Cancer of the colon and rectum is an important public health issue, constituting a major cause of worldwide morbidity and mortality (Pisani et al, 2002
; Jemal et al, 2009
). In Europe, CRC is the second most common malignancy among women after breast cancer and the third most frequent in men after prostate and lung cancer. Moreover, CRC is the second most common cause of cancer death for both sexes, accounting for 12% of all tumour-related deaths (Parkin et al, 2001b
; Ferlay et al, 2010
). Early diagnosis of CRC and early detection of recurrence after surgery are critical for effective treatment and/or positive clinical outcome. Endoscopic examination of the colon remains the most reliable screening method for this type of malignancy (Newcomb et al, 1992
; Lieberman et al, 2000
All existing classification systems for CRC distinguish between patients with early-stage CRC and those with very advanced-stage disease; nonetheless, they are less efficient in predicting the prognosis of patients with intermediate levels of tumour burden (McLeod and Murray, 1999
). On the basis of studies published over the last few years, the American Society of Clinical Oncology Tumour Marker Panel and the European Group on Tumour Markers have recently suggested that preoperative carcinoembryonic antigen (CEA) levels may be used as an independent prognostic factor, assisting in staging and surgical treatment planning. It should also be noted that CEA is the marker of choice for monitoring the response of metastatic disease to systemic therapy (Duffy et al, 2003
; Locker et al, 2006
). However, neither CEA nor any other biomarkers that have been proposed in the past, such as CA19-9, have enough sensitivity for colon cancer detection (van der Schouw et al, 1992
; Pokorny et al, 2000
; Locker et al, 2006
-DOPA decarboxylase is a PLP-dependent enzyme participating in the catecholamine biosynthesis pathway, responsible principally for the synthesis of the key neurotransmitters DA and 5-HT (Christenson et al, 1972
). Biogenic amines are generally considered to participate in various processes, such as angiogenesis, cell proliferation, differentiation and apoptosis (Berry et al, 1996
; Medina et al, 1999
; Lang et al, 2005
), which implies a potentially significant role of DDC in cancer pathobiology and progression. Interestingly enough, it has recently been shown that catecholamines, including DA itself, inhibit erythrocyte apoptosis by preventing scramblase activation and subsequent phosphatidylserine exposure on the cell membrane (Lang et al, 2005
), which in turn triggers clearance of apoptotic cells by macrophages.
mRNA expression is used for the differential diagnosis of neuroblastoma from other pediatric small round-cell malignancies (Gilbert et al, 1999
; Bozzi et al, 2004
). Quantification of DDC
mRNA expression using real-time RT-PCR has been proposed as a method useful for the prediction of peritoneal recurrence in patients with gastric carcinoma (Sakakura et al, 2004
). In addition, DDC protein expression is a biomarker of neuroendocrine differentiation in SCLC cells and prostate carcinoma (Gilbert et al, 2000
; Wafa et al, 2007
mRNA levels were also found to be particularly elevated in cancerous prostate tissue, in comparison with benign prostate hyperplasia. High-expression levels of DDC
were found to be associated with more aggressive prostate tumours (Avgeris et al, 2008
Several peripheral cancers are characterised by an extremely high DDC activity, associated with the tumour. This is especially apparent with lung cancers of small-cell origin, although variants showing no protein expression have been observed as well (Berry et al, 1996
). Remarkable increase in DDC activity, in comparison with normal tissue levels, is also seen in primary intestinal cancer and its related metastases in the spleen and liver (Gilbert et al, 1995
). The significance of this increase in DDC activity and resultant monoamine synthesis by the cancer cells is still unknown (Berry et al, 1996
), yet it is closely related to the implication of DDC in cancer.
In this study, we investigated the expression of the DDC gene in colorectal adenocarcinoma and its prognostic significance. Our study revealed a statistically significant, negative association between DDC mRNA expression levels and the histologic tumour grade (P=0.011). Colorectal tumours of low histologic grade (I) were more frequently DDC-positive, in contrast with malignancies of high grade (II/III). These data seem to indicate that higher DDC expression is associated with well-differentiated intestinal tumours.
In accordance with the above-mentioned results, the Kaplan–Meier analysis showed significantly higher DFS and OS time for patients having positive DDC mRNA expression (P=0.009 and P=0.027, respectively). Cox univariate regression analysis showed that DDC-positive patients had a significantly lower risk of relapse (~5 times) and a higher probability of survival (~4 times). In the Cox multivariate regression model, the levels of DDC mRNA were adjusted for patients' nodal status, Dukes' stage and histologic tumour grade. When all these non-molecular parameters were included in the multivariate analysis model, DDC mRNA expression did not show statistically significant independence as a prognostic factor for DFS or OS of patients with colorectal adenocarcinoma.
In conclusion, this study revealed that higher mRNA expression levels of DDC are related with less advanced and/or aggressive tumours. Our results imply that DDC mRNA overexpression is linked to favorable prognosis in patients with colorectal adenocarcinoma and may constitute a useful tissue biomarker. Involvement of DDC in apoptosis of colon cancer cells and/or response of DDC-positive tumours to chemotherapy are two potential explanations, but further investigation is required to clarify the role of DDC in CRC.