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Featured researches published by James K.J. Diss.


Clinical Cancer Research | 2005

Voltage-Gated Sodium Channel Expression and Potentiation of Human Breast Cancer Metastasis

Scott P. Fraser; James K.J. Diss; Athina-Myrto Chioni; Maria E. Mycielska; Huiyan Pan; Rezan Fahrioglu Yamaci; Filippo Pani; Zuzanna Siwy; Monika Krasowska; Zbigniew J. Grzywna; William J. Brackenbury; Dimis Theodorou; Meral Koyutürk; Handan Kaya; Esra Battaloglu; Manuela Tamburo De Bella; Martin J. Slade; Robert Tolhurst; Carlo Palmieri; Jie Jiang; David S. Latchman; R. Charles Coombes; M.B.A. Djamgoz

Purpose: Ion channel activity is involved in several basic cellular behaviors that are integral to metastasis (e.g., proliferation, motility, secretion, and invasion), although their contribution to cancer progression has largely been ignored. The purpose of this study was to investigate voltage-gated Na+ channel (VGSC) expression and its possible role in human breast cancer. Experimental Design: Functional VGSC expression was investigated in human breast cancer cell lines by patch clamp recording. The contribution of VGSC activity to directional motility, endocytosis, and invasion was evaluated by in vitro assays. Subsequent identification of the VGSC α-subunit(s) expressed in vitro was achieved using reverse transcription-PCR, immunocytochemistry, and Western blot techniques and used to investigate VGSCα expression and its association with metastasis in vivo. Results: VGSC expression was significantly up-regulated in metastatic human breast cancer cells and tissues, and VGSC activity potentiated cellular directional motility, endocytosis, and invasion. Reverse transcription-PCR revealed that Nav1.5, in its newly identified “neonatal” splice form, was specifically associated with strong metastatic potential in vitro and breast cancer progression in vivo. An antibody specific for this form confirmed up-regulation of neonatal Nav1.5 protein in breast cancer cells and tissues. Furthermore, a strong correlation was found between neonatal Nav1.5 expression and clinically assessed lymph node metastasis. Conclusions: Up-regulation of neonatal Nav1.5 occurs as an integral part of the metastatic process in human breast cancer and could serve both as a novel marker of the metastatic phenotype and a therapeutic target.


Prostate Cancer and Prostatic Diseases | 2005

A potential novel marker for human prostate cancer: voltage-gated sodium channel expression in vivo.

James K.J. Diss; D Stewart; F Pani; Christopher S. Foster; Marjorie M. Walker; A Patel; M.B.A. Djamgoz

Functional expression of voltage-gated sodium channel α-subunits (VGSCαs), specifically Nav1.7, is associated with strong metastatic potential in prostate cancer (CaP) in vitro. Furthermore, VGSC activity in vitro directly potentiates processes integral to metastasis. To investigate VGSCα expression in CaP in vivo, immunohistochemistry and real-time PCR were performed on human prostate biopsies (n>20). VGSCα immunostaining was evident in prostatic tissues and markedly stronger in CaP vs non-CaP patients. Importantly, RT-PCRs identified Nav1.7 as the VGSCα most strikingly upregulated (∼20-fold) in CaP, and the resultant receiver-operating characteristics curve demonstrated high diagnostic efficacy for the disease. It is concluded that VGSCα expression increases significantly in CaP in vivo and that Nav1.7 is a potential functional diagnostic marker.


European Biophysics Journal | 2004

Voltage-gated Na + channels: multiplicity of expression, plasticity, functional implications and pathophysiological aspects

James K.J. Diss; Scott P. Fraser; M.B.A. Djamgoz

Voltage-gated Na+ channels (VGSCs) are well known for mediating regenerative cell membrane depolarization and conduction of electrical signalling in nerves and muscles. However, VGSCs may also be expressed in traditionally “non-excitable” cell types, including lymphocytes, glia, fibroblasts and metastatic cancer cells of epithelial origin. Both the diversity and modulation of VGSC expression are far more complex than was initially apparent. There are at least 10 different genes that encode the α-subunits of VGSCs. Since VGSCs can contribute to a range of human disease conditions, it is important to understand both the control and consequences of VGSC functioning and how these aspects may be altered under pathophysiological conditions. Such mechanisms can be at the transcriptional, pre-translational or post-translational levels. This article reviews recent literature that has contributed to our understanding of how individual VGSC subtypes can generate their unique physiological signatures within different cell types. We also highlight emerging areas of interest, in particular, the finding of multiple expression of individual VGSC subtypes within single cells, the generation of alternative splice variants and the increasingly complex set of mechanisms of plasticity through which individual VGSC subtypes may be subtly controlled, including intracellular trafficking of VGSC protein.


