Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43

Abstract

Gap junction intercellular communication capacity and connexin expression are reportedly decreased in human lung cancer. The mechanisms by which connexins, the gap junction proteins, act as tumor suppressors are unclear. In order to understand the involvement of connexins in tumorigenesis, we analyzed the effect of the heterologous deletion of Gja1 [the connexin43 (Cx43) gene] on the development of lung adenomas in mice. Heterozygous (Cx43(+/-)) and wild-type mice (Cx43(+/+)) were treated or not with single doses of urethane at 15 and 17 days after birth. Twenty-five weeks later, both the number and size of nodules were increased in Cx43(+/-) mice as compared with Cx43(+/+) mice. Moreover, the lesions were histologically more aggressive in the heterozygous mice. However, no increase in spontaneous lesions was observed in the lungs of untreated Cx43(+/-) mice. Heterozygous mice effectively presented lower expression of Cx43 genes and decreased amounts of Cx43. In conclusion, our results indicate that deletion of one allele of the Cx43 gene clearly favors the carcinogenic effect of urethane administration and results in a higher susceptibility to lung adenoma formation in mice.

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

“…In lung, Cx32 and Cx43 have been shown to act as tumor suppressors following chemical (DEN and urethane) (Avanzo et al, 2004;King and Lampe, 2004a) and radiation exposure (King and Lampe, 2004b). Previously published histological analysis of irradiated mouse lung tissue revealed a modest increase in lung tumor incidence in p27 þ / þ ,Cx32-KO mice compared to wild-type mice (King and Lampe, 2004b).…”

“…Following exposure to radiation, Cx32-KO mice demonstrated an overall increase in tumor burden predominantly due to increased liver and lung tumorigenesis (King and Lampe, 2004b). Indeed, both Cx32 and Connexin43 have recently been shown to act as tumor suppressors in mouse lung following chemical induction (DEN and urethane) (Avanzo et al, 2004;King and Lampe, 2004a). Interestingly, a significant portion of radiationinduced Cx32-KO lung tumors also displayed decreased levels of the cell cycle regulator/tumor suppressor p27 KIP1 (King and Lampe, 2004b).…”

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

“…Enhancement of GJ function increases the cytotoxicity of chemotherapy drugs (21). Conversely, inhibition of GJ function decreases the cytotoxicity of chemotherapy drugs (22,23). However, the mechanisms of these processes remain unclear.…”

Connexin subtype expression during oral carcinogenesis: A pilot study in patients with oral squamous cell carcinoma

“…King et al (4) described a correlation between endogenous Cx43 mRNA and protein expression and increased growth control, with decreased growth capacity in HeLa cervical cancer cells. Cx43 knockout in mice leads to astrocytes exhibiting altered expression of genes associated with apoptosis, cell growth, transcription factors (10,11), and increased susceptibility of mice to pulmonary neoplasia (6). Cx26 and Cx43 expression in MDA-MB-231 breast cancer cells (5) provided similar results.…”

“…First described in cultured hepatoma cells (2), the association between GJIC and carcinogenesis has since been described in various types of tumours, such as cervical (3,4), mammary (5), bronchial (6) and colorectal carcinoma (7). Depending on tumour progression, GJIC has different functions (8).…”