Carcinogenesis Advance Access originally published online on January 23, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis, Vol. 25, No. 5, 669-680,
May 2004
Carcinogenesis vol.25 no.5 © Oxford University Press 2004; all rights reserved.
ARTICLE |
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
1 Cancer Prevention Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and 2 Department of Pathobiology, University of Washington, Seattle, WA 98195, USA
3 To whom correspondence should be addressed Email: tking{at}fhcrc.org
Loss of connexin expression/gap junction intercellular communication (GJIC) has been correlated with decreased growth control and increased tumorigenesis. Studies utilizing Connexin32 (Cx32)-deficient knockout mice have demonstrated that loss of Cx32 increases susceptibility to chemically induced liver tumorigenesis. Here, in addition to dramatically increased liver tumorigenesis, we show that tumor induction utilizing X-ray radiation resulted in a statistically significant increase in overall tumor burden in Cx32-deficient mice compared with wild-type mice due to tumorigenesis in several other tissues (lung, adrenal, lymph and small intestine) even when excluding prevalent liver tumors. Irradiated Cx32-deficient mice were particularly sensitive to liver tumorigenesis (46% incidence compared with 18% in wild-type mice, P = 0.007) demonstrating that Cx32 functions as a hepatic tumor suppressor in response to radiation-associated mutation events. Cx32-deficient mice also exhibited increased lung tumorigenesis (bronchioloalveolar) with an increased progression to carcinoma when compared with wild-type mice. Two Cx32-deficient mice developed an uncommon, invasive medullary adrenal tumor type (pheochromocytoma) not observed in irradiated wild-type mice. Immunohistochemical analysis revealed increased levels of activated mitogen-activated protein kinase (MAPK) (p44/Erk1, p42/Erk2) in Cx32-deficient mouse liver tumors (P = 0.006), lung tumors (P = 0.056) and adrenal tumors (primary and metastases) compared with wild-type counterparts implicating elevated activation of MAPK-interacting pathways in Cx32-deficient tumorigenesis. Interestingly, lung tumors from Cx32-deficient mice also demonstrated decreased p27Kip1 levels compared with wild-type lung tumors (P = 0.05). This study demonstrates that loss of Cx32/GJIC plays a significant role in radiation-induced tumorigenesis of the liver and importantly that Cx32 may also play a role in tumor suppression and/or tumor progression in other tissue types such as lung and adrenal gland. Additionally, this mouse model suggests that MAPK-related pathways may be preferentially activated or conversely that tumors harboring activated MAPK pathways may selectively progress towards more advanced tumor states in the absence of Cx32-mediated GJIC.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Hirabayashi, B.-I. Yoon, I. Tsuboi, Y. Huo, Y. Kodama, J. Kanno, T. Ott, J. E. Trosko, and T. Inoue Protective Role of Connexin 32 in Steady-State Hematopoiesis, Regeneration State, and Leukemogenesis Experimental Biology and Medicine, May 1, 2007; 232(5): 700 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Plante, D. G. Cyr, and M. Charbonneau Sexual Dimorphism in the Regulation of Liver Connexin32 Transcription in Hexachlorobenzene-Treated Rats Toxicol. Sci., March 1, 2007; 96(1): 47 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. McLachlan, Q. Shao, H.-l. Wang, S. Langlois, and D. W. Laird Connexins Act as Tumor Suppressors in Three-dimensional Mammary Cell Organoids by Regulating Differentiation and Angiogenesis. Cancer Res., October 15, 2006; 66(20): 9886 - 9894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Hix, D. A. Frey, M. D. McLaws, M. Osterlie, S. F. Lockwood, and J. S. Bertram Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative Carcinogenesis, September 1, 2005; 26(9): 1634 - 1641. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Trosko and B. L. Upham The emperor wears no clothes in the field of carcinogen risk assessment: ignored concepts in cancer risk assessment Mutagenesis, March 1, 2005; 20(2): 81 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J E Trosko The role of stem cells and cell-cell communication in radiation carcinogenesis: ignored concepts Br. J. Radiol., January 1, 2005; Supplement_27(1): 132 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. King and P. D. Lampe The Gap Junction Protein Connexin32 Is a Mouse Lung Tumor Suppressor Cancer Res., October 15, 2004; 64(20): 7191 - 7196. [Abstract] [Full Text] [PDF]
|
|