Abstract
BackgroundDipeptidyl-peptidase IV (EC 3.4.14.5) (DPPIV) is a serine peptidase involved in cell differentiation, adhesion, immune modulation and apoptosis, functions that control neoplastic transformation. Previous studies have demonstrated altered expression and activity of tissue and circulating DPPIV in several cancers and proposed its potential usefulness for early diagnosis in colorectal cancer (CRC).Methods and principal findingsThe activity and mRNA and protein expression of DPPIV was prospectively analyzed in adenocarcinomas, adenomas, uninvolved colorectal mucosa and plasma from 116 CRC patients by fluorimetric, quantitative RT-PCR and immunohistochemical methods. Results were correlated with the most important classic pathological data related to aggressiveness and with 5-year survival rates. Results showed that: 1) mRNA levels and activity of DPPIV increased in colorectal neoplasms (Kruskal-Wallis test, p<0.01); 2) Both adenomas and CRCs displayed positive cytoplasmic immunostaining with luminal membrane reinforcement; 3) Plasmatic DPPIV activity was lower in CRC patients than in healthy subjects (Mann-U test, p<0.01); 4) Plasmatic DPPIV activity was associated with worse overall and disease-free survivals (log-rank p<0.01, Cox analysis p<0.01).Conclusion/significance1) Up-regulation of DPPIV in colorectal tumors suggests a role for this enzyme in the neoplastic transformation of colorectal tissues. This finding opens the possibility for new therapeutic targets in these patients. 2) Plasmatic DPPIV is an independent prognostic factor in survival of CRC patients. The determination of DPPIV activity levels in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice.
Highlights
colorectal cancer (CRC) is the third commonest malignancy in males and females in the United States, with more than 136,500 estimated new cases and more than 50,000 estimated deaths in 2014 [1]
When DPPIV activity was analyzed throughout the colorectal adenoma-adenocarcinoma sequence, higher activity was found in CRCs and adenomas than in the adjacent uninvolved mucosa (Kruskal-Wallis test, p = 0.015)
Regarding CRC, the adenoma-carcinoma sequence in the large bowel describes that the gradual progression from normal to dysplastic epithelium, and to carcinoma, is the result of the successive accumulation of genetic mutations that lead to altered levels of several glycoproteins, like some peptidases [6,8]
Summary
CRC is the third commonest malignancy in males and females in the United States, with more than 136,500 estimated new cases and more than 50,000 estimated deaths in 2014 [1]. Huge resources are being invested in prevention and early diagnosis of this disease. Population-based screening campaigns try to discover as much early tumors and precursor lesions as possible, aiming to decrease the incidence of the disease, to simplify the clinical management of patients once the lesion develops, and to improve survival. A large number of cellular metabolic processes still largely unknown are involved in the origin and development of neoplastic processes [7]. Dipeptidyl-peptidase IV (EC 3.4.14.5) (DPPIV) is a serine peptidase involved in cell differentiation, adhesion, immune modulation and apoptosis, functions that control neoplastic transformation. Previous studies have demonstrated altered expression and activity of tissue and circulating DPPIV in several cancers and proposed its potential usefulness for early diagnosis in colorectal cancer (CRC)
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