Increased serum and urinary levels of a parathyroid hormone-related protein COOH terminus in non-small cell lung cancer patients

Parathyroid hormone-related protein (PTHrP) is expressed in a variety of hu man cancers including lung cancer. Three mature peptides,vith different COO H-terminal regions, PTHrP (1-139), PTHrP (1-173), and PTHrP (1-141), are tr anslated from three different mRNAs through alternative splicing. In each, COOH-terminal fragment (C-PTHrP) is stable and measurable in the urine. In the present study, we measured concentrations of circulating and urinary C- PTHrP in 28 patients with primary lung cancer and normal serum calcium leve ls. We used PCR to evaluate PTHrP mRNA expression and its alternative splic ing types in 16 lung cancer cell lines and 17 lung cancer tissues. The aver age serum C-PTHrP level was 38.95 +/- 19.41 pmol/l in 28 lung cancer patien ts, whereas that in 10 normal subjects was 26.53 +/- 9.43; the difference w as statistically significant (P = 0.0065). Average urine C-PTHrP:urine crea tinine ratio was 7.56 +/- 5.17 x 10(-1) pmol/mg creatinine in 28 lung cance r patients, whereas it was 4.91 +/- 1.77 in 10 normal subjects; the differe nce was statistically significant (P = 0.0287). C-PTHrP radioimmunoassays d etected that 23% of non-small cell lung cancer patients had higher serum C- PTHrP levels, and 32% had higher urinary C-PTHrP:urine creatinine ratio tha n average + 2 SD of normal subjects. Reverse transcription-PCR detected PTH rP mRNA expression in 21 of 21 non-small cell lung cancer (NSCLC) samples a nd 3 of 12 small cell lung cancer samples. In the cancer cell lines and tis sues that had detectable PTHrP mRNA, PTHrP (1-139) mRNA was found in 21 of 24, PTHrP (1-173) mRNA was found in 19 of 24, and PTHrP (1-141) mRNA was fo und in 23 of 24. Our results suggest that all PTHrP mRNA expression is comm on in lung cancers. We found that NSCLCs cancers had detectable PTHrP mRNA, and serum and urinary C-PTHrP levels in NSCLC patients were significantly higher than those in normal subjects. We concluded that NSCLC produced PTHr P more frequently, but there was no clear significance of C-PTHrP measureme nt in lung cancer patients for cancer detection using the present assay. We suggested that PTHrP probably plays a role similar to a growth factor or p roliferation factor in lung cancer, especially NSCLC, at a level insufficie nt to cause humoral hypercalcemia of malignancy.