Abstract
BackgroundThe family of proprotein convertases has been recently implicated in tumorigenesis and metastasis in animal models. However, these studies have not yet been completely corroborated in human tumors.MethodsUsing 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.ResultsmRNA, 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.ConclusionThe 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.
Highlights
The family of proprotein convertases has been recently implicated in tumorigenesis and metastasis in animal models
Amongst the proprotein convertases (PCs), PC1 and PC2 are unique due to their processing activity specific to the regulated secretory pathway, and their localization in dense core secretory granules. Both proteins are synthesized in the Endoplasmic Reticulum (ER) as zymogens, transported through the Golgi apparatus, and the Trans Golgi Network (TGN) into mature secretory granules, and both are proteolytically activated along the way
PC2 mRNA was overexpressed two-fold in areas of unaffected and normal liver compared to areas of metastasis (P < 0.003, Figure 2A)
Summary
The family of proprotein convertases has been recently implicated in tumorigenesis and metastasis in animal models. These studies have not yet been completely corroborated in human tumors. Recent reports have demonstrated the pivotal role of the proprotein convertases (PCs) (1) in tumor growth and metastasis of HT29 human colon carcinoma cells (2), lung (3) or breast cancer cells (4). Amongst the PCs, PC1 and PC2 are unique due to their processing activity specific to the regulated secretory pathway, and their localization in dense core secretory granules Both proteins are synthesized in the Endoplasmic Reticulum (ER) as zymogens (primary cleavage of the zymogen of proPC1 occurs in the ER while that of proPC2 occurs in the granules), transported through the Golgi apparatus, and the Trans Golgi Network (TGN) into mature secretory granules, and both are proteolytically activated along the way. Recently a specific PC1 inhibitor, ProSAAS has been identified [10], but its physiological function remains unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
