Gap Junctions in Leiomyomas and the Human Female Reproductive Tract

Abstract

The aim of the study was to critically examine existing data on the contribution of gap junctions to the function of the female reproductive tract and their role in cancer and benign gynecologic disease such as uterine leiomyomas and to evaluate the potential for clinical applications of gap junction intercellular communication (GJIC) in the treatment of diseases of the female reproductive tract. Gap junction proteins are present in all organs of the female reproductive tract. GJIC is vital to folliculogenesis, embryo implantation, and vascular changes associated with pregnancy and synchronization of uterine contractions of parturition. Loss of GJIC is associated with malignancy, and therapeutic restoration of GJIC reduces tumor growth and reverses chemotherapy resistance. GJIC is critical for various cell and tissue functions including the function of the female reproductive tract. Exploitation of the properties of GJIC may lead to novel treatments for both benign and malignant gynecologic diseases. GJIC is critical for various cell and tissue functions including specialized functions of the female reproductive tract and potential maintenance of the benign behavior of uterine leiomyomas.

Keywords

gap junctions - connexin - intercellular communication - leiomyomas

• References

• 1 Stenchever M, Droegemueller W, Herbst A, Mishell D. Comprehensive Gynecology. St. Louis, London, Philadelphia, Sydney, Toronto: Mosby, Inc.; 2001
• 2 Talhouk R, Elble R, Bassam R , et al. Developmental expression patterns and regulations of connexins in the mouse mammary gland: expression of connexin 30 in lactogenesis. Cell Tissue Res 2005; 7: 595-607
• 3 Carabatsos MJ, Sellitto C, Goodenough DA, Albertini DF. Oocyte-granulosa cell heterologous gap junctions are required for the coordination of nuclear and cytoplasmic meiotic competence. Dev Biol 2000; 226 (2) 167-179
• 4 Gittens JE, Kidder GM. Differential contributions of connexin37 and connexin43 to oogenesis revealed in chimeric reaggregated mouse ovaries. J Cell Sci 2005; 118 (Pt 21) 5071-5078
• 5 Toler CR, Taylor DD, Gercel-Taylor C. Loss of communication in ovarian cancer. Am J Obstet Gynecol 2006; 194 (5) e27-e31
• 6 Gellhaus A, Dong X, Propson S , et al. Connexin 43 interacts with NOV: a possible mechanism for negative regulation of cell growth in choriocarcinoma cells. J Biol Chem 2004; 35: 36931-36942
• 7 Evans WH, Martin PE. Gap junctions: structure and function (Review). Mol Membr Biol 2002; 19 (2) 121-136
• 8 Kadle R, Zhang JT, Nicholson BJ. Tissue-specific distribution of differentially phosphorylated forms of Cx43. Mol Cell Biol 1991; 11 (1) 363-369
• 9 Mesnil M, Crespin S, Avanzo JL, Zaidan-Dagli ML. Defective gap junctional intercellular communication in the carcinogenic process. Biochim Biophys Acta 2005; 1719 (1-2) 125-145
• 10 Perkins G, Goodenough D, Sosinsky G. Three-dimensional structure of the gap junction connexon. Biophys J 1997; 72 (2, Pt 1) 533-544
• 11 Sosinsky GE, Nicholson BJ. Structural organization of gap junction channels. Biochim Biophys Acta 2005; 1711 (2) 99-125
• 12 Pointis G, Fiorini C, Defamie N, Segretain D. Gap junctional communication in the male reproductive system. Biochim Biophys Acta 2005; 1719 (1-2) 102-116
• 13 Simon AM, Goodenough DA. Diverse functions of vertebrate gap junctions. Trends Cell Biol 1998; 8 (12) 477-483
• 14 Evans WH, De Vuyst E, Leybaert L. The gap junction cellular internet: connexin hemichannels enter the signalling limelight. Biochem J 2006; 397 (1) 1-14
• 15 Goldberg GS, Valiunas V, Brink PR. Selective permeability of gap junction channels. Biochim Biophys Acta 2004; 1662 (1-2) 96-101
• 16 Weber PA, Chang HC, Spaeth KE, Nitsche JM, Nicholson BJ. The permeability of gap junction channels to probes of different size is dependent on connexin composition and permeant-pore affinities. Biophys J 2004; 87 (2) 958-973
• 17 Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC. Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev 2003; 83 (4) 1359-1400
• 18 Saito T, Oyamada M, Yamasaki H, Mori M, Kudo R. Co-ordinated expression of connexins 26 and 32 in human endometrial glandular epithelium during the reproductive cycle and the influence of hormone replacement therapy. Int J Cancer 1997; 73 (4) 479-485
