Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma‑associated epileptic discharge (Review)

  • Authors:
    • Hui Dong
    • Xing‑Wang Zhou
    • Xiang Wang
    • Yuan Yang
    • Jie‑Wen Luo
    • Yan‑Hui Liu
    • Qing Mao
  • View Affiliations

  • Published online on: September 26, 2017     https://doi.org/10.3892/mmr.2017.7618
  • Pages: 7890-7900
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Abstract

Connexin (Cx)43 is a multifunction protein which forms gap junction channels and hemi‑channels. It also contains abundant binding domains which possess the ability to interact with certain Cx43‑associated proteins and therefore serve a fundamental role in various physiological and pathological functions. However, the understanding of the association between cancer and Cx43 along with Cx43‑gap junctions (GJ) remains unclear. All available data illustrate that Cx43 and its associated GJ serve important functions in cancers. The expression levels of Cx43 demonstrate a downward trend and an increase in the levels of malignancy, particularly in astrocytomas. The GJ intercellular communication activity in glioma cells can be adjusted via Cx43 phosphorylation and through the combination of Cx43 and its associated protein. Available evidence reveals Cx43 as a tumor‑inhibiting factor that suppresses glioma growth and proliferation. However, its mechanism is also regarded as complicated and ambiguous. Furthermore, it is apparent that Cx43‑GJ and the carboxyl tail may contribute to glioma growth and proliferation too. However, this valuable role could be weakened by its effects on migration and invasiveness. The detailed mechanism remains unclear and full of controversies. Cx43 can enhance the motor ability and invasiveness of astrocytic glioma cells. It is also able to influence glioma cells to detach from the tumor core to the peritumoral neocortex. This peritumoral region has recently been regarded as the basic focus of glioma‑associated seizure. Thus, Cx43 may take part in the onset and development of glioma‑associated epileptic discharge. In addition, change and increase of Cx43 expression in GJs has been observed in seizure perilesional tissue, which is associated with brain tumors. Cx43 or GJ/hemi‑channels exert enduring effects in the promotion of glioma‑associated epileptic release through direct mass effects and change of the tumor microenvironment. However, there are still a number of issues concerning this aspect that require further exploration. Cx43, as a potential treatment target against this incurable disease and its common symptom of epilepsy, requires further investigation.

Introduction

Glioma accounts for the majority of central nervous system (CNS) malignancies. They are difficult to cure and always present a poor prognosis. Histologically, glioma can be divided into four classes: Astrocytomas, oligodendrogliomas, ependymomas and mixed gliomas; diffuse gliomas are the most common. According to the 2007 World Health Organisation CNS tumor classification (1), CNS gliomas are diagnosed as grade II (diffuse astrocytoma, oligodendroglioma and oligoastrocytic tumors), grade III (anaplastic astrocytoma, oligodendroglioma and oligoastrocytic tumors) and grade IV (glioblastoma multiforme; GBM). The evidence is that high grade gliomas (III and IV) are the most common, and GBM occupies ~30% of CNS gliomas (2). Although the therapeutic strategies of glioma involve continuous improvement and adjustment, the prognosis remains unsatisfactory. The Chinese Glioma Cooperative Group statistics (3) give a median general survival time (OS) of GBM at only 14.4 months, along with 5-year OS rates at 9%. Therefore, identification of the pathogenic mechanism of glioma is important, and novel therapeutic strategies to reduce the high mortality rates of CNS malignancies are required.

In the past, researchers have concentrated on exploring the molecular mechanism of glioma, which led to the discovery of isocitrate dehydrogenase 1, telomerase reverse transcriptase and various other molecules. A CNS glioma molecular classification has been suggested (35). The present review aimed to focus on a widely-studied molecule, connexin (Cx)43, which is largely expressed in astrocytes and which participates in the construction of gap junctions (GJs) of astrocytes or astrocytes and neurons (6). Cx43 is a multifunctional protein which not only constructs gap junction channels and hemi-channels (7), but also contains numerous binding domains which can interrelate with various Cx43 linked proteins, thus serving an elemental role in several physiological and pathological functions (8). Cx43 has been reported to be involved in the inception of certain neurodegenerative diseases, including Alzheimer's and Parkinson's disease (9), epilepsy secondary to focal cortical dysplasia (FCD) (10) and amyotrophic lateral sclerosis (11), among others. The role of Cx43 in glioma has also been widely and consistently explored.

The present review aimed at introducing the role of Cx43 in glioma from the following aspects: i) Expression of Cx43 and glioma grade; ii) inhibition of glioma proliferation, but improvement in invasion and migration; iii) consideration of Cx43 and the possibility of its promoting glioma-associated epileptic discharge; and iv) disease diagnosis and therapy.

Structure and function

Cx43 is encoded by the GJA1 gene and is strongly expressed in astrocytes. Cx43 is an elemental membrane protein, which contains three intracellular regions, two extracellular loops together with multiple trans-membrane domains. The intracellular region is composed of N- and C-terminal (CT) domains along with a loop that links the trans-membrane domains. Cx43CT comprises of amino acids 232–381, a plurality of binding-domains and phosphorylation sites (12). The present aimed to review the functions of Cx43 and specifically to its functions in constructing GJs. Astrocyte Cx43 gathers adjacent to the central pore and forms connexons. Subsequently, it is coupled with neighbouring astrocytes or neurons through apposing connexons to form GJ channels, which may directly exchange the cytoplasm between coupled astrocytes and permit swapping of ions together with certain small molecules. Astrocyte Cx43 may also form membrane hemi-channels, which are directly involved in material exchange between the extracellular milieu and astrocytes or neurons (1315).

From its special structure and character (forming GJ channels and hemi-channels), Cx43 can therefore serve important physiological and pathological functions in CNS through these two routes.

GJ channels and hemi-channels

Cx43 is highly expressed in astrocytes, lasting until adulthood. In relation to neurons, the typical feature of astrocyte GJs is to support the astrocytes in couple formation. This involves ions, amino acids, metabolites and certain small molecules to exchange through the cytomembrane between astrocytes in addition to extracellular milieu (16). The principal roles of astrocyte GJs are described below.

Potassium spatial buffering

When neurons are in an energized state, a large number of K+ ions efflux into the intercellular space. Aggregation of extracellular milieu K+ activates the inwardly rectifying K+ channel, and there is an excessive intake of K+, rapidly dispersed to adjacent astrocytes or neurons through GJs. Ultimately, the K+ homeostasis of this coupling is maintained and is considered to be beneficial in maintaining the normal microenvironment, in addition to the electrical activity of neurons (17).

Signal transduction

Mediated by Cx43, astrocytes form functional group coupling astrocytes networks which may contribute to long-range signal transduction. External stimulation can spread through astrocytes via calcium waves to participate in neuromodulation (18,19). Astrocytes also contain an adenylate cycle and phosphoinositide courier delivery system, which can transmit signals through second messengers, including cyclic adenosine monophosphate (20).

Nutritional support

Astrocytes take in glucose which can be delivered to neurons through the GJ to contribute to metabolic regulation of neurons (21). Additionally, through the GJs formed by Cx43 between astrocytes and neurons, these two cell types may directly achieve material exchange along with signal transduction (22).

Specific binding domains and phosphorylation sites

Cx43 is a structurally complex protein in the C-terminal domains. There are certain binding domains which can interrelate with paired molecules to contribute to the building and regulation of cell architecture, polarity, mobility, invasion and growth (8,12,23,24). According to the reviews put forward by Giepmans (8) and Tabernero et al (12), the interactions of Cx43 when closely associated with proteins are summarized in Table I.

Table I.

Cx43-interacting proteins.

Table I.

Cx43-interacting proteins.

