Impact of connexin32 deletion on E7 or RET/PTC3 oncogene-driven growth and neoplastic transformation of the thyroid gland.
Connexins (Cx) form gap junctions and allow direct cell-to-cell communication. Cx through gap junctions or by themselves play regulatory roles on cell growth and differentiation. Using genetically modified mice, we previously found that Cx32 acts as a down-regulator of growth in normal thyroid gland. In this study, we examined the impact of Cx32 ablation on oncogene-driven thyroid growth and neoplastic transformation. Cx32 knockout (Cx32-KO) mice were crossed with transgenic mice expressing, selectively in the thyroid gland, either the E7 or RET/PTC3 (RP3) oncogene. As already described, Cx32-KO mice had no detectable thyroid alteration in physiological conditions and mice expressing E7 or RP3 exhibited time-dependent thyroid hypertrophy and variable changes in expression of differentiation. The thyroid of E7 mice evolved towards a large colloid goitre whereas RP3 mice developed a hyperplastic thyroid of variable size, and the largest glands (about 40% of total) represented a profound tissue remodeling with proliferative papillary formations. E7-induced thyroid hypertrophy was reduced by about 40% in Cx32-KO mice as compared with wild-type (WT) littermates. On the contrary, thyroid hypertrophy induced by thyrotropin stimulation (in response to goitrogen treatment) was enhanced by about 40% in Cx32-KO mice as compared with WT mice. Thyroid hypertrophy of RP3 mice and the proportion of glands showing extensive tissue remodeling were drastically reduced in mice devoid of Cx32. Our data show that Cx32, which negatively controls thyroid growth activated by thyrotropin via the cAMP pathway, would act as a positive effector of thyroid growth triggered by oncogenes acting through other signaling cascades.
Prost
Gaëlle
G
Institut National de Santé et de Recherche Médicale, UMR 664, Lyon F-69372, France.
Bernier-Valentin
Françoise
F
Croset
Martine
M
Rousset
Bernard
B
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D017630:Connexins / Q000235:genetics* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013961:Thyroid Gland / Q000254:growth & development / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D000242:Cyclic AMP; D050725:Papillomavirus E7 Proteins; D051096:Proto-Oncogene Proteins c-ret; D000097002:Gap Junction beta-1 Protein; C494999:Ret protein, mouse