Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27^Kip1-Deficient Mice

Abstract

Connexin32 knockout mice (Cx32-KO) exhibit increased chemical and radiation-induced liver and lung tumorigenesis. This increased tumor incidence is associated with altered tumor biology including enhanced tumor progression and an increased percent of MAPK-active tumors. Likewise, mice lacking the tumor suppressor/cell cycle regulator p27Kip1 exhibit increased tumorigenesis in a variety of tissues following chemical and radiation induction. Interestingly, in a double-deficient mouse model (DKO), additional loss of p27Kip1 in a Cx32-KO background results in attenuation of liver and lung tumorigenesis as well as MAPK activation profiles, suggesting pathway interaction. While these mouse strains exhibit altered liver and lung tumor susceptibility following both chemical (DEN) and radiation (X-ray) induction protocols, comparisons of the resulting tumor incidence, multiplicity, tumor progression, and MAPK activation in response to these two distinct carcinogens underscores the separate influence of each individual gene on both tumor formation and activation of specific oncogenic pathways. Furthermore, these studies demonstrate that different carcinogens interact disparately with Cx32/p27Kip1 genotypic backgrounds in situ resulting in varied tumorigenic response.

Intercellular Redistribution of cAMP Underlies Selective Suppression of Cancer Cell Growth by Connexin26

“…Furthermore, there are several documented cases where the exogenous expression of connexins in a transformed cell line can dramatically suppress its transformed properties and its ability to form tumors in nude mice [Cx43 in C6 glioma cells [ 11 ]; Cx43 in 10T1/2 embryonic mesenchymal cells [ 12 ]; Cx43 and Cx32 in LNCaP prostate cancer cells [ 13 ]; Cx26 in HeLa cervical cancer cells [ 14 ]; Cx26 and Cx43 in MDA-MB-231 breast cancer cells [ 15 , 16 ], and; Cx32 in SKHep1 hepatoma cells [ 17 ]. The latter is also consistent with an increase in hepatic tumorigenesis observed in Cx32-/- mice [ 8 , 18 ].…”

Connexins: sensors and regulators of cell cycling

“…observed that effects on cell growth can occur independently of changes in channel activity, in casu GJIC [112,114,118,121,122,[142][143][144]148,156,160,[204][205][206][207][208][209][210][211][212][213][214][215]. In consistence with these observations is the fact that connexin proteins, as single entities, can affect the production and/or activity of cell growth regulators, including p27 Kip1 , cyclin A, cyclin D1, cyclin D2, cdk5, cdk6, ERK1/2, signal transducer and activator of transcription protein 3, Src, human EGF receptor 2, FGF1 and FGF receptor 3 which may [122,[142][143][144]152,155,169,[216][217][218][219][220][221] or may not [122,[142][143][144]148,156,160,209,212,222,…”

Androgen-regulated Formation and Degradation of Gap Junctions in Androgen-responsive Human Prostate Cancer Cells

“…For example, Cx32 is abundantly expressed in the hepatocytes, and knockout mice for this Cx exhibit a higher incidence of chemical-and radiation-induced liver tumors than their wild-type counterparts, respectively (Temme et al, 1997;Lampe, 2005a, 2005b). Also, Cx32 has been documented to act as a lung tumor suppressor, as assessed by higher bronchioloalveolar tumor incidence (King and Lampe, 2004;King et al, 2005aKing et al, , 2005b. Distinct dominant mutations in Cx26, a Cx abundantly expressed in the inner ear and skin, have been shown to cause not only hearing loss but also autosomal dominant disorders of epidermal keratinization and differentiation (Kelsell et al, 2001).…”