Protein and phosphorylation sitesAmino acidsFunctionCx43 interaction
  ZO-1379–382Tight junctions, adherens junctions, cytoskeleton build, signal transductionInversely regulates gap Junctional communication and Hemichannel activity, prevents cytoplasmic localization and malignization
  Src247,265, 274–283Phosphorylates Cx43 oncogenic activityInhibits Cx43-based GJC, Tumor suppression, but excludes the C-terminal tail for ZO-1 binding
  Tubulin234–262Combines into dimers, assembles microtubulesModulates cell polarity, Motility and directional cell migration
  Cadherins, catenin and actin Adherens junctions, β-catenin modulates Wnt-mediated gene transcriptionModulate cell motility
  CK1, PKA MAPK, PKG, PKC Phosphorylates Cx43Upregulate Cx43 assembly Inhibit Cx43-based GJC

[i] Cx, connexin; ZO, zonula occludens; CK, creatine kinase; PK, protein kinase; MAPK, mitogen-activated protein kinase; GJC, gap junction communication; Src, proto-oncogene tyrosine-protein kinase.

Expression of Cx43 and glioma grade

In standard physiological states, Cx43 is prominently expressed in astrocytes. However, when the cell becomes malignant, the expression of Cx43 is downregulated. Thus, Sin et al (25) suggested that decreased Cx43 expression is accompanied by greater proliferation and malignancy of tumors. By studying the expression of Cx43 in human glioma and normal tissue microarray slides, mainly by western blot analysis and immunohistochemical staining, Sin et al (26) and Ye et al (27) noted a reduced expression of Cx43 in the tumor center as the glioma malignancy increased. Grade I and II primary astrocyte gliomas may express an enhanced immunoreactivity compared with normal brain tissue. However, it lacks the distinct disrupting staining of normal astrocytes. In high grade glioma, the expression of Cx43 is commonly reduced compared with normal tissues. It is also decreased in the majority of GBM, where the expression of Cx43 protein is insignificant (12,26,27). However, Crespin et al (28) did not share this point of view. First, in spite of the modest inverse association between tumor grade and Cx43 expression, over half of glioblastomas still express Cx43. Secondly, the expression of Cx43 between grade II and III astrocytes gliomas is not significantly different. Additionally, the various expression levels of Cx43 between grade III astrocytoma and oligodendroglioma suggest that Cx43 can act as a marker in discriminating against grade III oligodendroglioma in addition to astrocytoma. In reality, expression of Cx43 differs within the same tumor. For instance, Cx43 is rarely labelled at the membranes and in the cytoplasm of GBM cells. Nevertheless, it is abundant at the plasma membrane of reactive astrocytes in the surrounding tumor mass (26,28). The notable features of these areas are tumor cell infiltration and reactive astrocytes (26,29). The peritumor cortex not infiltrated by glioma cells may increase Cx43 immunoreactivity and reactive astrocytes. However, this appearance is perhaps associated with the existence of epileptic seizures (30). Besides, this conclusion may not be valid; the origin of glioma associated seizure stemming from the peritumor area and infiltration by glioma cells has been widely accepted (31). Therefore, the above conclusion may require further elucidation. In addition, due to the driving factor of glioma pathogenesis partly being ascribed to cancer stem cells (CSCs), Hitomi et al (32) explored the expression levels of Cx43 in GBM glioma stem cells (GSCs). The results indicated that Cx43 is predominantly expressed in non-GSCs while Cx46 is expressed in CSCs. Yu et al (33) further identified lower expression of Cxs and the loss of GJ-like structures together with dysfunction of GJ intracellular function in GSCs.

Cx43 and glioma proliferation, invasion and migration

Glial tumors, as the most common supratentorial neoplasms, are particularly difficult to cure. This is made more difficult with a poor prognosis, largely due to tumor cell migration, invasion and proliferation. This section briefly introduces the role of Cx43 in glioma migration, invasion and proliferation in addition to its possible mechanism. Previous studies (12,25,34,35) focused more on the association between Cx43 and cancer, including astrocytic glioma. However, more recent studies have proposed novel insights. The present review aimed to examine the association of Cx43 and astrocytic glioma in light of previous reviews and new findings.

Inhibition of glioma growth and proliferation

Thus far, the majority of studies have indicated that Cx43, as a tumor suppressor factor, inhibits astrocytoma growth and proliferation in a variety of ways. Treatments that regulate Cx43 expression, including tolbutamide (36,37), selective β2-AR agonist (38), 17-β estradiol (E2) (39), ciliary neurotrophic factor (40) and low doses of γ-radiation (41) have been verified. Cx43 may therefore inhibit glioma growth and proliferation (Table II).

Table II.

Cx43 and the regulation of glioma proliferation and growth.

Table II.

Cx43 and the regulation of glioma proliferation and growth.

Author (date)ModelRegulated proteinsRegulatory mechanism Regulation of Cx43Effect on cell growth and proliferation(Refs.)
Moinfar et al (2016)17-β estradiol (E2) treated-C6 cellEstradiol ReceptorsCx43↓Proliferation↑(39)
Ye et al (2015)PKC, MAPK, and PTK inhibitors treated-U251 cellPKC, MAPK, and PTKCx43↓ and p-Cx43↓Proliferation↓(27)
Mostafavi et al (2014)Selective β2-AR agonist treated-1321N1 astrocytoma cellsβ2-AR, cAMP-EpacCx43↑Proliferation↓(38)
Jin et al (2013) miR-125b-transfected U87 and U251 glioma cells Cx43↓Proliferation↑(64)
Ghosh et al (2014)Low doses of γ-radiation treated-U87 cellsERK-1/2, p38-MAPK activationCx43↑and GJ↑Proliferation↓(41)
Hao et al (2012)AS-miR-221/222 transfect U251 cells Cx43↑Proliferation↓(65)
Zhang et al (2010)Ad-bFGF-siRNA transfect U251 cells Cx43↑Proliferation↓(67)
Ozog et al (2002)CNTFR-α treated C6 glioma cellsCNTFRαCx43↑and GJ↑Proliferation and growth↓(40)
Sanchez-Alvarez et al (2001)Tolbutamide-treated C6p21, p27, Rbp,Cx43↑and GJ↑Proliferation and growth↓(36)
Sanchez-Alvarez (2006)glioma cells (37)
P.A. Robe et al (2000)TGF-β1-treated C6 glioma cells p-Cx43↓and GJ↓Proliferation↑(66)
Effect on the GSCs phenotype
Shi-Cang Yu et al (2012)Reconstitution of Cx43 GSCsE-CadherinWnt/b-Catenin PathwayProliferation↓(33)
Gangoso et al (2014)Reconstitution of Cx43 GSCsc-Src, Sox2, Id1, cadherinc-Src activity↓→Id1↓→ Sox2↑→ GSC self-renewal↓Proliferation↓(42)
Intervention in cell metabolism
Herrero-Gonzalez et al (2009)Transfection of Cx43-siRNA astrocytesEndothelin-1glucose uptake ↑Proliferation↑(43)
Gang Li et al (2015)Sprague-Dawley ratsCx43 and AQP4Cx43↑→edema (44)
Kolar et al (2015)GL261 glioma cells and mouseCx43 and Podoplanin Podoplanin→ischemia (45)
Wei Zhang et al (2003)T98G-Cx43 cellsCx43, GJ, VEGFVEGF high expression in T98G-Cx43 cells (46)
Ruochun Huang (2002)Cx43-transfected cells U251Cx43, MCP-1Cx43 downregulates MCP-1, then inhibits angiogenesisProliferation↓(47)
Participation in cell cycle regulation
Sanchez-Alvarez et al (2006)Tolbutamide treated C6p21, p27, Rbp,p21, p27↑→Rbp↓→Proliferation and growth ↓(37)
Tabernero et al (2006)glioma cellsE2F, cyclin EE2F↓→cyclin E↓ (51)
Geng Y et al (1996) (52)
Regulated growth factor and proliferation related protein
Sin et al (2008)Cx43 expression C6 cellCCN1↑ Proliferation ↑(53)
Sin et al (2008) CCN3↑ Proliferation ↓(53)
Fu et al (2004) (54)
Bradshaw et al (1993) Osteopontin↑ Proliferation ↓(55)
Bradshaw et al (1993) IGFBP4↑, IGF-1↓, (56)
Goldberg et al (2000) IGFP↓, bFGFK, PDGF↓ Proliferation ↓(57)
Xia et al (2003) (58)
González-Sánchez et al (2016)Cx43 expression C6 cellPTEN, Cskc-Scr activity↓Proliferation ↓(59)
Ghosh et al (2014)Knock-down of Cx43 expression U87 cellp38, ERK-1/2p38, ERK-1/2 activity↓Proliferation ↑(41)

The specific mechanism of how Cx43 influences glioma proliferation remains to be elucidated. However, the following mechanisms may contribute to the regulation of Cx43 in glioma proliferation (Table II).

