Abnormal expression and processing of the proprotein convertases PC1 and PC2 in human colorectal liver metastases

Using RT PCR, immunoblot and immunohistochemistry we assessed the presence and the processing patterns of the convertases PC1 and PC2 as well as the PC2 specific chaperone 7B2 in human liver metastases originating from colorectal cancer and compared them to unaffected and normal liver. Furthermore, we assessed the presence and processing profiles of PC1, PC2 and 7B2 in primary colon cancers.mRNA, protein expression, and protein cleavage profiles of proprotein convertases 1 and 2 are altered in liver colorectal metastasis, compared to unaffected and normal liver. Active PC1 protein is overexpressed in tumor, correlating with its mRNA profile. Moreover, the enhanced PC2 processing pattern in tumor correlates with the overexpression of its specific binding protein 7B2. These results were corroborated by immunohistochemistry. The specific and uniform convertase pattern observed in the metastases was present only in a fraction of primary colon cancers.The uniformly altered proprotein convertase profile in liver metastases is observed only in a fraction of primary colon cancers, suggesting possible selection processes involving PCs during metastasis as well as an active role of PCs in liver metastasis. In addition, the exclusive presence of 7B2 in metastatic tumors may represent a new target for early diagnosis, prognosis and/or treatment.Liver metastasis remains the major cause of therapeutic failure in colorectal carcinoma. Amongst the 300,000 people that are given the diagnosis of colorectal cancer (CRC) every year in Europe and North America, 60% will eventually develop liver metastases, and several of them will succumb from their disease. Metastasis microenvironment conditioned by the tumor itself, may represent an alternative to the "seed-soil" theory. Indeed recent reports have demonstrated the pivotal role of the proprotein convertases (PCs) (1) in tumor growth and metastasis of HT-29 human colon carcinoma cells (2), lung (3) or breast cancer cells (4). To date ei