Significance of dipeptidyl peptidases as marker enzyme of oral cancer

二肽基肽酶（Dipeptidyl peptidases， DPP）根据底物特异性分为I-IV类。其中，DPP IV特异性水解n端甘氨酸脯氨酸，存在于微粒体膜中；DPP II特异性裂解n端赖丙氨酰，主要存在于溶酶体中。我们报道了口腔癌患者血清DPP IV活性显著降低，而血清DPP II活性显著升高，提示它们可能成为口腔癌的标志物。然而，改变血清酶活性的确切机制是什么，以及在癌变的哪个阶段血清酶水平开始改变，仍然是未知的。本研究采用9,10-二甲基-1,2-苯并蒽（DMBA）致鼠颊袋癌的方法，研究了癌前组织和癌组织中酶的表达及血清酶活性水平的变化。应用DMBA诱导乳头状瘤后第8 ~ 10周，血清dpp4水平逐渐下降。随着原位癌或早期浸润性癌的发生，酶水平进一步降低（p<0.001），当病理诊断为鳞状细胞癌时，酶水平降至正常水平的一半以下。该酶水平在肿瘤切除时升高，在肿瘤复发至死亡时再次降低。相比之下，血清DPP II活性在癌变早期略有升高，随着鳞状细胞癌的发展而显著升高（p<0.01）。该酶的活性与DPP IV的活性呈反比变化。兔抗大鼠DPP IV血清免疫组织染色未发现正常组织与癌前组织或癌前组织有明显差异。这些发现提示血清DPP IV和II活性可能是有用的肿瘤负荷标志物；尤其是DPP IV活性，从癌变早期就开始改变。

Dipeptidyl peptidases(DPP) are classified into four types, I-IV, according to the substrate specificity. Among them, DPP IV specifically hydrolyzes N-terminal glycylprolyl and is present in microsomal membranes, and DPP II specifically cleaves N-terminal lysylalanyl and is mainly in lysosomes. We have reported that serum DPP IV activity was significantly decreased in oral cancer patients whereas serum DPP II activity was significantly increased, suggesting that they become a possible marker of oral cancer. However, what is the precise mechanism for changing serum enzyme activities and at which stage of carcinogenesis the serum enzyme level begins to be changed, are still unknown.In the present study, the enzyme expression in the precancerous and cancerous tissues and the change of serum enzyme activity level were investigated using hamster buccal pouch carcinogenesis with 9,10-dimethyl-1,2-benzanthracene (DMBA). The serum DPP IV level was decreased gradually from the 8th to 10th week when papillomas were induced by DMBA application. The enzyme level was further decreased as carcinoma in situ or early invasive carcinoma developed (p<0.001), and reached to less than half of the normal level at the time when tumors were diagnosed as squamous cell carcinoma histologically. This enzyme level was increased by tumor excision and decreased again by tumor recurrence toward death. In contrast, serum DPP II activity showed a minor increase in the early stage of carcinogenesis, and increased significantly as squamous cell carcinoma developed (p<0.01). This enzyme activity tended to change reciprocally to DPP IV activity. Immunohistological staining with rabbit anti-rat DPP IV serum did not detect the significant difference between normal and precancerous or cancerous tissues.These findings suggest that serum DPP IV and II activities might be useful as tumor-burden markers ; especially, DPP IV activity, which changed from the early stage of carcinogenesis.