Expression of “Connexin 43” in Colorectal Carcinomas: Histopathological and Immunohistochemical Study

Essam Ayad; Ahmed Naeem Eesa; Rabab Radi; Lubna Omer El Farouk Abdel-Salam

doi:10.3889/oamjms.2020.4676

Authors

Essam Ayad Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
Ahmed Naeem Eesa Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
Rabab Radi Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
Lubna Omer El Farouk Abdel-Salam Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt

DOI:

https://doi.org/10.3889/oamjms.2020.4676

Keywords:

Colorectal cancer, Gap junction, Immunohistochemistry, Cx 43

Abstract

BACKGROUND: Colorectal cancer is one of the most common cancers worldwide and leading cause of cancer related deaths. Connexins are integral membrane proteins that form channels between adjacent cells. Gap junction intercellular communication plays essential roles in tissue homoeostasis and regulation of cell growth and differentiation. Connexins can act as either tumor suppressors or tumor promoters. The human connexin protein family contains 21 members, of which the most widely studied is connexin 43 (Cx 43).

OBJECTIVES: Investigation of immunohistochemical expression of Cx 43 in cases of colorectal adenoma and carcinoma and correlation of this expression with the clinico-pathological aspects of the tumors.

MATERIALS AND METHODS: Seventy formalin fixed paraffin embedded BC tissue sections were randomly collected. All the available data were collected from the patients’ reports. The paraffin blocks were sectioned and stained with hematoxylin and eosin stains for histologic evaluation. Additional sections were immunostained with Cx 43.

RESULTS: Cx 43 expression was negative in all studied cases.

CONCLUSION: Cx 43 is a tumor suppressor that is lost early in colorectal carcinogenesis and can be considered as potential target for cancer chemoprevention and chemotherapy aiming at restoration of normal connexin expression and functional gap junctions.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Enkhbat T, Nishi M, Takasu C, Yoshikawa K, Jun H, Tokunaga T, et al. Programmed cell death ligand 1 expression is an independent prognostic factor in colorectal cancer. Anticancer Res. 2018;38(6):3367-73. https://doi.org/10.21873/ anticanres.12603 PMid:29848685

Hamilton SR, Bosman FT, Boffetta P. In: Bosman FT, Carneiro F, Hruban RH and Theise ND, editors. Carcinoma of the colon and rectum. In: WHO Classification of Tumors of the Digestive System. 4th ed. Lyon: IARC Press; 2010. p. 132-46.

Khorshed E. Gastrointestinal tract tumors. In: Mokhatr NM, MA Ghoneim, MH Hussein, editors. Cancer Pathology Registry 2000-2011. Bethesda, Maryland: National Cancer Institute; 2016. p. 32-48.

Loewenstein WR, Kanno Y. Intercellular communication and the control of tissue growth: Lack of communication between cancer cells. Nature. 1966;209(5029):1248-9. https://doi.org/10.21873/ anticanres.12603 PMid:5956321

Aasen T, Mesnil M, Naus CC, Lampe PD, Laird DW. Gap junctions and cancer: Communicating for 50 years. Nat Rev Cancer. 2016;16(12):775-88. https://doi.org/10.1038/ nrc.2016.105 PMid:27782134

Saez JC, Leybaert L. Hunting for connexin hemichannels. FEBS Lett. 2014;588(8):1205-11. https://doi.org/10.1016/j. febslet.2014.03.004 PMid:24631534

Laird DW, Lampe PD. Therapeutic strategies targeting connexins. Nat Rev Drug Discov. 2018;17(12):905-21. https:// doi.org/10.1038/nrd.2018.138 PMid:30310236

Delvaeye T, Vandenabeele P, Bultynck G, Leybaert L, Krysko DV. Therapeutic targeting of connexin channels: New views and challenges. Trends Mol Med. 2018;24(12):1036-53. https://doi.org/10.1016/j.molmed.2018.10.005 PMid:30424929

Tan LW, Bianco T, Dobrovic A. Variable promoter region CpG island methylation of the putative tumor suppressor gene connexin 26 in breast cancer. Carcinogenesis. 2002;23(2):231- 6. https://doi.org/10.1093/carcin/23.2.231 PMid:11872627

Kandouz M, Batist G. Gap junctions and connexins as therapeutic targets in cancer. Expert Opin Ther Targets. 2010;14(7):681-92. https://doi.org/10.1517/14728222.2010.487866 PMid:20446866

King TJ, Bertram JS. Connexins as targets for cancer chemoprevention and chemotherapy. Biochim Biophys Acta. 2005;1719(1-2):146-60. PMid:16263076