Affecting the GSC phenotype

GSCs are cells which possess the capability for self-renewal and are considered among the driving factors in glioma pathogenesis. Notably, Cx43 is mostly expressed in non-GSCs, and the expression of Cx43 in GSCs is low (32,33). When reconstituting Cx43 in GSCs, the tumorigenicity of GSCs is inhibited, while self-renewal and proliferation are delayed. Yu et al (33) described the interaction of Cx43 with epithelial cadherin as having an influence on CSC phenotype through the Wnt/β-Catenin signaling pathway; this may be a potential mechanism. Additionally, as a proto-oncogene, Scr and its interaction with Cx43 are also considered to be involved in glioma proliferation regulation. Tabernero et al (12) hypothesized c- proto-oncogene tyrosine-protein kinase (Src) inhibiting Src activity as the main initiator of Cx43. It has an effect on GSCs: Gangoso et al (42) transfected Cx43 to GSCs and identified that Ki-67-positive glioma cells decreased and expressed Cx43, while downregulating DNA-binding protein inhibitor (a transcriptional regulator) expression via inhibition of Src activity. Consequently, there was reduced (sex determining region Y)-box (Sox2) expression, downregulation of Sox2 and a reduction in GSC self-renewal (Fig. 1).

Intervention in cell metabolism

Cancer cells detect rapid proliferation by adapting to metabolic environmental changes. For glioblastoma, uptake of enough glucose or the transformation of metabolism strategies to enable the cells to survive in a hypoxic tumor microenvironment is a key precondition for the growth and proliferation of GBM cells. Cx43 increases GJ channel and hemi-channel coupling, enabling the exchange of ions, amino acids, metabolites and certain small molecules through the cytomembrane and between astrocytes, together with the extracellular milieu. Notably, that inhibition of GJs or downregulation of Cx43 expression leads to an increase in glucose uptake (43). Accordingly, this is the main energy substance for glioma cells. Cx43 and its associated GJs are capable of influencing the peritumoral microenvironment of edema (44), ischemia (45) and angiogenesis (46,47), and of interfering with glioma cell metabolism. This may further influence glioma growth and proliferation. Equally, deletion of Cx43 in astrocytes has been observed to inhibit oligodendrocyte precursor cell proliferation by reducing matrix glucose levels (48).

Participation in cell cycle regulation

Cx43 may deter the cell cycle from G1 to S-phase or M-phase (49,50). It is also capable of rebuilding Cx43 in glioma cells which could delay the progression of cells from G0/G1 to S-phase (37). Cx43 has been observed to increase the expression of p21 and p27, and then weaken retinoblastoma phosphorylation (pRb) (37,51). pRb phosphorylation promotes the release of E2 transcription factor, which is associated with the expression of cyclin E (52). Cx43 possibly regulates the glioma cell cycle by decreasing pRb phosphorylation, subsequently inhibiting cyclin E expression.

Regulation of growth factor and proliferation-associated proteins

Several growth factors (GFs) may also affect the growth and proliferation of cells. Previous research indicates that Cx43 can regulate certain GF expression levels. For instance, Cx43-transfected glioblastoma cells (U251) downregulate the expression of MCP-1, a factor that can further promote angiogenesis, and then suppress glioma cell proliferation (47). Restored Cx43 expression in C6 glioma cells was also determined as being able to upregulate secretory proteins cysteine-rich angiogenic inducer (CCN)1 together with CCN3 expression (53). Notably, over-expression of CCN3 and its interaction with Cx43 are conducive to a decrease in glioma growth rate. Overexpression of CCN1 exhibits an opposite function (53,54). Similarly, Cx43 transfected to C6 rat glioma cells also regulates the expression of secreted proteins. For instance, it decreases insulin-like growth factor protein, basic fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor 1 and N-methylpurine DNA glycosylase-E8 protein expression levels while increasing CCN3, insulin-like growth factor-binding protein 4 and osteopontin levels (5558); this is the common outcome of suppressed glioma cell proliferation. Additionally, Cx43 adjusts certain kinase activities to affect the growth and proliferation of cells. For instance, Cx43 recruits phosphatase and tensin homolog and C-terminal Src kinase to inhibit c-Src activity (59). Additionally, c-Src equally combines with the C-terminal of Cx43 to reduce the oncogenic activity of c-Src (12,42,60). Cx43 can also modify the activity of other proliferation-associated proteins, including p38, extracellular signal-regulated kinases-1/2 (44) and zonula occludens (ZO)-1 (12), to affect the proliferation of glioma cells. Suzhi et al (61) noted that Cx43 could transfer microRNA (miR)-124-3p between coupling cells and improve the antiproliferative ability of miR-124-3p.

Regulation of gene expression

Cx43 regulates gene expression, perhaps as a potential mechanism that influences glioma cell proliferation. However, there are not enough relevant studies to support this hypothesis. Dang et al (62) identified that the carboxyl-tail of Cx43 localizes to the nucleus and inhibits cell growth. Mennecier et al (63) also noted that Cx43 may enter into the nucleus of glioma cell lines. Thus, it may be hypothesized that Cx43 regulates gene expression directly or indirectly to affect the proliferation and growth of glioma cells.

Controversy of the effect of Cx43 on glioma cell invasion and migration

From the above discussion, it can be deduced that Cx43 is a tumor-suppression factor. However, this valuable role can be weakened by its effects on migration and invasiveness. The majority of the literature reports that Cx43 enhances glioma invasion (24,26,68,69), while certain studies report the inhibitory action of Cx43 in glioma invasion and migration (65,70,71). Although Cx43 is present in a lower expression state in a malignant glioma mass, a high expression of Cx43 is detected at the plasma membrane of the reactive astrocytes around the peritumor area (26,28), and in tumor cell infiltration and reactive astrocytes. In this area, malignant glioma cells form functional GJ communication between themselves and astrocytes (28,72), establishing a tight cell network (71). This may be the structural basis of the effect of Cx43 effect the invasion and migration of malignant glioma cells by GJ-dependent and independent mechanisms.

GJ-dependent mechanisms

Reduction of GJ activity has been reported to improve cell migration (71,73). However, more studies report that the overexpression of Cx43 encourages glioma cell migration and invasion in a GJ channel-dependent manner (69,72,74). Aftab et al (71) demonstrated that downregulation of Cx43 expression in the U118 human glioma cell line is a way to increase migration by reducing cell-extracellular matrix adhesion, and change the migration pattern from collective to single cell. It was also demonstrated that Cx43-GJ serves more prominent roles in mediating migration and invasion behaviors compared with the C-terminal tail interaction. Functional GJ coupling also contributes to long-range signal transduction, and adjusts the formation of calcium waves (18,19,41,75). Additionally, it transmits signals through second messengers (20). Through these ways, Cx43-GJ may promote the transformation of malignant astrocytes by regulating a glioma-associated signaling pathway. Furthermore, Cx43 located in lipid raft microdomains can also regulate homocellular and heterocellular GJ communications between cancer and stroma cells, and can control the tumor phenotype (68,69). Consequently, such actions may influence glioma invasion behaviors. Additionally, a Cx43-constructed glioma-astrocyte GJ can modulate glioma invasive behavior by direct transfer of miRs (72). Cx43-GJ is involved in tumor microtube-mediated cell-to-cell communication and influences the motility of glioma cells (75).

