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Increased Serum and Urinary Levels of a Parathyroid Hormone-related Protein COOH Terminus in Non-Small Cell Lung Cancer Patients

First Department of Medicine, Asahikawa Medical College, Asahikawa 078-8510, Japan

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.

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