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

Dong,Hui; Zhou,Xing‑Wang; Wang,Xiang; Yang,Yuan; Luo,Jie‑Wen; Liu,Yan‑Hui; Mao,Qing

doi:10.3892/mmr.2017.7618

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
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Affiliations: Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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.

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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