GJ-independent mechanisms

Cx43 promotes glioma cell invasion through GJ-reliant mechanisms, which are not always recognized. Sin et al (26) suggested that astrocytic Cx43 may aid glioma cells to detach from the glioma core. However, Cx43 may mediate glioma invasion solely in a GJ-independent manner since the expression of Cx43-T154A has demonstrated no effect on glioma invasion (26). This conclusion contradicts the previously discussed findings in the present review. Certain Cx43-associated proteins merge with Cx43 extracellular loops or C-terminal regions to improve adhesive connections or to regulate cytoskeletal dynamics, which alter the structure of Cx43 to facilitate malignant glioma cell invasion and migration by independent mechanisms. A wound healing motility assay indicated that the C-terminal of Cx43 is required for Cx43-mediated C6 glioma cell motility (24). For instance, Cx43 interacts with ZO-1 protein, which could prevent the cytoplasmic localization and lead to glioma cell invasion (12,76). Cx43 interacts with other cytoskeleton proteins and tight junctions or adherens junctions associated with proteins, including tubulin, cadherins, catenin and actin, to modulate polarity, motility and directional migration of cells (12,24,77,78). In addition, Cx43 interacts with c-Src and inhibits Src activity, sequentially modulating cell polarity, motility and invasion through several signaling pathways (Fig. 1) (12,79,80). In brief, there is no consensus on the effect of Cx43 on glioma invasion and migration, and the detailed mechanism remains unclear.

Cx43 may promote glioma-associated epileptic discharge

The association between Cx43/-GJ and epilepsy has widely been studied in the last 20 years. Earlier studies failed to consider that Cx43 is associated with epilepsy, since expression of Cx43 had not identified significant differences between epileptogenic and nonepileptogenic tissues, in living tissue assays (81) and animal models (82). Nevertheless, the majority of studies have identified Cx43 as capable of participating in the genesis and development of certain types of epilepsy. For instance, Cx43 is increasingly expressed in the hippocampus tissue of patients with refractory temporal lobe epilepsy (83,84) and in FCD type IIB (10). Cx43/-GJ were also altered in either lithium pilocarpine-induced epilepsy (84) or in kainic-acid-induced status epilepticus models (85). Notably, the inhibition of the Cx43 GJ with carbenoxolone can shorten the duration of seizures and reduce the amplitude of the seizure discharges (86). In view of the above, Cx43 may be to be associated with the genesis and development of certain types of epilepsy, in addition to glioma-associated epilepsy.

Glioma-associated epilepsy may be defined as seizure which directly arises from the existence of supratentorial glioma. It is the presenting feature in ≤87% of low-grade gliomas and ≤50% of gliomas overall (87). Epilepsy is usually the initial symptom of glioma patients and a significant factor affecting their post-operative quality of life (88). However, the detailed mechanism of glioma-associated epilepsy remains to be elucidated. It may be a combination of direct mass effects and the change of the tumor microenvironment.

Overall, Cx43 is highly expressed in peritumoral astrocytes (29) which facilitate glioma cells detachment from the tumor core (26). Glioma cells invade the neocortex structure, a special peritumoral region where single neurons are bounded by very few or a single tumor cell (89). This peritumoral region has recently been considered as the basic focus of glioma-associated seizure (31,90,91). GJ changes (89) and the increase of Cx43 expression (30) have been identified in the perilesional tissue of seizures associated with brain tumors. GJ or Cx43-glial coupling may explain glioma-induced epileptogenesis (92). Cx43 and its associated GJ are capable of influencing the peritumoral microenvironment, including edema (44), ischemia (45) and angiogenesis (46,47) which may induce epileptic discharge through direct effects of mass. Cx43-GJ is involved in the generation of sharp wave-ripple (34). It propagates neuronal activity through long-range signal transduction and Ca+ waves, then promotes a synchronized discharge of neurons (93). Cx43-GJ can also influence seizure discharge by regulating K+ redistribution and neuronal energy supply (94). Peritumoral reactive astrocytes can highly express Cx43. Cx43, in this context, may serve a predominant role in the regulation of neurotransmitters, including glutamate. First, Cx43-hem channels/GJ in astrocytes can control glutamate (95,96), release ATP (96) and sustain glutamatergic synaptic efficacy (97). Second, Cx43 knockdown may raise cortical glutamate transporter (GLT)-1 in addition to glutamate aspartate transporter (GLAST) protein expression levels, and control transcription and translation of glial glutamate transporters excitatory amino acid transporter (EAAT)-1 and EAAT-2 (98). Similarly, blocking the gap junction has been reported to suppress transcriptional activity of GLT-1 promoter, but increase GLAST gene transcription (99). The spinal astrocytic Cx43 has also been reported to be capable of activating N-methyl D-aspartate receptors (100) and elemental ionotropic glutamate receptors in the postsynaptic membrane (101). In essence, peritumoral Cx43 high immunoreactivity is mainly on the reactive astrocytes (29), and demonstrates Cx43 to be potentially associated with astrocyte reactivity. A recent study observed that reactive astrocytes not only limit glutamate uptake, but also inhibit the production of gamma-aminobutyric acid. Furthermore, this leads to a loss of inhibition and an increase in neuronal excitability (102). Even so, it can be hypothesized that Cx43 can possibly promote glioma-associated epileptic discharge through these aforementioned ways. The relevant studies remain scarce, and further studies are required to identify the exact mechanism of Cx43 in glioma-associated epilepsy.

In summary, the special microenvironment of glioma (tumor cell infiltration and high expression of Cx43 in reactive astrocytes) may identify why glioma patients present with epilepsy and why they possess a favorable prognosis but are prone to relapses (101). Cx43 also presents in temozolomide resistance and resistance to radiotherapy in glioblastoma cells. The peritumoral region has been considered the basic focus of glioma-associated seizure (31). It is hypothesized that early stage glioma cells highly express Cx43, and migrate and invade the host parenchyma with a low proliferation index (26).

Facilitating disease diagnosis and therapy

Investigating biomolecules is useful facilitate disease diagnosis and therapy. The value of Cx43 in glioma diagnosis and therapy is beginning to be recognized. Abakumova (103) demonstrated that the Cx43-targeted T1 contrast agent may efficiently visualize glioma C6 and its borders in vitro and in vivo. MAbE2Cx43 s was covalently associated with the Phthalosens derivative photosensitizer delivery of fluorescent agents to the glioma tissue. This may be valuable in demonstrating the optimal border and increase the extent of resection due to improved visualization of the glioma (104). Similarly, Cx43/-GJ may help brain tumor cells to interconnect a functional and resistant network (75), which confer temozolomide resistance (105108) and radiotherapy resistance (75) in glioblastoma cells. The Cx43-antibody MAbE2Cx43 has been demonstrated to be potentially part of a combined therapy for poorly differentiated gliomas (108).

Conclusion

In regular physiological conditions, Cx43 is highly expressed in astrocytes. However, this expression is restrained when the malignant transformation of astrocytes and the levels of Cx43 are reduced, along with an increase in the degrees of malignancy in astrocytomas. The association between the expression of Cx43 and degrees of glioma implicates Cx43 as a tumor suppressor, inhibiting glioma cell proliferation. However, the majority of data have indicated that Cx43 may enhance the motor ability and invasiveness of astrocytic glioma cells, and to facilitate glioma cell separation from the tumor core to the surroundings. This can be interpreted as Cx43 in the early stages of glioma progression, with a relatively low proliferative index of glioma cells, predisposing glioma cells to migrate and integrate with the host parenchyma (26). Simultaneously, reactive astrocytes and the tumor cell invade into peritumoral tissue comprising the significant surrounding microenvironment, making an ideal environment for epileptic discharge. It is undoubtable that Cx43 or GJ /hemi-channels have a contribution in promoting glioma-associated epileptic discharge through direct mass effects and the change of tumor microenvironment, particularly the effect in excitatory neurotransmitter-glutamate regulation. Notably, Cx43 expression is considerably upregulated in astrocytes reactive due to tissue damage during surgery. This could promote tumor proliferation, in addition to migration (109), and then facilitate glioma recurrence following resection (110). This can partially explain post-operative epileptic seizures in glioma patients and those with no epilepsy prior to surgery.