Naus CC, Laird DW. Implications and challenges of connexin connections to cancer. Nat Rev Cancer. 2010;10(6):435-41. https://doi.org/10.1038/nrc2841 PMid:20495577

Sirnes S, Lind GE, Bruun J, Fykerud TA, Mesnil M, Lothe RA, et al. Connexins in colorectal cancer pathogenesis. Int J Cancer. 2015;137(1):1-11. https://doi.org/10.1002/ijc.28911 PMid:24752574

Ismail R, Rashid R, Andrabi K, Parray FQ, Besina S, Shah MA, et al. Pathological implications of Cx43 down-regulation in human colon cancer. Asian Pac J Cancer Prev. 2014;15(7):2987- 91. https://doi.org/10.7314/apjcp.2014.15.7.2987 PMid:24815435

Bosman F, Carneiro F, Hruban R, Theise N. Tumors of the colon and rectum. In: Kleihues P, Louis DN, editors. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: IARC Press; 2010. p. 132.

Jessup JM, Goldberg RM, Asare EA, Benson AB 3rd, Brierley JD, Chang GJ, et al. Definitions of AJCC TNM. In: Amin MB, Edge SB, Greene FL., editors. AJCC Cancer Staging Manual. 8th ed. Berlin: Springer; 2017. p. 268-9.

Bresalier RS. Colorectal Cancer. In: Feldman M, Friedman LS, Brandt LJ., editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 9th ed. Philadelphia, PA: Elsevier; 2010. p. 2191-238. https://doi. org/10.1016/b978-1-4160-6189-2.00123-2

Radić J, Krušlin B, Šamija M, Ulamec M, Milošević M, Jazvić M, et al. Connexin 43 expression in primary colorectal carcinomas in patients with Stage III and IV disease. Anticancer Res. 2016;36(5):2189-96. PMid:27127122

Nemeth L, Maddur S, Puri P. Immunolocalization of the gap junction protein connexin 43 in the interstitial cells of cajal in the normal and Hirschsprung’s disease bowel. J Pediatr Surg. 2000;35(6):823-8. https://doi.org/10.1053/jpsu.2000.6851 PMid:10873019

Dubina MV, Iatckii NA, Popov DE, Vasil’ev SV, Krutovskikh VA. Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer. Oncogene. 2002;21(32):4992-6. https://doi.org/10.1038/sj.onc.1205630 PMid:12118378

Kanczuga-Koda L, Sulkowski S, Koda M, Sobaniec- Lotowska M, Sulkowska M. Expression of connexins 26, 32 and 43 in the human colon--an immunohistochemical study. Folia Histochem Cytobiol. 2004;42(4):203-7. https://doi.org/10.5603/ fhc.2013.0043 PMid:15704645

Sirnes S, Bruun J, Kolberg M, Kjenseth A, Lind GE, Svindland A, et al. Connexin43 acts as a colorectal cancer tumor suppressor and predicts disease outcome. Int J Cancer. 2012;131(3):570- 81. https://doi.org/10.1002/ijc.26392 PMid:21866551

Hsu M, Andl T, Li G, Meinkoth JL, Herlyn M. Cadherin repertoire determines partner-specific gap junctional communication during melanoma progression. J Cell Sci. 2000;113(Pt 9):1535-42. PMid:10751145

Fujimoto K, Nagafuchi A, Tsukita S, Kuraoka A, Ohokuma A, Shibata Y. Dynamics of connexins, E-cadherin and alpha-catenin on cell membranes during gap junction formation. J Cell Sci. 1997;110(Pt 3):311-22. PMid:9057084

Solan JL, Lampe PD. Connexin phosphorylation as a regulatoy event link to gap junction Chanel assembly. Biochim Biophys Acta. 2005;1711(2):154-63. https://doi.org/10.1016/j. bbamem.2004.09.013 PMid:15955300

Decrock E, De Vuyst E, Vinken M, Van Moorhem M, Vranckx K, Wang N, et al. Connexin43 hemichannels contribute to the propagation of apoptotic cell death in a rat C6 glioma cellmodel. Cell Death Differ. 2009;16(1):151-63. https://doi.org/10.1038/ cdd.2008.138 PMid:18820645

Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993;7(5):812-21. https://doi.org/10.1101/ gad.7.5.812 PMid:8491378

