we further investigated 20 cases by whole genome and fine-tiling oligonucleotide array-based CGH to demonstrate gains and losses, and compared with the clinicopathologic background. The chromosomal aberrations in UUT-UC specimens from dialysis patients were more complex than in bladder urothelial carcinoma (B-UC). Our data showed that gains at 5p, 7, 19q, and losses at 4q, 9p, and 15q are common in UUT-UC of ESRD patients. Gains in regions associated with DNA repair genes were noted in this study. High-stage and high-grade tumors displayed more copy number variants. In addition, female ESRD patients with UUT-UC had more frequent chromosomal aberrations than their male counterparts. In conclusion, unique chromosomal aberrations were indentified in UUT-UC in ESRD patients.

Glucose/Glutathione Co-triggered Tumor Hypoxia Relief and Chemodynamic Therapy to Enhance Photothermal Therapy in Bladder Cancer.

Photothermal therapy (PTT) is a potential treatment for cancer that makes use of near-infrared (NIR) laser irradiation and is expected to assist traditional anti-cancer drug therapies; however, the therapeutic efficacy of PTT is restricted by thermal resistance due to the overexpression of heat shock proteins and insufficient penetration depth of lasers. Thus, PTT needs to be combined with additional therapeutic methods to obtain the optimal therapeutic efficacy for cancer. Herein, a multifunctional therapeutic platform combining PTT with glucose-triggered chemodynamic therapy (CDT) and glutathione (GSH)-triggered hypoxia relief was developed via GOx@MBSA-PPy-MnO2 NPs (GOx for glucose oxidase, M for Fe3O4, BSA for bovine serum albumin, and PPy for polypyrrole). GOx@MBSA-PPy-MnO2 NPs have excellent photothermal efficiency and can release Mn2+, which catalyzes the transformation of H2O2 into hydroxyl radicals (·OH) and O2 via a Fenton-like reaction, effectively destroying cancer cells and relieving tumor hypoxia. Meanwhile, a high content of H2O2 was produced via GOx catalysis of glucose, further enhancing the CDT efficiency. In addition, in vitro and in vivo experiments showed that the inhibition of cancer cell proliferation and effective inhibition of tumors could be caused by the combined PTT/glucose-triggered CDT effects and hypoxia relief of the GOx@MBSA-PPy-MnO2 NPs. Overall, this work provides evidence of a synergistic therapy that remarkably improves therapeutic efficacy and significantly prolongs the lifetime of mice compared with controls.

An Effective SARS-CoV-2 Electrochemical Biosensor with Modifiable Dual Probes Using a Modified Screen-Printed Carbon Electrode.

Due to the severe acute respiratory syndrome coronavirus (SARS-CoV-2, also called coronavirus disease 2019 (COVID-19)) pandemic starting in early 2020, all social activities ceased in order to combat its high transmission rate. Since vaccination combats one aspect for halting the spread of the virus, the biosensor community has looked at another aspect of reducing the burden of the COVID-19 pandemic on society by developing biosensors that incorporate point-of-care (POC) testing and the rapid identification of those affected in order to deploy appropriate measures. In this study, we aim first to propose a screen-printed carbon electrode (SPCE)-based electrochemical biosensor that meets the ASSURED criteria (i.e., affordable, sensitive, specific, user-friendly, rapid, equipment-free, and deliverable) for POC testing, but more importantly, we describe the novelty of our biosensor's modifiability that uses custom dual probes made from target nucleic acid sequences. Additionally, regarding the sensitivity of the biosensor, the lowest sample concentration was 10 pM (p = 0.0257) without amplification, which might challenge the traditional technique of reverse transcriptase-polymerase chain reaction (RT-PCR). The purpose of this study is to develop a means of diagnostics for the current pandemic as well as to provide an established POC platform for future epidemics.

Gain of TPPP as a predictor of progression in patients with bladder cancer.

The present study investigated the role of tubulin polymerization promoting protein (TPPP) in the regulation of bladder cancer (BC) cell proliferation and migration, in addition to the association between TPPP gene copy number amplification and clinicopathological characteristics of BC. TPPP gene amplification was measured in human BC epithelial cells and samples obtained from 52 patients with BC via fluorescence in situ hybridization. TPPP gain was defined as mean TPPP copy number >2.2 per nucleus (cutoff). The neutrophil-to-lymphocyte ratio (NLR) was also obtained from the preoperative data of the patients. For in vitro assays, BC cell lines were transfected with either TPPP small interfering RNAs or scrambled control, following which cell proliferation and migration were determined using Cell Counting Kit-8 and Transwell migration assays, respectively. The percentage of cells with TPPP copy number amplification in the four BC epithelial cell lines (MGH-U1, -U1R, -U3, -U4) examined (86.0-100.0%) was found to be higher compared with that in the normal human uroepithelial cell lines (3.0 and 9.0%). Patients were divided into one- (1.9%), two- (55.8%), three- (7.7%), four- (26.9%) and five-copy (7.7%) types. Results calculated using Fisher's exact test indicated that the gain of TPPP in patients with BC associated significantly with age (P<0.05), advanced histological grade (P<0.001), tumor stage (P<0.05), histological type (P<0.001) and NLR (P<0.05). In MGH-U1R and MGH-U4 cells, cell proliferation and migration were revealed to be significantly lower following TPPP knockdown compared with those in cells transfected with the scrambled control. In conclusion, findings from the present study suggest that TPPP is important for cell proliferation, cell migration and BC progression, such that TPPP copy number assessment would be advised for preoperative urine cytology for urothelial neoplasia diagnosis.