Previously published reviews (12,25) have presented the roles of Cx43 in glioma proliferation in two mechanisms: GJ-dependent and GJ-independent. To the best of our knowledge, the present review was the first to introduce the exact mechanism of these functions and the roles of Cx43 in glioma-associated epilepsy. Certainly, there are still a number of challenges that require further exploration. If Cx43 is associated with the prognosis of glioma patients, then its potential as a treatment target requires further study. Peritoneal tissue which highly express Cx43 is involved in the incidence of glioma and is associated with epilepsy; thus, should be explored further.

In conclusion, the roles of Cx43 in glioma proliferation, in the present review, can be directed to the association between glioma and epilepsy. A number of identifiable challenges in this current review can be the subject of further studies. More importantly, future studies could also aid understanding of any other ways through which Cx43 and other expressions are associated with incidences of glioma and with epilepsy.

References

1 

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Shen F, Wu CX, Yao Y, Peng P, Qin ZY, Wang Y, Zheng Y and Zhou LF: Transition over 35 years in the incidence rates of primary central nervous system tumors in Shanghai, China and histological subtyping based on a single center experience spanning 60 years. Asian Pac J Cancer Prev. 14:7385–7393. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, et al: CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett. 375:263–273. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, et al: Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell. 164:550–563. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Foote MB, Papadopoulos N and Diaz LA Jr: Genetic Classification of Gliomas: Refining Histopathology. Cancer Cell. 28:9–11. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Almad AA, Doreswamy A, Gross SK, Richard JP, Huo Y, Haughey N and Maragakis NJ: Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis. GLIA. 64:1154–1169. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Sharrow AC, Li Y, Micsenyi A, Griswold RD, Wells A, Monga SS and Blair HC: Modulation of osteoblast gap junction connectivity by serum, TNFalpha, and TRAIL. Exp Cell Res. 314:297–308. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Giepmans BN: Gap junctions and connexin-interacting proteins. Cardiovasc Res. 62:233–245. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Freitas-Andrade M and Naus CC: Astrocytes in neuroprotection and neurodegeneration: The role of connexin43 and pannexin1. Neuroscience. 323:207–221. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Garbelli R, Frassoni C, Condorelli DF, Salinaro A Trovato, Musso N, Medici V, Tassi L, Bentivoglio M and Spreafico R: Expression of connexin 43 in the human epileptic and drug-resistant cerebral cortex. Neurology. 76:895–902. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Almad AA, Doreswamy A, Gross SK, Richard JP, Huo Y, Haughey N and Maragakis NJ: Connexin 43 in Astrocytes Contributes to Motor Neuron Toxicity in Amyotrophic Lateral Sclerosis. Glia. 64:1154–1169. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Tabernero A, Gangoso E, Jaraíz-Rodríguez M and Medina JM: The role of connexin43-Src interaction in astrocytomas: A molecular puzzle. Neuroscience. 323:183–194. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Giaume C, Fromaget C, Aoumari A, Cordier J, Glowinski J and Gros D: Gap junctions in cultured astrocytes: Single-channel currents and characterization of channel-forming protein. Neuron. 6:133–143. 1991. View Article : Google Scholar : PubMed/NCBI

14 

Giaume C, Koulakoff A, Roux L, Holcman D and Rouach N: Astroglial networks: A step further in neuroglial and gliovascular interactions. Nat Rev Neurosci. 11:87–99. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Giaume C, Leybaert L, Naus CC and Sáez JC: Connexin and pannexin hemichannels in brain glial cells: Properties, pharmacology, and roles. Front Pharmacol. 4:882013. View Article : Google Scholar : PubMed/NCBI

16 

Bennett MV, Contreras JE, Bukauskas FF and Sáez JC: New roles for astrocytes: Gap junction hemichannels have something to communicate. Trends Neurosci. 26:610–617. 2003. View Article : Google Scholar : PubMed/NCBI

17 

Nagy JI and Rash JE: Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Brain Res Rev. 32:29–44. 2000. View Article : Google Scholar : PubMed/NCBI

18 

Scemes E: Components of astrocytic intercellular calcium signaling. Mol Neurobiol. 22:167–179. 2000. View Article : Google Scholar : PubMed/NCBI

19 

van den pol AN, Finkberiner SM and Cornell-Bell AH: Calcium excitability and oscillations in suprachiasmatic nucleus neurons and glia in vitro. J Neurosci. 12:2648–2664. 1992.PubMed/NCBI

20 

Mehta PP, Yamamoto M and Rose B: Transcription of the gene for the gap junctional protein connexin43 and expression of functional cell-to-cell channels are regulated by c AMP. Mol Biol Cell. 3:839–850. 1992. View Article : Google Scholar : PubMed/NCBI

21 

Giaume C, Tabernero A and Medina JM: Metabolic trafficking through astrocytic gap junctions. Glia. 21:114–123. 1997. View Article : Google Scholar : PubMed/NCBI

22 

Nedergaard M: Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science. 263:1768–1771. 1994. View Article : Google Scholar : PubMed/NCBI

23 

Zhang W, Nwagwu C, Le DM, Yong VW, Song H and Couldwell WT: Increased invasive capacity of connexin43-overexpressing malignant glioma cells. J Neurosurg. 99:1039–1046. 2003. View Article : Google Scholar : PubMed/NCBI

24 

Bates DC, Sin WC, Aftab Q and Naus CC: Connexin43 Enhances Glioma Invasion by a Mechanism Involving the Carboxy Terminus. GLIA. 55:1554–1564. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Sin WC, Crespin S and Mesnil M: Opposing roles of connexin43 in glioma progression. Biochim Biophys Acta. 1818:2058–2067. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Sin WC, Aftab Q, Bechberger JF, Leung JH, Chen H and Naus CC: Astrocytes promote glioma invasion via the gap junction protein connexin43. Oncogene. 35:1504–1516. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Ye XY, Jiang QH, Hong T, Zhang ZY, Yang RJ, Huang JQ, Hu K and Peng YP: Altered expression of connexin43 and phosphorylation connexin43 in glioma tumors. Int J Clin Exp Pathol. 8:4296–4306. 2015.PubMed/NCBI

28 

Crespin S, Fromont G, Wager M, Levillain P, Cronier L, Monvoisin A, Defamie N and Mesnil M: Expression of a gap junction protein, connexin43, in a large panel of human gliomas: New insights. Cancer Med. 5:1742–1752. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Kolar K, Freitas-Andrade M, Bechberger JF, Krishnan H, Goldberg GS, Naus CC and Sin WC: Podoplanin: A marker for reactive gliosis in gliomas and brain injury. J Neuropathol Exp Neurol. 74:64–74. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Aronica E, Gorter JA, Jansen GH, Leenstra S, Yankaya B and Troost D: Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex. Acta Neuropathol. 101:449–459. 2001.PubMed/NCBI

31 

Pallud J, Le van Quyen M, Bielle F, Pellegrino C, Varlet P, Cresto N, Baulac M, Duyckaerts C, Kourdougli N, Chazal G, et al: Cortical GABAergic excitation contributes to epileptic activities around human glioma. Sci Transl Med. 6:244ra892014. View Article : Google Scholar : PubMed/NCBI