FEBS Letters | 2004

T-lymphocyte invasiveness: control by voltage-gated Na+ channel activity

Scott P. Fraser; James K.J. Diss; Louise J Lloyd; Filippo Pani; Athina-Myrto Chioni; Andrew J. T. George; M.B.A. Djamgoz

Whole‐cell patch‐clamp recordings showed that a sub‐population (10%) of Jurkat cells, a model of human T‐cells, expressed a functional voltage‐gated sodium channel, which was tetrodotoxin (TTX)‐resistant. Expression of voltage‐gated sodium channel protein was confirmed by western blots. Semi‐quantitative PCR analysis revealed that mRNAs for the α‐subunits of multiple voltage‐gated sodium channel subtypes were present but indicated that Nav1.5 was the predominant subtype, consistent with the TTX‐resistant nature of the recorded currents. Importantly, 10 μM TTX reduced the number of Jurkat cells invading a Matrigel basement membrane by 93.0 ± 5.5%. Since similar sodium channels have also been detected in normal human T‐lymphocytes, it is concluded that the activity of voltage‐gated sodium channels could represent a novel mechanism potentiating the invasive capacity of these cells.


Journal of Biological Chemistry | 2011

Angiogenic Functions of Voltage-gated Na+ Channels in Human Endothelial Cells MODULATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) SIGNALING

Petros Andrikopoulos; Scott P. Fraser; Lisa Patterson; Zahida Ahmad; Hakan Burcu; Diego Ottaviani; James K.J. Diss; Carol Box; Suzanne A. Eccles; Mustafa B. A. Djamgoz

Voltage-gated sodium channel (VGSC) activity has previously been reported in endothelial cells (ECs). However, the exact isoforms of VGSCs present, their mode(s) of action, and potential role(s) in angiogenesis have not been investigated. The main aims of this study were to determine the role of VGSC activity in angiogenic functions and to elucidate the potentially associated signaling mechanisms using human umbilical vein endothelial cells (HUVECs) as a model system. Real-time PCR showed that the primary functional VGSC α- and β-subunit isoforms in HUVECs were Nav1.5, Nav1.7, VGSCβ1, and VGSCβ3. Western blots verified that VGSCα proteins were expressed in HUVECs, and immunohistochemistry revealed VGSCα expression in mouse aortic ECs in vivo. Electrophysiological recordings showed that the channels were functional and suppressed by tetrodotoxin (TTX). VGSC activity modulated the following angiogenic properties of HUVECs: VEGF-induced proliferation or chemotaxis, tubular differentiation, and substrate adhesion. Interestingly, different aspects of angiogenesis were controlled by the different VGSC isoforms based on TTX sensitivity and effects of siRNA-mediated gene silencing. Additionally, we show for the first time that TTX-resistant (TTX-R) VGSCs (Nav1.5) potentiate VEGF-induced ERK1/2 activation through the PKCα-B-RAF signaling axis. We postulate that this potentiation occurs through modulation of VEGF-induced HUVEC depolarization and [Ca2+]i. We conclude that VGSCs regulate multiple angiogenic functions and VEGF signaling in HUVECs. Our results imply that targeting VGSC expression/activity could be a novel strategy for controlling angiogenesis.


Journal of Cellular Physiology | 2008

Alternative splicing of Nav1.5: An electrophysiological comparison of ‘neonatal’ and ‘adult’ isoforms and critical involvement of a lysine residue

Rustem Onkal; Joanna H. Mattis; Scott P. Fraser; James K.J. Diss; Dongmin Shao; Kenji Okuse; M.B.A. Djamgoz

In developmentally regulated D1:S3 splicing of Nav1.5, there are 31 nucleotide differences between the 5′‐exon (‘neonatal’) and the 3′‐exon (‘adult’) forms, resulting in 7 amino acid differences in D1:S3‐S3/S4 linker. In particular, splicing replaces a conserved negative aspartate residue in the ‘adult’ with a positive lysine. Here, ‘neonatal’ and ‘adult’ Nav1.5 α‐subunit splice variants were stably transfected into EBNA‐293 cells and their electrophysiological properties investigated by whole‐cell patch‐clamp recording. Compared with the ‘adult’ isoform, the ‘neonatal’ channel exhibited (1) a depolarized threshold of activation and voltage at which the current peaked; (2) much slower kinetics of activation and inactivation; (3) 50% greater transient charge (Na+) influx; (4) a stronger voltage dependence of time to peak; and (5) a slower recovery from inactivation. Tetrodotoxin sensitivity and VGSCβ1‐4 mRNA expression levels did not change. The significance of the charge‐reversing aspartate to lysine substitution was investigated by mutating the lysine in the ‘neonatal’ channel back to aspartate. In this ‘neonatal K211D’ mutant, the electrophysiological parameters studied strongly shifted back towards the ‘adult’, that is the lysine residue was primarily responsible for the electrophysiological effects of Nav1.5 D1:S3 splicing. Taken together, these data suggest that the charge reversal in ‘neonatal’ Nav1.5 would (1) modify the channel kinetics and (2) prolong the resultant current, allowing greater intracellular Na+ influx. Developmental and pathophysiological consequences of such differences are discussed. J. Cell. Physiol. 216: 716–726, 2008,


Prostate Cancer and Prostatic Diseases | 2008

Beta-subunits of voltage-gated sodium channels in human prostate cancer: quantitative in vitro and in vivo analyses of mRNA expression

James K.J. Diss; Scott P. Fraser; Marjorie M. Walker; A Patel; David S. Latchman; M.B.A. Djamgoz

We previously identified high levels of Nav1.7 voltage-gated sodium channel α-subunit (VGSCα) mRNA and protein in human prostate cancer cells and tissues. Here, we investigated auxillary β-subunit (VGSCβs) expression. In vitro, the combined expression of all four VGSCβs was significantly (∼4.5-fold) higher in strongly compared to weakly metastatic cells. This was mainly due to increased β1-expression, which was under androgenic control. In vivo, β1–β4 mRNAs were detectable and their expression in CaP vs non-CaP tissues generally reflected the in vitro levels in relation to metastatic potential. The possible role(s) of VGSCβs (VGSCα-associated and VGSCα-independent) in prostate cancer are discussed.


