Recent evidence suggests that K-ras protooncogene
protein p21 may have a
tumor-suppressive role in the context of development of
lung adenocarcinoma. Levels of K-ras p21, raf-1,
mitogen-activated protein kinases Erk 1 and 2, the phosphorylated-activated forms of Erk 1 and 2 (Erk 1P and 2P), and
proliferating cell nuclear antigen (
PCNA) were measured by immunoblotting in mouse lung
tumors (5 to 9 mm in size) caused by
N-nitrosodimethylamine (NDMA) and in control lungs. In
tumors compared with normal lung, cell membrane-associated K-ras p21 was significantly decreased and cytosolic K-ras p21 increased. Total, membrane, and cytosolic raf-1 and Erk 1P and 2P were increased in
tumors compared with normal lung. A single dose of 5 nmol/kg
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) given after NDMA resulted in a significant 2.4-fold increase in
tumor multiplicity. A significantly greater decrease in membrane-associated K-ras p21 and increase in total and membrane associated raf-1 occurred in the NDMA/
TCDD tumors compared with the NDMA-only
tumors.
PCNA levels increased in
tumors, a finding confirmed by immunohistochemistry, and correlated with
tumor size after NDMA/
TCDD treatment but not after NDMA only. The increase in raf-1 in the
tumors was confirmed by immunohistochemistry, which also revealed an increase in raf-1-positive alveolar macrophages specifically associating with
tumors from the earliest stages. These results suggest a possible
tumor-suppressive function for K-ras p21 in lung and a positive role for raf-1 and Erk 1/2 in lung
tumorigenesis.
TCDD may promote
tumors by contributing to downregulation of K-ras and stimulation of raf-1.