32 

Hitomi M, Deleyrolle LP, Mulkearns-Hubert EE, Jarrar A, Li M, Sinyuk M, Otvos B, Brunet S, Flavahan WA, Hubert CG, et al: Differential connexin function enhances self-renewal in glioblastoma. Cell Rep. 11:1031–1042. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Yu SC, Xiao HL, Jiang XF, Wang QL, Li Y, Yang XJ, Ping YF, Duan JJ, Jiang JY, Ye XZ, et al: Connexin 43 reverses malignant phenotypes of glioma stem cells by modulating E-cadherin. Stem Cell. 30:108–120. 2012. View Article : Google Scholar

34 

Moinfar Z, Dambach H and Faustmann PM: Influence of drugs on gap junctions in glioma cell lines and primary astrocytes in vitro. Front Physiol. 5:1862014. View Article : Google Scholar : PubMed/NCBI

35 

Naus CC and Laird DW: Implications and challenges of connexin connections to cancer. Nat Rev Cancer. 10:435–441. 2010. View Article : Google Scholar : PubMed/NCBI

36 

Sánchez-Alvarez R, Tabernero A, Sánchez-Abarca LI, Orfao A, Giaume C and Medina JM: Proliferation of C6 glioma cells is blunted by the increase in gap junction communication caused by tolbutamide. FEBS Lett. 509:1–206. 2001. View Article : Google Scholar : PubMed/NCBI

37 

Sánchez-Alvarez R, Paíno T, Herrero-González S, Medina JM and Tabernero A: Tolbutamide reduces glioma cell proliferation by increasing connexin43, which promotes the up-regulation of p21 and p27 and subsequent changes in retinoblastoma phosphorylation. Glia. 54:125–134. 2006. View Article : Google Scholar : PubMed/NCBI

38 

Mostafavi H, Khaksarian M, Joghataei MT, Soleimani M, Hassanzadeh G, Eftekhari S, Soleimani M, Mousavizadeh K, Estiri H, Ahmadi S and Hadjighassem MR: Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac. Mol Med Rep. 9:2405–2410. 2014. View Article : Google Scholar : PubMed/NCBI

39 

Moinfar Z, Dambach H, Schoenebeck B, Förster E, Prochnow N and Faustmann PM: Estradiol receptors regulate differential connexin 43 expression in F98 and C6 glioma cell lines. PLoS One. 11:e01500072016. View Article : Google Scholar : PubMed/NCBI

40 

Ozog MA, Bechberger JF and Naus CC: Ciliary neurotrophic factor (CNTF) in combination with its soluble receptor (CNTFRalpha) increases connexin43 expression and suppresses growth of C6 glioma cells. Cancer Res. 62:3544–3548. 2002.PubMed/NCBI

41 

Ghosh S, Kumar A, Tripathi RP and Chandna S: Connexin-43 regulates p38-mediated cell migration and invasion induced selectively in tumour cells by low doses of γ-radiation in an ERK-1/2-independent manner. Carcinogenesis. 35:383–395. 2014. View Article : Google Scholar : PubMed/NCBI

42 

Gangoso E, Thirant C, Chneiweiss H, Medina JM and Tabernero A: A cell-penetrating peptide based on the interaction between c-Src and connexin43 reverses glioma stem cell phenotype. Cell Death Dis. 5:e10232014. View Article : Google Scholar : PubMed/NCBI

43 

Herrero-González S, Valle-Casuso JC, Sánchez-Alvarez R, Giaume C, Medina JM and Tabernero A: Connexin43 is involved in the effect of endothelin-1 on astrocyte proliferation and glucose uptake. Glia. 57:222–233. 2009. View Article : Google Scholar : PubMed/NCBI

44 

Li G, Liu X, Liu Z and Su Z: Interactions of connexin 43 and aquaporin-4 in the formation of glioma-induced brain edema. Mol Med Rep. 11:1188–1194. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Kolar K, Freitas-Andrade M, Bechberger JF, Krishnan H, Goldberg GS, Naus CC and Sin WC: Podoplanin: A marker for reactive gliosis in gliomas and brain injury. J Neuropathol Exp Neurol. 74:64–74. 2015. View Article : Google Scholar : PubMed/NCBI

46 

Zhang W, DeMattia JA, Song H and Couldwell WT: Communication between malignant glioma cells and vascular endothelial cells through gap junctions. J Neurosurg. 98:846–853. 2003. View Article : Google Scholar : PubMed/NCBI

47 

Huang R, Lin Y, Wang CC, Gano J, Lin B, Shi Q, Boynton A, Burke J and Huang RP: Connexin 43 suppresses human glioblastoma cell growth by down-regulation of monocyte chemotactic protein 1, as discovered using protein array technology. Cancer Res. 62:2806–2812. 2002.PubMed/NCBI

48 

Niu J, Li T, Yi C, Huang N, Koulakoff A, Weng C, Li C, Zhao CJ, Giaume C and Xiao L: Connexin-based channels contribute to metabolic pathways in the oligodendroglial lineage. J Cell Sci. 129:1902–1914. 2016. View Article : Google Scholar : PubMed/NCBI

49 

Zhang YW, Nakayama K, Nakayama K and Morita I: A novel route for connexin 43 to inhibit cell proliferation: Negative regulation of S-phase kinase-associated protein (Skp 2). Cancer Res. 63:1623–1630. 2003.PubMed/NCBI

50 

Kamei J, Toyofuku T and Hori M: Negative regulation of p21 by beta-catenin/TCF signaling: A novel mechanism by which cell adhesion molecules regulate cell proliferation. Biochem Biophys Res Commun. 312:380–387. 2003. View Article : Google Scholar : PubMed/NCBI

51 

Tabernero A, Sánchez-Alvarez R and Medina JM: Increased levels of cyclins D1 and D3 after inhibition of gap junctional communication in astrocytes. J Neurochem. 96:973–982. 2006. View Article : Google Scholar : PubMed/NCBI

52 

Geng Y, Eaton EN, Picón M, Roberts JM, Lundberg AS, Gifford A, Sardet C and Weinberg RA: Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene. 12:1173–1180. 1996.PubMed/NCBI

53 

Sin WC, Bechberger JF, Rushlow WJ and Naus CC: Dose-dependent differential upregulation of CCN1/Cyr61 and CCN3/NOV by the gap junction protein connexin43 in glioma cells. J Cell Biochem. 103:1772–1782. 2008. View Article : Google Scholar : PubMed/NCBI

54 

Fu CT, Bechberger JF, Ozog MA, Perbal B and Naus CC: CCN3 (NOV) interacts with connexin43 in C6 glioma cells: Possible mechanism of connexin-mediated growth suppression. J Biol Chem. 279:36943–36950. 2004. View Article : Google Scholar : PubMed/NCBI

55 

Bradshaw SL, Naus CC, Zhu D, Kidder GM, D'Ercole AJ and Han VK: Alterations in the synthesis of insulin-like growth factor binding proteins and insulin-like growth factors in rat C6 glioma cells transfected with a gap junction connexin43 cDNA. Regul Pept. 48:99–112. 1993. View Article : Google Scholar : PubMed/NCBI

56 

Bradshaw SL, Naus CC, Zhu D, Kidder GM and Han VK: Insulin-like growth factor binding protein-4 gene expression is induced by transfection of gap junction connexin43 gene in a C6 glioma cell line. Growth Regul. 3:26–29. 1993.PubMed/NCBI

57 

Goldberg GS, Bechberger JF, Tajima Y, Merritt M, Omori Y, Gawinowicz MA, Narayanan R, Tan Y, Sanai Y, Yamasaki H, et al: Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells. Cancer Res. 60:6018–6026. 2000.PubMed/NCBI

58 

Xia ZB, Pu PY, Huang Q, You YP, Wang GX and Wang CY: Preliminary study on the mechanism of connexin 43 gene transfection in the control of glioma cell proliferation. Zhonghua Zhong Liu Za Zhi. 25:4–8. 2003.(In Chinese). PubMed/NCBI

