Effect of immunosuppression in miRNAs from extracellular vesicles of colorectal cancer and their influence on the pre-metastatic niche

Valeria Tubita,Elisenda Banon-Maneus,Josep M Campistol,Daniel Moya-Rull,Ignacio Revuelta,Federico Oppenheimer,Hernando Del Portillo,Maria José Ramirez-Bajo,Jordi Rovira,Joan Segui-Barber,David Cucchiari,Fritz Diekmann,Juan José Lozano

doi:10.1038/s41598-019-47581-y

Abstract

Colorectal cancer (CRC) occurs with more aggressiveness in kidney transplant recipients compared to the general population. Immunosuppressive therapy plays a crucial role in the development of post-transplant malignancy. Concretely, cyclosporine A (CsA) has intrinsic pro-oncologic properties, while several studies report a regression of cancer after the introduction of rapamycin (RAPA). However, their effect on the extracellular vesicle (EV) content from CRC cell lines and their relevance in the pre-metastatic niche have not yet been studied. Here, we investigated the effect of RAPA and CsA in EV-miRNAs from metastatic and non-metastatic CRC cell lines and the role of relevant miRNAs transferred into a pre-metastatic niche model. EV-miRNA profiles showed a significant upregulation of miR-6127, miR-6746-5p, and miR-6787-5p under RAPA treatment compared to CsA and untreated conditions in metastatic cell lines that were not observed in non-metastatic cells. From gene expression analysis of transfected lung fibroblasts, we identified 22 shared downregulated genes mostly represented by the histone family involved in chromatin organization, DNA packaging, and cell cycle. These results suggest that EV-miR-6127, miR-6746-5p and miR-6787-5p could be a potential epigenetic mechanism induced by RAPA therapy in the regulation of the pre-metastatic niche of post-transplant colorectal cancer.

Highlights

Cancer in solid-organ transplant recipients represents the consequence of long-term immunosuppression
While cyclosporine A (CsA) has been described to activate necroptosis independently of the calcineurin pathway, its promoting effects on tumour proliferation and progression are undoubted[4,12,13,14]. Even though these mechanisms explain some of the differences observed in post-transplant malignancy (PTM) incidence and behaviour, this cannot be applied to all tumours and different colorectal cancer (CRC) subtypes[15,16]
We have previously reported that the KRAS mutation plays a relevant role in CRC progression in renal transplant recipients[5]

Summary

Introduction

Cancer in solid-organ transplant recipients represents the consequence of long-term immunosuppression. Other tumours in KTRs have a higher incidence compared to the general population, but their behaviour is not as aggressive as that of CRC4–6 These differences are largely due to the specific pro- and anti-neoplastic effects of the different immunosuppressive agents employed in KTRs. Two of the most commonly used drugs with different effects on carcinogenesis are rapamycin (RAPA) and cyclosporine A (CsA); while RAPA has anti-angiogenic and anti-proliferative effects, CsA promotes tumour formation and progression[7,8]. While CsA has been described to activate necroptosis independently of the calcineurin pathway, its promoting effects on tumour proliferation and progression are undoubted[4,12,13,14] Even though these mechanisms explain some of the differences observed in post-transplant malignancy (PTM) incidence and behaviour, this cannot be applied to all tumours and different CRC subtypes[15,16]. We studied the role of EVs in the pre-metastatic niche formation represented by a lung fibroblast cell line

Methods

Results

Conclusion