Voltage-Gated Na+ Channel SCN5A Is a Key Regulator of a Gene Transcriptional Network That Controls Colon Cancer Invasion
01 Sep 2010-Cancer Research (American Association for Cancer Research)-Vol. 70, Iss: 17, pp 6957-6967
TL;DR: Probabilistic modeling of loss-of-function screens and microarray data established an unequivocal role of VGSC SCN5A as a high level regulator of a colon cancer invasion network, involving genes that encompass Wnt signaling, cell migration, ectoderm development, response to biotic stimulus, steroid metabolic process, and cell cycle control.
Abstract: Voltage-gated Na(+) channels (VGSC) have been implicated in the metastatic potential of human breast, prostate, and lung cancer cells. Specifically, the SCN5A gene encoding the VGSC isotype Na(v)1.5 has been defined as a key driver of human cancer cell invasion. In this study, we examined the expression and function of VGSCs in a panel of colon cancer cell lines by electrophysiologic recordings. Na(+) channel activity and invasive potential were inhibited pharmacologically by tetrodotoxin or genetically by small interfering RNAs (siRNA) specifically targeting SCN5A. Clinical relevance was established by immunohistochemistry of patient biopsies, with strong Na(v)1.5 protein staining found in colon cancer specimens but little to no staining in matched-paired normal colon tissues. We explored the mechanism of VGSC-mediated invasive potential on the basis of reported links between VGSC activity and gene expression in excitable cells. Probabilistic modeling of loss-of-function screens and microarray data established an unequivocal role of VGSC SCN5A as a high level regulator of a colon cancer invasion network, involving genes that encompass Wnt signaling, cell migration, ectoderm development, response to biotic stimulus, steroid metabolic process, and cell cycle control. siRNA-mediated knockdown of predicted downstream network components caused a loss of invasive behavior, demonstrating network connectivity and its function in driving colon cancer invasion.
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TL;DR: A broad understanding of the Vm as a bioelectrical signal in cancer cells is provided by examining several key types of ion channels that contribute to its regulation by examining the mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation.
Abstract: Membrane potential (Vm), the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. Vm is a key biophysical signal in non-excitable cells, modulating important cellular activities, such as proliferation and differentiation. Therefore, the multiplicities of various ion channels/transporters expressed on different cells are finely tuned in order to regulate the Vm. It is well established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized Vm that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of Vm has functional roles in cancer cell migration. In addition, hyperpolarization is necessary for stem cell differentiation. For example, both osteogenesis and adipogenesis are hindered in human mesenchymal stem cells under depolarizing conditions. Therefore, in the context of cancer, membrane depolarization might be important for the emergence and maintenance of cancer stem cells, giving rise to sustained tumor growth. This review aims to provide a broad understanding of the Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which Vm regulates cancer cell proliferation, migration and differentiation will be discussed. In the long term, Vm might be a valuable clinical marker for tumor detection with prognostic value, and could even be artificially modified in order to inhibit tumor growth and metastasis.
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Cites background from "Voltage-Gated Na+ Channel SCN5A Is ..."
...…functional VGSCs have been found in a number of cancer types [reviewed in Brackenbury (2012)], and suppressing VGSCs with siRNA or pharmacological agents inhibits migration and invasion (Roger et al., 2003; Fraser et al., 2005; Brackenbury et al., 2007; House et al., 2010; Yang et al., 2012)....
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TL;DR: After presenting general principles by which transport proteins affect cell migration, the role of channels and transporters involved in cell migration is discussed systematically.
Abstract: Cell motility is central to tissue homeostasis in health and disease, and there is hardly any cell in the body that is not motile at a given point in its life cycle. Important physiological processes intimately related to the ability of the respective cells to migrate include embryogenesis, immune defense, angiogenesis, and wound healing. On the other side, migration is associated with life-threatening pathologies such as tumor metastases and atherosclerosis. Research from the last ∼15 years revealed that ion channels and transporters are indispensable components of the cellular migration apparatus. After presenting general principles by which transport proteins affect cell migration, we will discuss systematically the role of channels and transporters involved in cell migration.
359 citations
TL;DR: Arguments are provided to substantiate the relation of cancer hallmarks to ion channel dysfunction to channelopathies, as disease states causally linked with inherited mutations of ion channel genes that alter channel's biophysical properties in a broader context of the disease state.
Abstract: Genomic instability is a primary cause and fundamental feature of human cancer. However, all cancer cell genotypes generally translate into several common pathophysiological features, often referre...
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TL;DR: The understanding of how patterning information is encoded in bioelectrical networks, which may require concepts from computational neuroscience, will have transformative implications for embryogenesis, regeneration, cancer, and synthetic bioengineering.
Abstract: In addition to biochemical gradients and transcriptional networks, cell behavior is regulated by endogenous bioelectrical cues originating in the activity of ion channels and pumps, operating in a wide variety of cell types. Instructive signals mediated by changes in resting potential control proliferation, differentiation, cell shape, and apoptosis of stem, progenitor, and somatic cells. Of importance, however, cells are regulated not only by their own Vmem but also by the Vmem of their neighbors, forming networks via electrical synapses known as gap junctions. Spatiotemporal changes in Vmem distribution among nonneural somatic tissues regulate pattern formation and serve as signals that trigger limb regeneration, induce eye formation, set polarity of whole-body anatomical axes, and orchestrate craniofacial patterning. New tools for tracking and functionally altering Vmem gradients in vivo have identified novel roles for bioelectrical signaling and revealed the molecular pathways by which Vmem changes are transduced into cascades of downstream gene expression. Because channels and gap junctions are gated posttranslationally, bioelectrical networks have their own characteristic dynamics that do not reduce to molecular profiling of channel expression (although they couple functionally to transcriptional networks). The recent data provide an exciting opportunity to crack the bioelectric code, and learn to program cellular activity at the level of organs, not only cell types. The understanding of how patterning information is encoded in bioelectrical networks, which may require concepts from computational neuroscience, will have transformative implications for embryogenesis, regeneration, cancer, and synthetic bioengineering.
257 citations
Cites background from "Voltage-Gated Na+ Channel SCN5A Is ..."
..., 2013; Yamashita, 2013), it is not surprising that control of ion flux (Park et al., 2008; House et al., 2010) and membrane voltage (Morokuma et al....
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...…2012; Inaba et al., 2012; Zhang et al., 2012; Cao et al., 2013; Yamashita, 2013), it is not surprising that control of ion flux (Park et al., 2008; House et al., 2010) and membrane voltage (Morokuma et al., 2008a; Blackiston et al., 2011; Chernet and Levin, 2013a, 2013b; Yang and Brackenbury,…...
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...Of interest, many forward genetic approaches have identified ion channel genes responsible for patterning phenotypes, as have unbiased transcriptional network analyses in development (Langlois and Martyniuk, 2013) and cancer (House et al., 2010)....
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TL;DR: This article concludes a series of papers concerned with the flow of electric current through the surface membrane of a giant nerve fibre by putting them into mathematical form and showing that they will account for conduction and excitation in quantitative terms.
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