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Claudin-7 Is Frequently Overexpressed in Ovarian Cancer and Promotes Invasion  [PDF]
Neetu Dahiya, Kevin G. Becker, William H. Wood,, Yongqing Zhang, Patrice J. Morin
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022119
Abstract: Background Claudins are tight junction proteins that are involved in tight junction formation and function. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. Here, we investigate in detail the expression patterns of claudin-7, as well as its possible functions in EOC. Methodology/Principal Findings A total of 95 ovarian tissue samples (7 normal ovarian tissues, 65 serous carcinomas, 11 clear cell carcinomas, 8 endometrioid carcinomas and 4 mucinous carcinomas) were studied for claudin-7 expression. In real-time RT-PCR analysis, the gene for claudin-7, CLDN7, was found to be upregulated in all the tumor tissue samples studied. Similarly, immunohistochemical analysis and western blotting showed that claudin-7 protein was significantly overexpressed in the vast majority of EOCs. Small interfering RNA-mediated knockdown of claudin-7 in ovarian cancer cells led to significant changes in gene expression as measured by microarrays and validated by RT-PCR and immunoblotting. Analyses of the genes differentially expressed revealed that the genes altered in response to claudin-7 knockdown were associated with pathways implicated in various molecular and cellular functions such as cell cycle, cellular growth and proliferation, cell death, development, and cell movement. Through functional experiments in vitro, we found that both migration and invasion were altered in cells where CLDN7 had been knocked down or overexpressed. Interestingly, claudin-7 expression was associated with a net increase in invasion, but also with a decrease in migration. Conclusion/Significance Our work shows that claudin-7 is significantly upregulated in EOC and that it may be functionally involved in ovarian carcinoma invasion. CLDN7 may therefore represent potential marker for ovarian cancer detection and a target for therapy.
TRIP-Br2 promotes oncogenesis in nude mice and is frequently overexpressed in multiple human tumors
Jit Cheong, Lakshman Gunaratnam, Zhi Zang, Christopher M Yang, Xiaoming Sun, Susan L Nasr, Khe Sim, Bee Peh, Suhaimi Rashid, Joseph V Bonventre, Manuel Salto-Tellez, Stephen I Hsu
Journal of Translational Medicine , 2009, DOI: 10.1186/1479-5876-7-8
Abstract: Oncogenic potential of TRIP-Br2 was demonstrated by (1) inoculation of NIH3T3 fibroblasts, which were engineered to stably overexpress ectopic TRIP-Br2, into athymic nude mice for tumor induction and (2) comprehensive immunohistochemical high-throughput screening of TRIP-Br2 protein expression in multiple human tumor cell lines and human tumor tissue microarrays (TMAs). Clinicopathologic analysis was conducted to assess the potential of TRIP-Br2 as a novel prognostic marker of human cancer. RNA interference of TRIP-Br2 expression in HCT-116 colorectal carcinoma cells was performed to determine the potential of TRIP-Br2 as a novel chemotherapeutic drug target.Overexpression of TRIP-Br2 is sufficient to transform murine fibroblasts and promotes tumorigenesis in nude mice. The transformed phenotype is characterized by deregulation of the E2F/DP-transcriptional pathway through upregulation of the key E2F-responsive genes CYCLIN E, CYCLIN A2, CDC6 and DHFR. TRIP-Br2 is frequently overexpressed in both cancer cell lines and multiple human tumors. Clinicopathologic correlation indicates that overexpression of TRIP-Br2 in hepatocellular carcinoma is associated with a worse clinical outcome by Kaplan-Meier survival analysis. Small interfering RNA-mediated (siRNA) knockdown of TRIP-Br2 was sufficient to inhibit cell-autonomous growth of HCT-116 cells in vitro.This study identifies TRIP-Br2 as a bona-fide protooncogene and supports the potential for TRIP-Br2 as a novel prognostic marker and a chemotherapeutic drug target in human cancer.Deregulation of E2F transcriptional activity due to alterations in the p16INK4a/cyclin D/RB pathway is a hallmark of many human cancers and more than half of all NCI-60 cell lines [1]. To date, the E2F family of proteins has been shown to be involved in the regulation of genes whose expression is pivotal for normal cell cycle progression and numerous other cellular processes such as DNA repair, programmed cell death and differentiation [2-4]. T
Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients
Bahriye Aktas, Mitra Tewes, Tanja Fehm, Siegfried Hauch, Rainer Kimmig, Sabine Kasimir-Bauer
Breast Cancer Research , 2009, DOI: 10.1186/bcr2333
Abstract: 2 × 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1 and HER2 transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [Twist1, Akt2, PI3Kα] and separately for the tumor stem-cell markers ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample.97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts. CTC were detected in 69/226 (31%) cancer samples. In the CTC (+) group, 62% were positive for at least one of the EMT markers and 69% for ALDH1, respectively. In the CTC (-) group the percentages were 7% and 14%, respectively. In non-responders, EMT and ALDH1 expression was found in 62% and 44% of patients, in responders the rates were 10% and 5%, respectively.Our data indicate that a major proportion of CTC of metastatic breast cancer patients shows EMT and tumor stem cell characteristics. Further studies are needed to prove whether these markers might serve as an indicator for therapy resistant tumor cell populations and, therefore, an inferior prognosis.Recurrence in breast cancer is explained by hematogenous dissemination of tumor cells in very early stages of the disease not being detectable by common staging procedures [1,2]. Although the prognostic value of these cells has been shown by several groups [3-7], it is assumed that the metastatic potential of a tumor is based on the presence of a low number of stem cell-like tumor cells that have been identified in tumor tissue to be the active source of metastatic spread [8-10]. In this regard, one study confirmed a putative stem cell phenotype in disseminated tumor cells (DTCs) [11], and another study showed that the majority of early DTCs detected in the bone marrow of breast cancer patients with a CD44+/CD24- phenotype correlated with a higher prevalence of bone metastases [12]. One candidate marker for a cancer stem cell phe
Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer  [PDF]
Erica Lynn Bradshaw-Pierce,Todd M. Pitts,Kelly McPhillips,Brion William Murray
Frontiers in Pharmacology , 2013, DOI: 10.3389/fphar.2013.00022
Abstract: P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB1 (P-gp) expression was evaluated by microarray for these cell lines. P-gp expression was determined by western blot and activity determined by rhodamine efflux assay. Knock down of P-gp and pharmacologic inhibition of P-gp to restore PF-309 activity was performed in vitro. PF-309 activity was evaluated in vivo in cell line xenograft models and in primary patient derived tumor xenografts (PDTX). Mice were treated with 25 mg/kg PF-309 orally, twice daily. On the last day of treatment, tumor and plasma were collected for PF-309 analysis. Here we show that ABCB1 gene expression correlates with resistance to PF-309 treatment in vitro and the expression and activity of P-gp was verified in a panel of resistant cells. Furthermore, inhibition of P-gp increased the sensitivity of resistant cells, resulting in a 4–100-fold decrease in the IC50s. Eleven cell line xenografts and 12 PDTX models were treated with PF-309. From the cell line xenografts, we found a significant correlation between ABCB1 gene expression profiles and tumor response. We evaluated tumor and plasma concentrations for eight tumor models (three cell line xenografts and five PDTX models) and a significant correlation was found between tumor concentration and response. Additionally, we show that tumor concentration is approximately fourfold lower in tumors that express P-gp, verified by western blot. Our in vitro and in vivo data strongly suggests that PF-309 efficacy is influenced by the expression of tumor P-gp.
