Nishigaki Y, Ohsaki Y, Toyoshima E, Kikuchi K
First Department of Medicine, Asahikawa Medical College, Japan.
Clin Cancer Res. 1999 Jun;5(6):1473-81.
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.
甲状旁腺激素相关蛋白（PTHrP）在包括肺癌在内的多种人类癌症中表达。通过可变剪接从三种不同的mRNA翻译出具有不同COOH末端区域的三种成熟肽，即PTHrP（1 - 139）、PTHrP（1 - 173）和PTHrP（1 - 141）。在每种肽中，COOH末端片段（C - PTHrP）在尿液中是稳定且可测量的。在本研究中，我们测量了28例原发性肺癌且血清钙水平正常的患者循环血和尿液中C - PTHrP的浓度。我们使用聚合酶链反应（PCR）评估了16种肺癌细胞系和17个肺癌组织中PTHrP mRNA的表达及其可变剪接类型。28例肺癌患者的血清C - PTHrP平均水平为38.95±19.41 pmol/L，而10名正常受试者的该水平为26.53±9.43 pmol/L；差异具有统计学意义（P = 0.0065）。28例肺癌患者的尿C - PTHrP与尿肌酐比值平均为7.56±5.17×10⁻¹ pmol/mg肌酐，而10名正常受试者的该比值为4.91±1.77；差异具有统计学意义（P = 0.0287）。C - PTHrP放射免疫分析检测到23%的非小细胞肺癌患者血清C - PTHrP水平较高，32%的患者尿C - PTHrP与尿肌酐比值高于正常受试者平均值 + 2标准差。逆转录 - PCR在21份非小细胞肺癌（NSCLC）样本中的21份以及12份小细胞肺癌样本中的3份检测到PTHrP mRNA表达。在可检测到PTHrP mRNA的癌细胞系和组织中，24份中的21份发现了PTHrP（1 - 139）mRNA，24份中的19份发现了PTHrP（1 - 173）mRNA，24份中的23份发现了PTHrP（1 - 141）mRNA。我们的结果表明，所有PTHrP mRNA表达在肺癌中很常见。我们发现非小细胞肺癌可检测到PTHrP mRNA，且NSCLC患者的血清和尿液C - PTHrP水平显著高于正常受试者。我们得出结论，NSCLC更频繁地产生PTHrP，但使用当前检测方法在肺癌患者中检测C - PTHrP对于癌症检测尚无明确意义。我们认为PTHrP可能在肺癌，尤其是NSCLC中发挥类似于生长因子或增殖因子的作用，但其水平不足以引起恶性肿瘤体液性高钙血症。
