DECREASED EXPRESSION OF THE ADENOMATOUS POLYPOSIS-COLI (APC) AND MUTATED IN COLORECTAL-CANCER (MCC) GENES IN MOUSE LUNG NEOPLASIA

A decrease in the intracellular concentrations of the transcripts far some tumor suppressor genes has been found during murine lung tumorige nesis; for p15(INK4b) and p16(INK4a), this was due to homozygous delet ions. We report here a decrease in the mRNA levels of the mutated in c olorectal cancer (Mcc) and adenomatous polyposis coli (Apc) genes in m ouse lung tumors and some neoplastic cell lines. This was assessed bot h by northern blotting and reverse transcriptase-polymerase chain reac tion of RNA isolated from lung tumors that had been induced by urethan e, N-nitrosodiethylamine, or 3-methylcholanthrene in (A/J x C57BL/6) F -1 or A/J mice. A reduced amount of both Nice and Apc messages was als o seen when two neoplastic cell lines, a spontaneous transformant (E9) and a line derived from a chemically induced solid tumor (82-132), we re compared with two independently derived nontumorigenic cell lines ( E10 and C10); E9 was derived from E10, and all of these lines are prob ably of alveolar type 2 cell origin. A cell line derived from a chemic ally induced papillary lung tumor probably of bronchiolar Clara cell o rigin (LM2) had Mcc mRNA levels similar to those of C10 and E10 but re duced Apc mRNA levels. A line (p53-823) derived from a papillary tumor that arose in a mouse with a mutated p53 transgene had a reduced amou nt of the Mcc gene product only. These differential changes in the rel ative amounts of Apc and Nice messages in LM2 and p53-823 cells may se rve as useful models for studying the regulation of their expression. Both messages had half-lives of 6-9 h in normal E10 and neoplastic E9 cells, so decreased message stability does not account for these reduc tions. This is the first report of estimated degradation rates of thes e mRNAs. Apc and Mcc message content did not vary as a function of gro wth status of the cell lines. Single-strand conformation polymorphism analysis did not reveal mutations in Apc coding regions known to have a high mutation frequency in human colon tumors. Loss of heterozygosit y of Apc and Mcc was not found in tumors that developed in the F, mice , implying a lack of allelic deletions. These changes in tumor suppres sor gene expression may contribute to the development and maintenance of neoplasia in lung epithelium. (C) 1998 Wiley-Liss, Inc.