OncomiR Addiction Is Generated by a miR-155 Feedback Loop in Theileria-Transformed Leukocytes

Abstract

The intracellular parasite Theileria is the only eukaryote known to transform its mammalian host cells. We investigated the host mechanisms involved in parasite-induced transformation phenotypes. Tumour progression is a multistep process, yet ‘oncogene addiction’ implies that cancer cell growth and survival can be impaired by inactivating a single gene, offering a rationale for targeted molecular therapies. Furthermore, feedback loops often act as key regulatory hubs in tumorigenesis. We searched for microRNAs involved in addiction to regulatory loops in leukocytes infected with Theileria parasites. We show that Theileria transformation involves induction of the host bovine oncomiR miR-155, via the c-Jun transcription factor and AP-1 activity. We identified a novel miR-155 target, DET1, an evolutionarily-conserved factor involved in c-Jun ubiquitination. We show that miR-155 expression led to repression of DET1 protein, causing stabilization of c-Jun and driving the promoter activity of the BIC transcript containing miR-155. This positive feedback loop is critical to maintain the growth and survival of Theileria-infected leukocytes; transformation is reversed by inhibiting AP-1 activity or miR-155 expression. This is the first demonstration that Theileria parasites induce the expression of host non-coding RNAs and highlights the importance of a novel feedback loop in maintaining the proliferative phenotypes induced upon parasite infection. Hence, parasite infection drives epigenetic rewiring of the regulatory circuitry of host leukocytes, placing miR-155 at the crossroads between infection, regulatory circuits and transformation.

miR-146a and miR-155 Delineate a MicroRNA Fingerprint Associated with Toxoplasma Persistence in the Host Brain

“…We compared host miRNA expression levels in cells infected with Toxoplasma , Theileria or Cryptosporidium using our dataset and previously published datasets and this revealed that these apicomplexan parasites modulate the expression of a restricted panel of miRNAs in a specific manner, most likely in order to suit their respective biology. This can be illustrated by miR-155, a microRNA implicated in immune response (Lindsay, 2008) that was strongly induced by both Toxoplasma (Figures S1B) and Theileria (Marsolier J et al, 2013) while being unaffected by Crytosporidium infection (Zhou et al, 2009). …”

What’s the Damage? The Impact of Pathogens on Pathways that Maintain Host Genome Integrity

“…This results in deregulation of the p53 checkpoint pathway and is critical for parasite pathogenesis. Theileria infection induces expression of the miR-155 oncomiR, which targets DET1, a component of the ubiquitin ligase complex containing DNA damage-binding protein 1 (DDB1) (Marsolier et al, 2013). These recent studies provide evidence for links between parasite-encoded proteins and host signaling pathways that regulate apoptosis and damage signaling.…”

Theileria-transformed bovine leukocytes have cancer hallmarks

“…In fact, the use of Theileria-transformed bovine cells to study these phenotypes has already begun, with Theileria-transformed bovine cells being used as a xenograft model in mice [98]. Using standard cancer biology assays, in vitro systems have been developed as well [19]. The fact that no genomic instability has been reported in infected cells may indicate an absence of the confounding effects of the 99.9% bystander mutations that are found in most cancer cell lines [99].…”

“…Pattern-recognition receptors can also activate NF-kB to induce in vivo antimicrobial programs that are crucial for innate and adaptive immunity [16], and many pathogens have the ability to suppress NF-kB signaling [17,18]. The IkB kinase (IKK) complex activates NF-kB, and Theileria schizonts have been shown to constitutively activate the IKK complex on their cell surface, possibly by trans-autophosphorylation [19]. Consequently, investigations into the mechanisms by which Theileria parasites manage to evade the immunostimulatory effects of NF-kB signaling provide an opportunity to discover novel therapeutics against Theileria infection.…”

“…These have been extensively reviewed elsewhere [15], and include mitogen-activated protein kinases, SRC family kinases, casein kinase-2, and phosphatidylinositide 3-kinase, as well as miRNA deregulation [19]. These other cancer-related affected pathways may also yield alternative chemotherapies to Theileria infection.…”