59 

González-Sánchez A, Jaraíz-Rodríguez M, Domínguez-Prieto M, Herrero-González S, Medina JM and Tabernero A: Connexin43 recruits PTEN and Csk to inhibit c-Src activity in glioma cells and astrocytes. Oncotarget. 7:49819–49833. 2016. View Article : Google Scholar : PubMed/NCBI

60 

Herrero-González S, Gangoso E, Giaume C, Naus CC, Medina JM and Tabernero A: Connexin43 inhibits the oncogenic activity of c-Src in C6 glioma cells. Oncogene. 29:5712–5723. 2010. View Article : Google Scholar : PubMed/NCBI

61 

Suzhi Z, Liang T, Yuexia P, Lucy L, Xiaoting H, Yuan Z and Qin W: Gap junctions enhance the antiproliferative effect of microRNA-124-3p in glioblastoma cells. J Cell Physiol. 230:2476–2488. 2015. View Article : Google Scholar : PubMed/NCBI

62 

Dang X, Doble BW and Kardami E: The carboxy-tail of connexin-43 localizes to the nucleus and inhibits cell growth. Mol Cell Biochem. 242:1–2. 2003. View Article : Google Scholar

63 

Mennecier G, Derangeon M, Coronas V, Hervé JC and Mesnil M: Aberrant expression and localization of connexin43 and connexin30 in a rat glioma cell line. Mol Carcinog. 47:391–401. 2008. View Article : Google Scholar : PubMed/NCBI

64 

Jin Z, Xu S, Yu H, Yang B, Zhao H and Zhao G: miR-125b inhibits connexin43 and Promotes glioma growth. Cell Mol Neurobiol. 33:1143–1148. 2013. View Article : Google Scholar : PubMed/NCBI

65 

Hao J, Zhang C, Zhang A, Wang K, Jia Z, Wang G, Han L, Kang C and Pu P: miR-221/222 is the regulator of Cx43 expression in human glioblastoma cells. Oncol Rep. 27:1–1510. 2012.

66 

Robe PA, Rogister B, Merville MP and Bours V: Growth regulation of astrocytes and C6 cells by TGFbeta1: Correlation with gap junctions. NeuroReport. 11:2837–2841. 2000. View Article : Google Scholar : PubMed/NCBI

67 

Zhang B, Feng X, Wang J, Xu X, Liu H and Lin N: Adenovirus-mediated delivery of bFGF small interfering RNA increases levels of connexin 43 in the glioma cell line, U251. J Exp Clin Cancer Res. 29:32010. View Article : Google Scholar : PubMed/NCBI

68 

Zhang W, Nwagwu C, Le DM, Yong VW, Song H and Couldwell WT: Increased invasive capacity of connexin43-overexpressing malignant glioma cells. J Neurosurg. 99:1039–1046. 2003. View Article : Google Scholar : PubMed/NCBI

69 

Strale PO, Clarhaut J, Lamiche C, Cronier L, Mesnil M and Defamie N: Down-regulation of Connexin43 expression reveals the involvement of caveolin-1 containing lipid rafts in human U251 glioblastoma cell invasion. Mol Carcinog. 51:845–860. 2012. View Article : Google Scholar : PubMed/NCBI

70 

Qin LJ, Jia YS, Zhang YB and Wang YH: Cyclooxygenase inhibitor induces the upregulation of connexin-43 expression in C6 glioma cells. Biomed Rep. 4:444–448. 2016. View Article : Google Scholar : PubMed/NCBI

71 

Aftab Q, Sin WC and Naus C: Reduction in gap junction intercellular communication promotes glioma migration. Oncotarget. 6:11447–11464. 2015. View Article : Google Scholar : PubMed/NCBI

72 

Hong X, Sin WC, Harris AL and Naus CC: Gap junctions modulate glioma invasion by direct transfer of microRNA. Oncotarget. 6:15566–15577. 2015. View Article : Google Scholar : PubMed/NCBI

73 

McDonough WS, Johansson A, Joffee H, Giese A and Berens ME: Gap junction intercellular communication in gliomas is inversely related to cell motility. Int J Dev Neurosci. 17:601–611. 1999. View Article : Google Scholar : PubMed/NCBI

74 

Osswald M, Jung E, Sahm F, Solecki G, Venkataramani V, Blaes J, Weil S, Horstmann H, Wiestler B, Syed M, et al: Brain tumour cells interconnect to a functional and resistant network. Nature. 528:93–98. 2015.PubMed/NCBI

75 

Reichert M, Müller T and Hunziker W: The PDZ domains of zonula occludens-1 induce an epithelial to mesenchymal transition of Madin-Darby canine kidney I cells. Evidence for a role of beta-catenin/Tcf/Lef signaling. J Biol Chem. 275:9492–9500. 2000. View Article : Google Scholar : PubMed/NCBI

76 

Lin JH, Takano T, Cotrina ML, Arcuino G, Kang J, Liu S, Gao Q, Jiang L, Li F, Lichtenberg-Frate H, et al: Connexin 43 enhances the adhesivity and mediates the invasion of malignant glioma cells. J Neurosci. 22:4302–4311. 2002.PubMed/NCBI

77 

Reszec J, Szkudlarek M, Hermanowicz A, Bernaczyk PS, Mariak Z and Chyczewski L: N-cadherin, beta-catenin and connexin 43 expression in astrocytic tumours of various grades. Histol Histopathol. 30:361–371. 2015.PubMed/NCBI

78 

Kirschstein T and Köhling R: Animal models of tumour-associated epilepsy. J Neurosci Methods. 260:109–117. 2016. View Article : Google Scholar : PubMed/NCBI

79 

Patel A, Sabbineni H, Clarke A and Somanath PR: Novel roles of Src in cancer cell epithelial-to-mesenchymal transition, vascular permeability, microinvasion and metastasis. Life Sci. 157:52–61. 2016. View Article : Google Scholar : PubMed/NCBI

80 

Elisevich K, Rempel SA, Smith BJ and Edvardsen K: Hippocampal connexin 43 expression in human complex partial seizure disorder. Exp Neurol. 145:154–164. 1997. View Article : Google Scholar : PubMed/NCBI

81 

Senner V, Köhling R, Püttmann-Cyrus S, Straub H, Paulus W and Speckmann EJ: A new neurophysiological/neuropathological ex vivo model localizes the origin of glioma-associated epileptogenesis in the invasion area. Acta Neuropathol. 107:1–7. 2004. View Article : Google Scholar : PubMed/NCBI

82 

Das A, GC IV Wallace, Holmes C, McDowell ML, Smith JA, Marshall JD, Bonilha L, Edwards JC, Glazier SS, Ray SK, et al: Hippocampal tissue of patients with refractory temporal lobe epilepsy is associated with astrocyte activation, inflammation, and altered expression of channels and receptors. Neuroscience. 220:237–246. 2012. View Article : Google Scholar : PubMed/NCBI

83 

Fonseca CG, Green CR and Nicholson LF: Upregulation in astrocytic connexin 43 gap junction levels may exacerbate generalized seizures in mesial temporal lobe epilepsy. Brain Res. 929:105–116. 2002. View Article : Google Scholar : PubMed/NCBI

84 

Su M and Tong XX: Astrocytic gap junction in the hippocampus of rats with lithium pilocarpine-induced epilepsy. Nan Fang Yi Ke Da Xue Xue Bao. 30:2738–2741. 2010.(In Chinese). PubMed/NCBI

85 

Takahashi DK, Vargas JR and Wilcox KS: Increased coupling and altered glutamate transport currents in astrocytes following kainic-acid-induced status epilepticus. Neurobiol Dis. 40:573–585. 2010. View Article : Google Scholar : PubMed/NCBI