Lactate-Dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1
Gian Kayser, Ahmad Kassem, Wulf Sienel, Luzie Schulte-Uentrop, Dominik Mattern, Konrad Aumann, Elmar Stickeler, Martin Werner, Bernward Passlick, Axel Hausen
Diagnostic Pathology , 2010, DOI: 10.1186/1746-1596-5-22
Abstract: Primary lung cancers (n = 269) and non neoplastic lung tissue (n = 35) were tested for LDH5 expression by immunohistochemistry using a polyclonal LDH5 antibody (ab53010). The results of LDH5 expression were correlated to clinico-pathological data as well as to patient's survival. In addition, the results of the previously tested Transketolase like 1 protein (TKTL1) expression were correlated to LDH5 expression.89.5% (n = 238) of NSCLC revealed LDH5 expression whereas LDH5 expression was not detected in non neoplastic lung tissues (n = 34) (p < 0.0001). LDH5 overexpression was associated with histological type (adenocarcinoma = 57%, squamous cell carcinoma = 45%, large cell carcinoma = 46%, p = 0.006). No significant correlation could be detected with regard to TNM-stage, grading or survival. A two sided correlation between the expression of TKTL1 and LDH5 could be shown (p = 0.002) within the overall cohort as well as for each grading and pN group. A significant correlation between LDH5 and TKTL1 within each histologic tumortype could not be revealed.LDH5 is overexpressed in NSCLC and could hence serve as an additional marker for malignancy. Furthermore, LDH5 correlates positively with the prognostic marker TKTL1. Our results confirm a close link between the two metabolic enzymes and indicate an alteration in the glucose metabolism in the process of malignant transformation.As one of the five lactate dehydrogenase (LDH) isoenzymes, LDH5 has the highest efficiency to catalyze pyruvate transformation to lactate. LDH5 overexpression in cancer cells induces an upregulated glycolytic metabolism and reduced dependence on the presence of oxygen. According to Warburg, malignant tumors generate lactate even in the presence of sufficient oxygen supply (Warburg effect) [1]. Upon this Thompson postulated a shift from oxidative phosphorylation to anaerobic glycolysis as a key element for malignant transformation of cells [2]. This change in the cells' glucose metabolism is not d
Functional and Anatomic Correlates of Two Frequently Observed Temporal Lobe Seizure-Onset Patterns  [PDF]
Ana Luisa Velascol,Charles L. Wilson,Thomas L. Babb,Jerome Engel Jr
Neural Plasticity , 2000, DOI: 10.1155/np.2000.49
Abstract: Intracranial depth electrode EEG records of 478 seizures, recorded in 68 patients undergoing diagnostic monitoring with depth electrodes, were evaluated to investigate the correlates of electrographic onset patterns in patients with temporal lobe seizures. The seizure onsets in 78% of these patients were identified as either hypersynchronous onsets, beginning with low-frequency, high-amplitude spikes, or low-voltage fast (LVF) onsets, increasing in amplitude as the seizure progressed. The number of patients (35) having hypersynchronous seizure onsets was nearly twice that of patients (18) having LVF onsets. Three major differences were seen among patients with the two seizure-onset patterns. When compared with patients having LVF onsets, patients with hypersynchronous seizure onsets had a significantly greater probability of having (1) focal rather than regional seizure onsets (p<0.01), (2) seizures spreading more slowly to the contralateral mesial temporal lobe (p<0.003), and (3) cell counts in resected hippocampal tissue showing greater neuronal loss (p<0.001). The results provide evidence that the most frequent electrographic abnormality associated with mesial temporal seizures is local hypersynchrony, a condition associated with major neuronal-loss in the hippocampus. The results also indicate that LVF seizure onsets more frequently represent widely distributed discharges, which interact with and spread more rapidly to surrounding neocortical areas.
Met Is the Most Frequently Amplified Gene in Endometriosis-Associated Ovarian Clear Cell Adenocarcinoma and Correlates with Worsened Prognosis  [PDF]
Yoriko Yamashita, Shinya Akatsuka, Kanako Shinjo, Yasushi Yatabe, Hiroharu Kobayashi, Hiroshi Seko, Hiroaki Kajiyama, Fumitaka Kikkawa, Takashi Takahashi, Shinya Toyokuni
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057724
Abstract: Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC.
