Reduced Cx43 Gap Junction Plaque Expression Differentiates Thyroid Carcinomas From Benign Disease | Endocrinology | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Munari-Silem Y, Guerrier A, Fromaget C, Rabilloud R, Gros D, Rousset B. Differential control of connexin-32 and connexin-43 expression in thyroid epithelial cells: evidence for a direct relationship between connexin-32 expression and histiotypic morphogenesis.  Endocrinology. 1994;135(2):724-7348033821PubMedGoogle ScholarCrossref
Statuto M, Audebet C, Tonoli H, Selmi-Ruby S, Rousset B, Munari-Silem Y. Restoration of cell-to-cell communication in thyroid cell lines by transfection with and stable expression of the connexin-32 gene: impact on cell proliferation and tissue-specific gene expression.  J Biol Chem. 1997;272(39):24710-247169305943PubMedGoogle ScholarCrossref
Tonoli H, Flachon V, Audebet C,  et al.  Formation of three-dimensional thyroid follicle-like structures by polarized FRT cells made communication competent by transfection and stable expression of the connexin-32 gene.  Endocrinology. 2000;141(4):1403-141310746644PubMedGoogle ScholarCrossref
Leithe E, Kjenseth A, Bruun J, Sirnes S, Rivedal E. Inhibition of connexin 43 gap junction channels by the endocrine disruptor ioxynil.  Toxicol Appl Pharmacol. 2010;247(1):10-1720510257PubMedGoogle ScholarCrossref
Naoi Y, Miyoshi Y, Taguchi T,  et al.  Connexin26 expression is associated with aggressive phenotype in human papillary and follicular thyroid cancers.  Cancer Lett. 2008;262(2):248-25618191019PubMedGoogle ScholarCrossref
Guerrier A, Fonlupt P, Morand I,  et al.  Gap junctions and cell polarity: connexin32 and connexin43 expressed in polarized thyroid epithelial cells assemble into separate gap junctions, which are located in distinct regions of the lateral plasma membrane domain.  J Cell Sci. 1995;108(pt 7):2609-26177593302PubMedGoogle Scholar
Atkinson B, edAtlas of Diagnostic Cytopathology. 2nd ed. Philadelphia, PA: WB Saunders Co; 2003
Leithe E, Kjenseth A, Sirnes S, Stenmark H, Brech A, Rivedal E. Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101.  J Cell Sci. 2009;122(pt 21):3883-389319808888PubMedGoogle ScholarCrossref
Mesnil M. Connexins and cancer.  Biol Cell. 2002;94(7-8):493-50012566222PubMedGoogle ScholarCrossref
Yamasaki H, Naus CC. Role of connexin genes in growth control.  Carcinogenesis. 1996;17(6):1199-12138681433PubMedGoogle ScholarCrossref
Langlois S, Cowan KN, Shao Q, Cowan BJ, Laird DW. The tumor-suppressive function of connexin43 in keratinocytes is mediated in part via interaction with caveolin-1.  Cancer Res. 2010;70(10):4222-423220406988PubMedGoogle ScholarCrossref
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):29132-2913812042301PubMedGoogle ScholarCrossref
Eghbali B, Kessler JA, Reid LM, Roy C, Spray DC. Involvement of gap junctions in tumorigenesis: transfection of tumor cells with connexin 32 cDNA retards growth in vivo.  Proc Natl Acad Sci U S A. 1991;88(23):10701-107051660148PubMedGoogle ScholarCrossref
Goldberg GS, Bechberger JF, Tajima Y,  et al.  Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells.  Cancer Res. 2000;60(21):6018-602611085522PubMedGoogle Scholar
Omori Y, Yamasaki H. Gap junction proteins connexin32 and connexin43 partially acquire growth-suppressive function in HeLa cells by deletion of their C-terminal tails.  Carcinogenesis. 1999;20(10):1913-191810506104PubMedGoogle ScholarCrossref
Avanzo JL, Mesnil M, Hernandez-Blazquez FJ,  et al.  Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43.  Carcinogenesis. 2004;25(10):1973-198215166089PubMedGoogle ScholarCrossref
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(4):483-49214688024PubMedGoogle ScholarCrossref
King TJ, Lampe PD. The gap junction protein connexin32 is a mouse lung tumor suppressor.  Cancer Res. 2004;64(20):7191-719615492231PubMedGoogle ScholarCrossref
Temme A, Buchmann A, Gabriel HD, Nelles E, Schwarz M, Willecke K. High incidence of spontaneous and chemically induced liver tumors in mice deficient for connexin32.  Curr Biol. 1997;7(9):713-7169285723PubMedGoogle ScholarCrossref
Rackauskas M, Neverauskas V, Skeberdis VA. Diversity and properties of connexin gap junction channels.  Medicina (Kaunas). 2010;46(1):1-1220234156PubMedGoogle Scholar
Original Article
Nov 2011

Reduced Cx43 Gap Junction Plaque Expression Differentiates Thyroid Carcinomas From Benign Disease

Author Affiliations

Author Affiliations: Departments of Otolaryngology–Head and Neck Surgery (Drs Darr, Patel, Yu, and Schantz) and Pathology (Drs Komorowski and McCormick), New York Eye & Ear Infirmary, New York, and Department of Microbiology and Immunology and Otolaryngology, New York Medical College, Valhalla (Drs Tiwari and Geliebter), New York.

Arch Otolaryngol Head Neck Surg. 2011;137(11):1161-1165. doi:10.1001/archoto.2011.186

Objective To investigate the expression of connexin 43 (Cx43) in benign vs malignant thyroid tissue for potential use as a diagnostic marker.

Design Retrospective study.

Subjects Thyroid specimens were obtained from 50 patients who underwent partial or total thyroidectomy at the New York Eye and Ear Infirmary, New York, New York, between 1999 and 2007. They included goiter (n = 5), follicular adenoma (n = 15), follicular carcinoma (n = 17), papillary thyroid carcinoma (PTC) (n = 7) and the follicular variant of PTC (n = 6).

Interventions Tissue sections (5 μm) were immunohistochemically stained for Cx43 with the avidin-biotin-peroxidase method using an automated stainer. The Cx43 membrane staining pattern was evaluated.

Results Twenty-three of 30 cancer specimens (77%) revealed a loss of Cx43 plaque staining at the cellular membrane compared with only 3 of 20 benign specimens (15%). Among the malignant specimens, loss of Cx43 plaque staining was observed in 11 of 17 follicular carcinomas (65%), 5 of 6 follicular variants of PTC (83%), and 7 of 7 PTCs (100%). In contrast, only 3 of 15 adenomas (20%) and 0 of 5 goiter samples demonstrated loss of Cx43 plaque staining at the cell membrane.

Conclusion Our data provide evidence that the absence of Cx43 plaque staining is associated with thyroid cancer and thus holds potential clinical utility as a marker for malignant disease.