• 19 Tanmahasamut P, Sidell N. Up-regulation of gap junctional intercellular communication and connexin 43 expression by retinoic acid in human endometrial stromal cells. J Clin Endocrinol Metab 2005; 7: 4151-4156
• 20 Tong D, Gittens J, Kidder G, Bai D. Patch-clamp study reveals that the importance of connexin 43-mediated gap junctional communication for ovarian folliculogenesis is strain specific in the mouse. Am J Physiol Cell Physiol 2005; 1: C290-C297
• 21 Gittens J, Barr K, Vanderhyden B, Kidder G. Interplay between paracrine signaling and gap junctional communication in ovarian follicles. J Cell Sci 2005; 118 (Pt 1) 113-122
• 22 Thomas FH, Vanderhyden BC. Oocyte-granulosa cell interactions during mouse follicular development: regulation of kit ligand expression and its role in oocyte growth. Reprod Biol Endocrinol 2006; 4: 19
• 23 Fitzharris G, Baltz J. Granulosa cells regulate intercellular pH of the murine growing oocyte via gap junctions: development of independent homeostasis during oocyte growth. Development 2006; 4: 591-599
• 24 Feranil JB, Isobe N, Nakao T. Expression of gap junction protein connexin 43 during follicular atresia in the ovary of swamp buffaloes. J Reprod Dev 2005; 51 (5) 675-681
• 25 Thomas RE, Armstrong DT, Gilchrist RB. Bovine cumulus cell-oocyte gap junctional communication during in vitro maturation in response to manipulation of cell-specific cyclic adenosine 3′,5′-monophosophate levels. Biol Reprod 2004; 70 (3) 548-556
• 26 Cheng Y, Inoue N, Matsuda-Minehata F, Goto Y, Maeda A, Manabe N. Changes in expression and localization of connexin 43 mRNA and protein in porcine ovary granulosa cells during follicular atresia. J Reprod Dev 2005; 51 (5) 627-637
• 27 Gabriel S, Winterhager E, Pfarrer C, Traub O, Leiser R. Modulation of connexin expression in sheep endometrium in response to pregnancy. Placenta 2004; 25 (4) 287-296
• 28 Nishimura T, Dunk C, Lu Y , et al. Gap junctions are required for trophoblast proliferation in early human placental development. Placenta 2004; 25 (7) 595-607
• 29 Kenny LC, Baker PN, Kendall DA, Randall MD, Dunn WR. The role of gap junctions in mediating endothelium-dependent responses to bradykinin in myometrial small arteries isolated from pregnant women. Br J Pharmacol 2002; 136 (8) 1085-1088
• 30 Veerareddy S, Cooke CL, Baker PN, Davidge ST. Vascular adaptations to pregnancy in mice: effects on myogenic tone. Am J Physiol Heart Circ Physiol 2002; 283 (6) H2226-H2233
• 31 Kilarski WM, Rothery S, Roomans GM , et al. Multiple connexins localized to individual gap-junctional plaques in human myometrial smooth muscle. Microsc Res Tech 2001; 54 (2) 114-122
• 32 Wray S, Jones K, Kupittayanant S , et al. Calcium signaling and uterine contractility. J Soc Gynecol Investig 2003; 10 (5) 252-264
• 33 Cluff A, Bystrom B, Klimaviciute A , et al. Prolonged labour associated with lower expression of syndecan 3 and connexin 43 in human uterine tissue. Reprod Biol Endocrinol 2006; 4: 4-24
• 34 Regidor P, Engel K, Regidor M , et al. Expression of the gap junction conneins Cx43, Cx45 and Cx26 in human uterine leiomyomata. Gynecol Endocrinol 2001; 2: 113-122
• 35 Andersen J. Comparing regulation of the connexin 43 gene by estrogen in uterine leiomyoma and pregnancy myometrium. Environ Health Perspect 2000; 108 (Suppl. 05) 811-815
• 36 Zhao K, Kuperman L, Geimonen E, Andersen J. Progestin represses human connexin43 gene expression similarly in primary cultures of myometrial and uterine leiomyoma cells. Biol Reprod 1996; 54 (3) 607-615
• 37 Wu JJ, Geimonen E, Andersen J. Increased expression of estrogen receptor beta in human uterine smooth muscle at term. Eur J Endocrinol 2000; 142 (1) 92-99
• 38 Loch-Caruso RK, Criswell KA, Grindatti CM, Brant KA. Sustained inhibition of rat myometrial gap junctions and contractions by lindane. Reprod Biol Endocrinol 2003; 1: 62
• 39 Wang CT, Loch-Caruso R. Phospholipase-mediated inhibition of spontaneous oscillatory uterine contractions by lindane in vitro. Toxicol Appl Pharmacol 2002; 182 (2) 136-147
• 40 Leszczyńska-Gorzelak B, Laskowska M, Oleszczuk J. Comparative analysis of the effectiveness of misoprostol and prostaglandin E(2) in the preinduction and induction of labor. Med Sci Monit 2001; 7 (5) 1023-1028
