Abstract
Colorectal cancer is characterized by aberrant Cyclooxigenase-2 (COX-2) and β-Catenin pathways. Recently, the protease inhibitor SerpinB3 has been described overexpressed in more advanced stages of this tumor. Aim of the study was to explore the possible relationship between these molecules in this setting. We evaluated colorectal cancer specimens from 105 patients and a positive correlation between SerpinB3, COX-2 and β-Catenin expression was observed, with higher levels in tumor than in adjacent tissue. The highest levels were associated with pathologic parameters of poor prognosis, including vascular invasion, lymph node metastasis and perineural invasion. The molecular and protein profiles of COX-2 and β-Catenin were analyzed in cell lines with different expression of SerpinB3. In those with high expression of SerpinB3, COX-2 and β-Catenin were higher than in controls. Cells with high levels of SerpinB3 showed higher proliferation and invasion compared to controls. In conclusion, in colorectal cancer SerpinB3, COX-2 and β-Catenin are positively correlated and associated with more advanced tumor stage. The in vitro experimental results support a driving role of SerpinB3 in the upregulation of COX-2/ β-Catenin positive loop, associated with a more aggressive cellular phenotype.
Highlights
Colorectal cancer (CRC) is a multistep process characterized by genetic aberrations of several oncogenes
We evaluated colorectal cancer specimens from 105 patients and a positive correlation between SerpinB3, COX-2 and β-Catenin expression was observed, with higher levels in tumor than in adjacent tissue
A significant higher expression of all three genes was detected in tumor tissue, compared to matched non-tumor tissue (Figure 1, upper panel). In line with these results, a significant correlation was found between the expression of the three molecules that was higher in tumor specimens, especially between COX-2 and SerpinB3 (Figure 1, lower panels)
Summary
Colorectal cancer (CRC) is a multistep process characterized by genetic aberrations of several oncogenes. Catanzaro et al have demonstrated that mutant K-RAS induces inflammatory cytokine production and tumorigenesis by upregulating SerpinB3 and SerpinB4 isoforms, both members of the serine/cysteine protease inhibitors family [8]. These serpins have been previously reported to stimulate liver carcinogenesis [9]. COX-2 enhances prostaglandin E2 (PGE2) levels, can induce inflammation, cell proliferation, angiogenesis, EMT and invasiveness and it was found increased in more advanced forms of breast, colon, biliary tract, skin, lung and liver cancer [20,21,22,23]. COX-2/PGE2 may exert their pro-oncogenic action through the stimulation of the β-Catenin/LEF1/
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