Qi F, Yuan Y, Zhi X, Huang Q, Chen Y, Zhuang W, et al. Synergistic effects of AKAP95, cyclin D1, cyclin E1, and Cx43 in the development of rectal cancer. Int J Clin Exp Pathol. 2015;8(2):1666-73. PMid:25973052

King TJ, Fukushima LH, Yasui Y, Lampe PD, Bertram JS. Inducible expression of the gap junction protein connexin43 decreases the neoplastic potential of HT‐1080 human fibrosarcoma cells in vitro and in vivo. Mol Carcinog. 2002;35(1):29-41. https://doi. org/10.1002/mc.10071 PMid:12203365

McLachlan E, Shao Q, Wang HL, Langlois S, Laird DW. Connexins act as tumor suppressors in three-dimensional mammary cell organoids by regulating differentiation and angiogenesis. Cancer Res. 2006;66(20):9886-94. https://doi. org/10.1158/0008-5472.can-05-4302 PMid:17047050

Zhang D, Chen C, Li Y, Fu X, Xie Y, Li Y, et al. Cx31.1 acts as a tumour suppressor in non-small cell lung cancer (NSCLC) cell lines through inhibition of cell proliferation and metastasis. J Cell Mol Med. 2012;16(5):1047-59. https://doi. org/10.1111/j.1582-4934.2011.01389.x PMid:21777377

Shao Q, Wang H, McLachlan E, Veitch GI, Laird DW. Down-regulation of Cx43 by retroviral delivery of small interfering RNA promotes an aggressive breast cancer cell phenotype. Cancer Res. 2005;65(7):2705-11. https://doi.org/10.1158/0008-5472. can-04-2367 PMid:15805269

Avanzo JL, Mesnil M, Hernandez-Blazquez FJ, Mackowiak II, Mori CM, da Silva TC, et al. Increased susceptibility to urethaneinduced lung tumors in mice with decreasedexpression of connexin43. Carcinogenesis. 2004;25(10):1973-82. https:// doi.org/10.1093/carcin/bgh193 PMid:15166089

Dagli ML, Yamasaki H, Krutovskikh V, Omori Y. Delayed liver regeneration and increased susceptibility to chemical hepatocarcinogenesis in transgenic mice expressing a dominant-negative mutant of connexin32 only in the liver. Carcinogenesis. 2004;25:483-92. https://doi.org/10.1093/carcin/bgh050

King TJ, Lampe PD. Mice deficient for the gap junction protein connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/ Erk1, p42/Erk2) activation. Carcinogenesis. 2004;25(5):669-80. https://doi.org/10.1093/carcin/bgh071 PMid:14742325

Han Y, Zhang PJ, Chen T, Yum SW, Pasha T, Furth EE. Connexin43 expression increases in the epithelium and stroma along the colonic neoplastic progression pathway: Implications for its oncogenic role. Gastroenterol Res Pract 2011;2011:561719. https://doi.org/10.1155/2011/561719 PMid:21754925

Bišćanin A, Ljubičić N, Boban M, Baličević D, Pavić I, Bišćanin MM, et al. CX43 Expression in colonic adenomas and surrounding mucosa is a marker of malignant potential. Anticancer Res. 2016;36(10):5437-42. https://doi.org/10.21873/ anticanres.11122 PMid:27798912

Ableser MJ, Penuela S, Lee J, Shao Q, Laird DW. Connexin 43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem. 2014;289(3):1592-603. https://doi.org/10.1158/1538- 7445.am2014-2467 PMid:24297173

Solan JL, Hingorani SR, Lampe PD. Changes in connexin43 expression and localization during pancreatic cancer progression. J Membrane Biol. 2012;245(5-6):255-62. https:// doi.org/10.1007/s00232-012-9446-2 PMid:22729649

Fostok SF, Bazzoun D, Lelievre SA, El-Sibai M, Talhouk RS. Silencing connexin 43 induces cell cycle entry and invasion in non-neoplastic mammary epithelial cells. Cancer Res. 2018;78(13 Suppl):4505. https://doi.org/10.1158/1538-7445. am2018-4505

Ruch RJ. Connexin43 suppresses lung cancer stem cells. Cancers. 2019;11(2):175. https://doi.org/10.3390/ cancers11020175 PMid:30717421

Ezumi K, Yamamoto H, Murata K, Higashiyama M, Damdinsuren B, Nakamura Y, et al. Aberrant expression of connexin 26 is associated with lung metastasis of colorectal cancer. Clin Cancer Res. 2008;14(3):677-84. https://doi. org/10.1158/1078-0432.ccr-07-1184 PMid:18245526