Abstract 2266: Characterization of activins and their related molecules in colorectal cancer according to clinical stage, tumor sidedness and the expression of PI3K/mTOR proteins

Background: Activins (activin-A, -B and AB) are produced by the dimerization of two β-subunits (βA- and βB-subunits) and their biological actions are controlled by their binding protein, follistatin. Activin-A is the most studied isoform in the biology of colorectal cancer (CRC), and none of the earlier studies explored the expression of the other activins. Objectives: This study measured the gene and protein expression of activins and their related molecules according to clinical stages and sidedness of primary sporadic CRC. Materials and methods: Paired malignant and normal colonic tissues from archived paraffin-embedded (n= 90 patients) alongside another set of fresh specimens (n= 40 patients) were collected. Activin β-subunits, type II receptors (ActRIIA & ActRIIB), follistatin and Smad4 mRNAs and proteins were measured by real-time PCR and immunohistochemistry in all samples. Mature activin-A, -B, -AB and follistatin proteins were measured in fresh samples by ELISA. Immunofluorescence was used to colocalise βA-subunit and ActRIIB with phosphorylated mTOR (p-mTOR(Ser2448)) and PI3K-p85-subunit-α (p-PI3K-p85α(Tyr607)), respectively. Results: The βA-subunit and ActRIIB mRNAs and proteins increased, whilst the βB-subunit, ActRIIA and Smad4 decreased, in malignant sites and the advanced cancer stages showed the maximal deregulations for all molecules. Moreover, the fresh malignant tissue levels of activin-A escalated steadily, whereas activin-AB declined, with clinical stages. The colocalisation of βA-subunit with p-mTOR(Ser2448) and ActRIIB with p-PI3K-p85α(Tyr607) also increased in the malignant tissues and was strongest during the late stages. Interestingly, follistatin showed an initial decrease in the cancerous specimens during the early stages followed by drastic increases in the advanced stages. While the targeted molecules were comparable between the right- and left-sided tumors in the early stages of cancer, more profound deregulations were detected in the right-sided cancers in the late stages. Conclusions: Activins and their associated molecules showed multi-layered stage-dependent dysregulations in CRC and were markedly altered in the right-sided tumors during the advanced stages of malignancy. More functional studies are needed to precisely identify the roles of activins in colon carcinogenesis. Acknowledgment: This project was funded by the DEANSHIP OF SCIENTIFIC RESEARCH AT UMM AL-QURA UNIVERSITY; Project (17-MED-1-01-0068). Citation Format: