Parathyroid hormone-related protein (
PTHrP) is expressed in a variety of human
cancers including
lung cancer. Three mature
peptides with different COOH-terminal regions,
PTHrP (1-139),
PTHrP (1-173), and
PTHrP (1-141), are translated 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 levels. We used PCR to evaluate
PTHrP mRNA expression and its alternative splicing types in 16
lung cancer cell lines and 17
lung cancer tissues. The average serum C-
PTHrP level was 38.95 +/- 19.41 pmol/l in 28
lung cancer patients, whereas that in 10 normal subjects was 26.53 +/- 9.43; the difference was statistically significant (P = 0.0065). Average urine C-
PTHrP:urine
creatinine ratio was 7.56 +/- 5.17 x 10(-1) pmol/mg
creatinine in 28
lung cancer patients, whereas it was 4.91 +/- 1.77 in 10 normal subjects; the difference was statistically significant (P = 0.0287). C-
PTHrP radioimmunoassays detected 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 than average + 2 SD of normal subjects. Reverse transcription-PCR detected
PTHrP mRNA expression in 21 of 21
non-small cell lung cancer (NSCLC) samples and 3 of 12
small cell lung cancer samples. In the
cancer cell lines and tissues 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 found in 23 of 24. Our results suggest that all
PTHrP mRNA expression is common 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
PTHrP more frequently, but there was no clear significance of C-
PTHrP measurement 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 proliferation factor in
lung cancer, especially NSCLC, at a level insufficient to cause
humoral hypercalcemia of malignancy.