86 

Oliveira R, Christov C, Guillamo JS, de Boüard S, Palfi S, Venance L, Tardy M and Peschanski M: Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biol. 6:72005. View Article : Google Scholar : PubMed/NCBI

87 

Liubinas SV, O'Brien TJ, Moffat BM, Drummond KJ, Morokoff AP and Kaye AH: Tumour associated epilepsy and glutamate excitotoxicity in patients with gliomas. J Clin Neurosci. 21:899–908. 2014. View Article : Google Scholar : PubMed/NCBI

88 

Armstrong TS, Grant R, Gilbert MR, Lee JW and Norden AD: Epilepsy in glioma patients: Mechanisms, management, and impact of anticonvulsant therapy. Neuro Oncol. 18:779–789. 2016. View Article : Google Scholar : PubMed/NCBI

89 

Elisevich K, Rempel SA, Smith B and Allar N: Connexin 43 mRNA expression in two experimental models of epilepsy. Mol Chem Neuropathol. 32:75–88. 1997. View Article : Google Scholar : PubMed/NCBI

90 

Köhling R, Senner V, Paulus W and Speckmann EJ: Epileptiform activity preferentially arises outside tumor invasion zone in glioma xenotransplants. Neurobiol Dis. 22:64–75. 2006. View Article : Google Scholar : PubMed/NCBI

91 

Buckingham SC, Campbell SL, Haas BR, Montana V, Robel S, Ogunrinu T and Sontheimer H: Glutamate release by primary brain tumors induces epileptic activity. Nat Med. 17:1269–1274. 2011. View Article : Google Scholar : PubMed/NCBI

92 

Kim LC, Song L and Haura EB: Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol. 6:587–595. 2009. View Article : Google Scholar : PubMed/NCBI

93 

Mylvaganam S, Ramani M, Krawczyk M and Carlen PL: Roles of gap junctions, connexins, and pannexins in epilepsy. Front Physiol. 5:1722014. View Article : Google Scholar : PubMed/NCBI

94 

Kékesi O, Ioja E, Szabó Z, Kardos J and Héja L: Recurrent seizure-like events are associated with coupled astroglial synchronization. Front Cell Neurosci. 9:2152015.PubMed/NCBI

95 

Jiang S, Wang YQ, Xu CF, Li YN, Guo R and Li L: Involvement of connexin43 in the infrasonic noise-induced glutamate release by cultured astrocytes. Neurochem Res. 39:833–842. 2014. View Article : Google Scholar : PubMed/NCBI

96 

Wei H, Deng F, Chen Y, Qin Y, Hao Y and Guo X: Ultrafine carbon black induces glutamate and ATP release by activating connexin and pannexin hemichannels in cultured astrocytes. Toxicology. 323:32–41. 2014. View Article : Google Scholar : PubMed/NCBI

97 

Chever O, Pannasch U, Ezan P and Rouach N: Astroglial connexin 43 sustains glutamatergic synaptic efficacy. Philos Trans R Soc Lond B Biol Sci. 369:201305962014. View Article : Google Scholar : PubMed/NCBI

98 

Unger T, Bette S, Zhang J, Theis M and Engele J: Connexin-deficiency affects expression levels of glial glutamate transporters within the cerebrum. Neurosci Lett. 506:12–16. 2012. View Article : Google Scholar : PubMed/NCBI

99 

Figiel M, Allritz C, Lehmann C and Engele J: Gap junctional control of glial glutamate transporter expression. Mol Cell Neurosci. 35:130–137. 2007. View Article : Google Scholar : PubMed/NCBI

100 

Shen N, Mo LQ, Hu F, Chen PX, Guo RX and Feng JQ: A novel role of spinal astrocytic connexin 43: Mediating morphine antinociceptive tolerance by activation of NMDA receptors and inhibition of glutamate transporter-1 in rats. CNS Neurosci Ther. 20:728–736. 2014. View Article : Google Scholar : PubMed/NCBI

101 

Huberfeld G and Vecht CJ: Seizures and gliomas-towards a single therapeutic approach. Nat Rev Neurol. 12:204–216. 2016. View Article : Google Scholar : PubMed/NCBI

102 

Robel S and Sontheimer H: Glia as drivers of abnormal neuronal activity. Nat Neurosci. 19:28–33. 2016. View Article : Google Scholar : PubMed/NCBI

103 

Abakumova T, Abakumov M, Shein S, Chelushkin P, Bychkov D, Mukhin V, Yusubalieva G, Grinenko N, Kabanov A, Nukolova N and Chekhonin V: Connexin 43-targeted T1 contrast agent for MRI, diagnosis of glioma. Contrast Media Mol Imaging. 11:15–23. 2016. View Article : Google Scholar : PubMed/NCBI

104 

Iusubalieva GM, Zorkina IaA, Baklaushev VP, Gurina OI, Goriaĭnov SA, Aleksandrova EV, Zhukov VIu, Savel'eva TA, Potapov AA and Chekhonin VP: Connexin-43 antibodies In Intraoperative diagnosis of experimental poorly differentiated gliomas. Zh Vopr Neirokhir Im N N Burdenko. 78:3–13. 2014.(In Russian). PubMed/NCBI

105 

Gielen PR, Aftab Q, Ma N, Chen VC, Hong X, Lozinsky S, Naus CC and Sin WC: Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology. 75:539–548. 2013. View Article : Google Scholar : PubMed/NCBI

106 

Murphy SF, Varghese RT, Lamouille S, Guo S, Pridham KJ, Kanabur P, Osimani AM, Sharma S, Jourdan J, Rodgers CM, et al: Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. Cancer Res. 76:139–149. 2016. View Article : Google Scholar : PubMed/NCBI

107 

Munoz JL, Rodriguez-Cruz V, Greco SJ, Ramkissoon SH, Ligon KL and Rameshwar P: Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis. 5:e11452014. View Article : Google Scholar : PubMed/NCBI

108 

Yusubalieva GM, Baklaushev VP, Gurina OI, Zorkina YA, Gubskii IL, Kobyakov GL, Golanov AV, Goryainov SA, Gorlachev GE, Konovalov AN, et al: Treatment of poorly differentiated glioma using a combination of monoclonal antibodies to extracellular connexin-43 fragment, temozolomide, and radiotherapy. Bull Exp Biol Med. 157:510–515. 2014. View Article : Google Scholar : PubMed/NCBI

109 

Okolie O, Bago JR, Schmid RS, Irvin DM, Bash RE, Miller CR and Hingtgen SD: Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model. Neuro Oncol. 18:1622–1633. 2016. View Article : Google Scholar : PubMed/NCBI

110 

Theodoric N, Bechberger JF, Naus CC and Sin WC: Role of gap junction protein Connexin43 in astrogliosis induced by brain injury. PLoS One. 7:e473112012. View Article : Google Scholar : PubMed/NCBI

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Spandidos Publications style
Dong H, Zhou XW, Wang X, Yang Y, Luo JW, Liu YH and Mao Q: Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma‑associated epileptic discharge (Review). Mol Med Rep 16: 7890-7900, 2017
APA
Dong, H., Zhou, X., Wang, X., Yang, Y., Luo, J., Liu, Y., & Mao, Q. (2017). Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma‑associated epileptic discharge (Review). Molecular Medicine Reports, 16, 7890-7900. https://doi.org/10.3892/mmr.2017.7618
MLA
Dong, H., Zhou, X., Wang, X., Yang, Y., Luo, J., Liu, Y., Mao, Q."Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma‑associated epileptic discharge (Review)". Molecular Medicine Reports 16.6 (2017): 7890-7900.
Chicago
Dong, H., Zhou, X., Wang, X., Yang, Y., Luo, J., Liu, Y., Mao, Q."Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma‑associated epileptic discharge (Review)". Molecular Medicine Reports 16, no. 6 (2017): 7890-7900. https://doi.org/10.3892/mmr.2017.7618