Low PTEN expression and overexpression of phosphorylated AktSer473 and AktThr308 are associated with poor overall survival in upper tract urothelial carcinoma.

The PI3K/Akt signaling pathway serves an essential role in various cellular processes, including cell growth, survival, cell motility, angiogenesis and cell metabolism. Loss of PTEN expression and hyperactivation of Akt can result in tumorigenesis. Previous studies observed expression of the Akt protein and absence of the PTEN protein in bladder cancer and non-small cell lung carcinoma tissues. The aim of the present study was to evaluate the expression status and prognostic value of PTEN and the PI3K/Akt signaling pathway in Taiwanese patients with upper tract urothelial carcinoma (UTUC). Archival formalin-fixed, paraffin-embedded (FFPE) tissues from 65 UTUC cases were stained via immunohistochemistry for PTEN, phosphorylated (p)Akt serine (Ser)473 and pAkt threonine (Thr)308. The expression levels of each protein were significantly correlated with clinicopathological parameters. PTEN, pAktSer473 and pAktThr308 protein expression levels were higher in adjacent normal tissues compared with those in tumor tissues. Cytoplasmic PTEN protein expression levels were lower in high-stage tumors compared with those in low-stage tumors, and nuclear and cytoplasmic pAktThr308 protein expression levels were higher in high-grade tumors compared with those in low-grade tumors. Univariate analysis showed that high pathological tumor stage (pT2-4) [P=0.01; hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.34-8.60], metastatic status (P=0.003; HR=3.55, 95% CI, 1.55-8.11), low cytoplasmic PTEN protein expression levels (P=0.016; HR=3.14; 95% CI, 1.24-7.95) and high cytoplasmic pAktSer473 protein expression levels (P=0.019, HR=2.71, 95% CI, 1.18-6.21) were predictive of poor overall survival. However, only metastatic status (P=0.031; HR=2.73; 95% CI, 1.10-6.78), low cytoplasmic PTEN protein expression levels (P=0.017; HR=3.29; 95% CI, 1.24-8.73) and high cytoplasmic pAktSer473 protein expression levels (P=0.027; HR=2.64; 95% CI, 1.12-6.23) remained significant in the multivariate analysis. Kaplan-Meier survival analysis showed that high T stage, metastasis, low expression levels of cytoplasmic PTEN protein and high expression levels of cytoplasmic pAktSer473 protein were significantly associated with poor survival (P=0.006, 0.001, 0.011 and 0.014, respectively). Co-expression of PTENlow/pAktSer473/high and pAktThr308/high phenotypes was associated with a less favorable overall survival (P=0.001). Overall, the present findings demonstrated that low expression levels of PTEN and high expression levels of pAktSer473 and pAktThr308 were predictors for poor overall survival in patients with UTUC.

Expression of ezrin is associated with invasion and dedifferentiation of hepatitis B related hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and constitutes the leading cause of cancer-related death among men, and second among women in Taiwan. Liver cirrhosis and HCC are relatively prevalent, and 80% to 85% of the patients with these conditions have positive results for hepatitis B surface antigen in Taiwan. Only 5% of the general population is seronegative for all hepatititis B virus (HBV) markers. This is the first study to determine the role of ezrin upon HBV HCC cell and patients with HBV HCC undergoing hepatectomy METHODS: Immunohistochemical study with ezrin in 104 human HBV-HCC cases were carried out to investigate its association with the clinicopathological features and the outcomes of 104 HBV-HCC patients undergoing hepatetomy. In addition, DNA constructs including the wild type ezrin (wt-ezrin) and mutant ezrin Tyr353 (Y353) were transfected into Hep3B cell to study its role in tumor invasion and differentiation. RESULTS: HBV HCC patients with ezrin over-expression independently have smaller tumor size, cirrhotic liver background, poor tumor differentiation, and more vascular invasion. Ezrin expression status has no impact on survival for HBV-HCC patients undergoing hepatectomy. The in vitro assay showed that wt-ezrin Hep3B cells have a significant higher level of AFP secretion and higher invasion ability as compared with the control and Y353- ezrin Hep3B cells. CONCLUSION: Ezrin over-expression contributed to de-differentiation and invasion of HBV-HCC cell. HBV-HCC patients with ezrin over-expression were independently associated with tumor with smaller size, cirrhotic liver background, poor differentiation, and vascular invasion.