MAL2 and tumor protein D52 (TPD52) are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome
Jennifer A Byrne, Sanaz Maleki, Jayne R Hardy, Brian S Gloss, Rajmohan Murali, James P Scurry, Susan Fanayan, Catherine Emmanuel, Neville F Hacker, Robert L Sutherland, Anna deFazio, Philippa M O'Brien
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-497
Abstract: Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally.MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p < 0.001; n = 124) and was an independent predictor of survival in the overall carcinoma cohort (hazard ratio (HR), 0.498; 95% confidence interval (CI), 0.34-0.728; p < 0.001; n = 221), and in serous carcinomas (HR, 0.440; 95% CI, 0.294-0.658; p < 0.001; n = 182).MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients.Epithelial ovarian carcinoma is a disease often characterised by poor outcome, despite intensive efforts to improve early disease detection, and to understand the causes of frequent treatment failure [1,2]. To improve our understanding of the underlying molecular basis of this histologically heterogeneous group of tumours, large numbers of cytogenetic and comparative expression studies have been undertaken. Cytogenetic analyses have consistently identified chromosome 8q gain as a common event in ovarian carcinoma [summarised in 3], and in other cancer types [4,5], and recent studies continue to highlight the fact that several distinct regions along chromosome 8q are increased in copy number [6-8]. One such region occurs at chromosome 8q24.12, and includes the gene enc
Insulin-like growth factor II mRNA binding protein 3 (IMP3) is overexpressed in prostate cancer and correlates with higher Gleason scores
Kristian Ikenberg, Florian R Fritzsche, Ursina Zuerrer-Haerdi, Irina Hofmann, Thomas Hermanns, Helge Seifert, Michael Müntener, Maurizio Provenzano, Tullio Sulser, Silvia Behnke, Josefine Gerhardt, Ashkan Mortezavi, Peter Wild, Ferdinand Hofst?dter, Maximilian Burger, Holger Moch, Glen Kristiansen
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-341
Abstract: Immunohistochemical stainings for IMP3 were performed on tissue microarray (TMA) organized samples from 507 patients: 31 normal prostate tissues, 425 primary carcinomas and 51 prostate cancer metastases or castration-resistant prostate cancers (CRPC). IMP3 immunoreactivity was semiquantitatively scored and correlated with clinical-pathologic parameters including survival.IMP3 is significantly stronger expressed in prostate carcinomas compared to normal prostate tissues (p < 0.0001), but did not show significant correlation with the pT-stage, the proliferation index (MIB1), preoperative serum PSA level and the margin status. Only a weak and slightly significant correlation was found with the Gleason score and IMP3 expression failed to show prognostic significance in clinico-pathological correlation-analyses.Although IMP3 is overexpressed in a significant proportion of prostate cancer cases, which might be of importance for novel therapeutic approaches, it does not appear to possess any immediate diagnostic or prognostic value, limiting its potential as a tissue biomarker for prostate cancer. These results might be corroborated by the fact, that two independent tumor cohorts were separately reviewed.Insulin-like growth factor II mRNA binding protein 3 (IMP3), an oncofetal protein and member of the insulin-like growth factor II mRNA binding protein family, has recently raised attention since it appears to play an important role in cell-migration and adhesion in various malignant neoplasms [1]. It functions in RNA shuttling and translational control: to date three members of this family are known: IMP1, IMP2 and IMP3 [2,3]. The human IMP3 gene is located at chromosome 7p15 with an identical sequence to that of KOC (KH domain containing protein overexpressed in cancer) and shows an overall sequence identitiy of 59% with other mRNA binding family members [4].Physiologically, IMP3 is commonly expressed during embryogenesis in mouse and human organs, but rarely in adult tis
Structural and Biophysical Characterization of the Cytoplasmic Domains of Human BAP29 and BAP31  [PDF]
Esben M. Quistgaard, Christian L?w, Per Moberg, Fatma Guettou, Karthik Maddi, P?r Nordlund
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071111
Abstract: Two members of the B-cell associated 31 (BAP31) family are found in humans; BAP29 and BAP31. These are ubiquitously expressed receptors residing in the endoplasmic reticulum. BAP31 functions in sorting of membrane proteins and in caspase-8 mediated apoptosis, while BAP29 appears to mainly corroborate with BAP31 in sorting. The N-terminal half of these proteins is membrane-bound while the C-terminal half is cytoplasmic. The latter include the so called variant of death effector domain (vDED), which shares weak sequence homology with DED domains. Here we present two structures of BAP31 vDED determined from a single and a twinned crystal, grown at pH 8.0 and pH 4.2, respectively. These structures show that BAP31 vDED forms a dimeric parallel coiled coil with no structural similarity to DED domains. Solution studies support this conclusion and strongly suggest that an additional α-helical domain is present in the C-terminal cytoplasmic region, probably forming a second coiled coil. The thermal stability of BAP31 vDED is quite modest at neutral pH, suggesting that it may assemble in a dynamic fashion in vivo. Surprisingly, BAP29 vDED is partially unfolded at pH 7, while a coiled coil is formed at pH 4.2 in vitro. It is however likely that folding of the domain is triggered by other factors than low pH in vivo. We found no evidence for direct interaction of the cytoplasmic domains of BAP29 and BAP31.
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