Global miRNA expression profiling of domestic cat livers following acute Toxoplasma gondii infection

Cong, Wei; Zhang, Xiao-Xuan; He, Jun-Jun; Li, Fa-Cai; Elsheikha, Hany M.; Zhu, Xing-Quan

Differentially expressed miRNAs were associated with signalling pathways involved mainly in cell cycling, apoptosis, oncogenesis, and host defense. Among the differentially expressed miRNAs, miR-21a-5p, miR-17-5p, miR-223-3p, miR-27a-5p, miR-126, and miR-486 were significantly upregulated in T. gondii-infected livers compared to controls. Of note, the level of miR-21a-5p expression was elevated in various cancer tissues, including rectal, gastric and lung tissues [25] [26] [27] and has been suggested to play a role in tumor biology [27] . The similarity between the expression of miR-21a-5p during T. gondii infection and various forms of cancers is interesting. One striking finding was the correlative link between upregulation of miR-17-92 in T. gondiiinfected human foreskin fibroblasts [28] and in human astrocyticglioma tissue [29] . The presence of RNA silencing machinery and small silencing RNAs in T. gondii genome [30] indicates that this parasite has the ability to use its own miRNAs to interrupt host cell functions in analogy to oncogenic viruses [31] . miR-17-5p, a key regulator of the G1/S phase cell cycle transition, was up-regulated in our study in agreement with others who reported overexpression of miR-17-5p in human and mouse spleen in response to T. gondii infection [21, 31] . T. gondii can increase miR-17~92 and miR-106b~25 that play key roles in the regulation of mammalian cell cycle by influencing the functionally intertwined pathways of apoptosis and G1/S cell cycle progression [32] . miR-17-5p targets mouse Bcl2l11, Zmat3, Aifm1, and Capn2 to increase host apoptotic process and targets mouse Ppp3r1 and Akt3 to promote cellular apoptosis process [21] . Also, miR-17-5p may function as both a tumor suppressor [33] and as an oncogenic activator [34] by targeting both anti-and proproliferative genes and by competing with each other in different cellular contexts [35] . The effect of T. gondii infection on the expression of miRNAs (miR-30c-1, miR-125b-2, miR-23b-27b-24-1, and miR-17~92 cluster genes) that have anti-apoptotic activity has been reported [36] . Modulating these apoptosis-related miRNAs with mimics The miR-223-3p has been implicated in the regulation of inflammatory response [37] and granulocyte production and function [38] , and can function as a tumor suppresser in osteosarcoma by regulating the osteosarcoma cell cycle progression and proliferation [39] . The level of miR-223-3p was significantly increased in infected samples, suggesting that T. gondii infection of feline liver stimulates the production of miR-223-3p, which plays a role in the activation of inflammatory response elicited in response to T. gondii infection. This is concordant with a previous study showing that miRNAs, such as miR-146a and miR-155, known to activate immune and inflammatory responses can influence host response to T. gondii infection [40] [41] [42] [43] . Also, the upregulation of miR-27a-5p (a regulator of lipid metabolism-related genes) and miR-21-5p in the infected liver samples suggests that both miR-27a-5p and miR-21-5p play a role in host response to infection. This assumption is supported by the association between inhibition of miR-21 and increased Cryptosporidium parvum burden [29] .