• 41 Saito Y, Seki H, Takahashi S, Maki M. The difference in sex hormone dependence for gap junction formation in the muscles of uterine leiomyoma and normal myometrium. Nippon Sanka Fujinka Gakkai Zasshi 1986; 38 (4) 595-601
• 42 Andersen J, Barbieri RL. Abnormal gene expression in uterine leiomyomas. J Soc Gynecol Investig 1995; 2 (5) 663-672
• 43 Ciray HN, Fu X, Olovsson M , et al. Presence and localization of connexins 43 and 26 in cell cultures derived from myometrial tissues from nonpregnant and pregnant women and from leiomyomas. Am J Obstet Gynecol 2000; 182 (4) 926-930
• 44 Andersen J, Grine E, Eng CL , et al. Expression of connexin-43 in human myometrium and leiomyoma. Am J Obstet Gynecol 1993; 169 (5) 1266-1276
• 45 Cesen-Cummings K, Houston KD, Copland JA, Moorman VJ, Walker CL, Davis BJ. Uterine leiomyomas express myometrial contractile-associated proteins involved in pregnancy-related hormone signaling. J Soc Gynecol Investig 2003; 10 (1) 11-20
• 46 Hu YQ, Liu YJ. [Expressions of Cx43 and Skp2 in epithelial ovarian tumor and their clinical significances]. Ai Zheng 2005; 24 (1) 104-109
• 47 Aasen T, Graham SV, Edward M, Hodgins MB. Reduced expression of multiple gap junction proteins is a feature of cervical dysplasia. Mol Cancer 2005; 4 (1) 31
• 48 Aasen T, Hodgins MB, Edward M, Graham SV. The relationship between connexins, gap junctions, tissue architecture and tumour invasion, as studied in a novel in vitro model of HPV-16-associated cervical cancer progression. Oncogene 2003; 22 (39) 7969-7980
• 49 Steinhoff I, Leykauf K, Bleyl U, Durst M, Alonso A. Phosphorylation of the gap junction protein Connexin 43 in CIN III lesions and cervical carcinomas. Cancer Lett 2006; 2: 291-297
• 50 Umhauer S, Ruch RJ, Fanning J. Gap junctional intercellular communication and connexin 43 expression in ovarian carcinoma. Am J Obstet Gynecol 2000; 182 (5) 999-1000
• 51 Rancourt C, Bergeron C, Lane D, Garon G, Piche A. Delivery of herpes simplex thymidine kinase bystander effect by engineered human mesothelial cells for the treatment of ovarian cancer. Cryotherapy 2003; 5 (6) 509-522
• 52 Spinella F, Rosanò L, Di Castro V, Nicotra MR, Natali PG, Bagnato A. Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in human ovarian carcinoma cells. J Biol Chem 2003; 278 (42) 41294-41301
• 53 Hanna E, Umhauer S, Roshong S , et al. Gap junctional intercellular communication and connexin 43 expression in human ovarian surface epithelial cells and ovarian carcinomas in vivo and in vitro. Carcinogenesis 1999; 7: 1369-1373
• 54 Fernstrom M, Koffler L, Abou-Rjaily G, Boucher P, Shewach D, Ruch R. Neoplastic reversal of human ovarian carcinoma cells transfected with connexin 43. Exp Mol Pathol 2002; 1: 54-60
• 55 Winterhager E, Kaufmann P, Gruemmer R. Cell-cell-communication during placental development and possible implications for trophoblast proliferation and differentiation. Placenta 2000; 21 (Suppl A): S61-S68
• 56 Saito T, Nishimura M, Kudo R, Yamasaki H. Suppressed gap junctional intercellular communication in carcinogenesis of endometrium. Int J Cancer 2001; 93 (3) 317-323
• 57 King TJ, Bertram JS. Connexins as targets for cancer chemoprevention and chemotherapy. Biochim Biophys Acta 2005; 1719 (1-2) 146-160
• 58 Trosko JE, Chang CC, Upham BL, Tai MH. Ignored hallmarks of carcinogenesis: stem cells and cell-cell communication. Ann N Y Acad Sci 2004; 1028: 192-201
• 59 Torsko J. The role of stem cells and gap junctional intercellular communication in carcinogenesis. J Biochem Mol Biol 2003; 1: 43-48
• 60 Vinken M, Vanhaecke T, Papeleu P, Snykers S, Henkens T, Rogiers V. Connexins and their channels in cell growth and cell death. Cell Signal 2006; 18 (5) 592-600
• 61 Trosko JE. The role of stem cells and gap junctional intercellular communication in carcinogenesis. J Biochem Mol Biol 2003; 36 (1) 43-48
• 62 Qin H, Shao Q, Curtis H , et al. Retroviral delivery of connexin genes to human breast tumor cells inhibits in vivo tumor growth by a mechanism that is independent of significant gap junctional intercellular communication. J Biol Chem 2002; 277 (32) 29132-29138
• 63 Kunishige I, Samejima Y, Moriyama A, Saji F, Murata Y. cAMP stimulates the bystander effect in suicide gene therapy of human choriocarcinoma. Anticancer Res 1998; 18 (5A) 3411-3419
• 64 Trosko JE, Ruch RJ. Gap junctions as targets for cancer chemoprevention and chemotherapy. Curr Drug Targets 2002; 3 (6) 465-482