Macrophage migration inhibitory factor of Syrian golden hamster has similar structure and function as human MIF and promotes pancreatic tumor growth

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster (Mesocricetus auratus), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize structure and function of hamster MIF, and finally evaluate its effect on pancreatic tumor growth in vivo. Initially, the recombinant hamster MIF (rha-MIF) was cloned, expressed and purified in bacterial expression system. The rha-MIF primary sequence, biochemical properties and crystal structure analysis showed a greater similarity with human MIF. The crystal structure of hamster MIF illustrates that it forms a homotrimer as known in human and mouse. However, hamster MIF exhibits some minor structural variations when compared to human and mouse MIF. The in vitro functional studies show that rha-MIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of rha-MIF into HapT1 pancreatic tumor bearing hamsters significantly enhanced the tumor growth and tumor associated angiogenesis. Together, the current study shows a structural and functional similarity between hamster and human MIF. Moreover, it has demonstrated that a high-level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growth in vivo.All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/449629 doi: bioRxiv preprint pleiotropic effects on immune cells, cancer cells, as well as non-cancerous cells made MIF more enigmatic to the researchers. Involvement of MIF in a number of human diseases like pulmonary hypertension, endothelial cell growth, atherosclerosis, wound healing, viral infection, many cancers including lung, colon, prostate, breast and pancreatic cancer has bagged a significant interest in this molecule [21]. In one of our All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/449629 doi: bioRxiv preprint 4 earlier published study, we have characterized HapT1 cell line-based Syrian hamster tumor as a model of pancreatic cancer associated desmoplasia, an event which plays a key role in human pancreatic cancer progression [10]. In that study, for the first time, global proteomics analysis of whole cell lysate from hamster pancreatic stellate cells (PSCs) showed expression of macrophage migration inhibitory factor (MIF)...