Journal of Cellular Physiology | 2010

Estrogen and non-genomic upregulation of voltage- gated Na+ channel activity in MDA-MB-231 human breast cancer cells: role in adhesion.

Scott P. Fraser; Iley Ozerlat-Gunduz; Rustem Onkal; James K.J. Diss; David S. Latchman; M.B.A. Djamgoz

External (but not internal) application of β‐estradiol (E2) increased the current amplitude of voltage‐gated Na+ channels (VGSCs) in MDA‐MB‐231 human breast cancer (BCa) cells. The G‐protein activator GTP‐γ‐S, by itself, also increased the VGSC current whilst the G‐protein inhibitor GDP‐β‐S decreased the effect of E2. Expression of GPR30 (a G‐protein‐coupled estrogen receptor) in MDA‐MB‐231 cells was confirmed by PCR, Western blot and immunocytochemistry. Importantly, G‐1, a specific agonist for GPR30, also increased the VGSC current amplitude in a dose‐dependent manner. Transfection and siRNA‐silencing of GPR30 expression resulted in corresponding changes in GPR30 protein expression but only internally, and the response to E2 was not affected. The protein kinase A inhibitor, PKI, abolished the effect of E2, whilst forskolin, an adenylate cyclase activator, by itself, increased VGSC activity. On the other hand, pre‐incubation of the MDA‐MB‐231 cells with brefeldin A (a trans‐Golgi protein trafficking inhibitor) had no effect on the E2‐induced increase in VGSC amplitude, indicating that such trafficking (‘externalisation’) of VGSC was not involved. Finally, acute application of E2 decreased cell adhesion whilst the specific VGSC blocker tetrodotoxin increased it. Co‐application of E2 and tetrodotoxin inhibited the effect of E2 on cell adhesion, suggesting that the effect of E2 was mainly through VGSC activity. Pre‐treatment of the cells with PKI abolished the effect of E2 on adhesion, consistent with the proposed role of PKA. Potential implications of the E2‐induced non‐genomic upregulation of VGSC activity for BCa progression are discussed. J. Cell. Physiol. 224: 527–539, 2010.


FEBS Letters | 1998

Expression of skeletal muscle‐type voltage‐gated Na+ channel in rat and human prostate cancer cell lines

James K.J. Diss; D. Stewart; Scott P. Fraser; Joel A. Black; Sulayman D. Dib-Hajj; Stephen G. Waxman; Simon N. Archer; M.B.A. Djamgoz

Previous electrophysiological work has demonstrated expression of a voltage‐gated Na+ channel (VGSC) specifically in two highly metastatic prostatic epithelial tumour cell lines: MAT‐LyLu (rat) and PC‐3 (human). However, the identity of the channel(s) present was uncertain. The present study used a combination of molecular biological techniques to demonstrate that full‐length skeletal muscle type 1 (SkM1) VGSC mRNA is present in the mRNA pool of the MAT‐LyLu cell line. mRNA for this particular channel type was also expressed in the PC‐3 cells. In situ hybridisation data suggested that the level and pattern of rSkM1 mRNA expression were different in the Dunning cells of markedly different metastatic potential. Interestingly, the same type of mRNA was also detected in the weakly metastatic counterparts of the cells: AT‐2 (rat) and LNCaP (human).


Prostate Cancer and Prostatic Diseases | 2006

Brn-3a neuronal transcription factor functional expression in human prostate cancer

James K.J. Diss; D J Faulkes; Marjorie M. Walker; A Patel; Christopher S. Foster; V Budhram-Mahadeo; M.B.A. Djamgoz; David S. Latchman

Neuroendocrine differentiation has been associated with prostate cancer (CaP). Brn-3a (short isoform) and Brn-3c, transcriptional controllers of neuronal differentiation, were readily detectable in human CaP both in vitro and in vivo. Brn-3a expression, but not Brn-3c, was significantly upregulated in >50% of tumours. Furthermore, overexpression of this transcription factor in vitro (i) potentiated CaP cell growth and (ii) regulated the expression of a neuronal gene, the Nav1.7 sodium channel, concomitantly upregulated in human CaP, in an isoform-specific manner. It is concluded that targeting Brn-3a could be a useful strategy for controlling the expression of multiple genes that promote CaP.

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Athina-Myrto Chioni

Queen Mary University of London

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A Patel

Imperial College London

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Filippo Pani

Imperial College London

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