Thioredoxin Reductase-1 as a Potential Biomarker in Fibroblast-Associated HCT116 Cancer Cell Progression and Dissemination in a Zebrafish Model

SIMPLE SUMMARY: Prognostic biomarkers, which are used to monitor colorectal cancer status and guide treatment decisions, are crucial. This study aimed to investigate thioredoxin reductase-1 (TrxR-1) expression, which has been related to disease progression in various cancers, for an indication of fibroblast-inducing colorectal cancer progression and metastasis. We suggest thioredoxin reductase-1 as a potential biomarker that can indicate the high proliferative fibroblast-induced-aggressiveness of HCT116 colorectal cancer cells in vitro and in vivo in adult zebrafish models. Therefore, TrxR-1 could be applied as a biomarker for colorectal cancer progression and prognostic evaluation. ABSTRACT: The tumor microenvironment, especially that of fibroblasts, strongly promotes colorectal cancer (CRC) progression. Progressive cancers usually accumulate high reactive oxygen species (ROS), leading to oxidative stress. The stress relates to the expression of thioredoxin reductase-1 (TrxR-1), which is an oxidative stress sensitivity molecule. This study aimed to investigate TrxR-1 expression as an indication of colon-fibroblast-inducing colorectal cancer progression and metastasis. We found that the high proliferative fibroblast-cultured media (FCM) contained pro-inflammatory cytokines that have a high ability to influence HCT116 and CRC cell progression, when compared with complete media (CM) as a control in terms of growth (CM = 100.00%, FCM = 165.96%), migration (CM = 32.22%, FCM = 83.07%), invasion (CM = 130 cells/field, FCM = 449 cells/field), and EMT transformation while decreasing E-cadherin expression (CM = 1.00, FCM = 0.69) and shape factor (CM = 0.94, FCM = 0.61). In addition, the overexpression of TrxR-1 is associated with cellular oxidant enchantment in FCM-treated cells. A dot plot analysis showed a strong relation between the EMT process and the overexpression of TrxR-1 in FCM-treated cells (CM = 13/100 cells, FCM = 45/100 cells). The cancer transplantation of the adult zebrafish model illustrated a significantly higher number of microtumors in FCM-treated cells (CM = 4.33 ± 1.51/HPF, FCM = 25.00 ± 13.18/HPF) disseminated in the intraperitoneal cavity with TrxR-1 positive cells. The overexpression of TrxR-1 indicated fibroblast-associated CRC progression in HCT116 cells and the zebrafish model. Therefore, TrxR-1 could be applied as a novel biomarker for colorectal cancer progression and prognostic evaluation.