Abstract
Avian leukosis is a neoplastic disease caused in part by subgroup J avian leukosis virus J (ALV-J). Micro ribonucleic acids (miRNAs) play pivotal oncogenic and tumour-suppressor roles in tumour development and progression. However, little is known about the potential role of miRNAs in avian leukosis tumours. We have found a novel tumour-suppressor miRNA, gga-miR-375, associated with avian leukosis tumorigenesis by miRNA microarray in a previous report. We have also previously studied the biological function of gga-miR-375; Overexpression of gga-miR-375 significantly inhibited DF-1 cell proliferation, and significantly reduced the expression of yes-associated protein 1 (YAP1) by repressing the activity of a luciferase reporter carrying the 3′-untranslated region of YAP1. This indicates that gga-miR-375 is frequently downregulated in avian leukosis by inhibiting cell proliferation through YAP1 oncogene targeting. Overexpression of gga-miR-375 markedly promoted serum starvation induced apoptosis, and there may be the reason why the tumour cycle is so long in the infected chickens. In vivo assays, gga-miR-375 was significantly downregulated in chicken livers 20 days after infection with ALV-J, and YAP1 was significantly upregulated 20 days after ALV-J infection (P<0.05). We also found that expression of cyclin E, an important regulator of cell cycle progression, was significantly upregulated (P<0.05). Drosophila inhibitor of apoptosis protein 1 (DIAP1), which is related to caspase-dependent apoptosis, was also significantly upregulated after infection. Our data suggests that gga-miR-375 may function as a tumour suppressor thereby regulating cancer cell proliferation and it plays a key role in avian leukosis tumorigenesis.
Highlights
Subgroup J avian leukosis virus (ALV-J), belonging to the family Retroviridae, subfamily Orthoretrovirinae and genus Alpharetrovirus, causes a variety of tumours in chickens
Livers of the infected chickens were bigger than the control group at 10 weeks (Figure 1A), and some developed tumour formations (Figure 1B). Micro ribonucleic acids (miRNAs) microarray profiling was performed in Specific pathogen-free (SPF) chicken livers of controls and animals infected with avian leukosis virus J (ALV-J) NX0101 strain, and the results showed that gga-miR-375 was significantly downregulated in SPF chicken livers of infected chickens at 10 weeks (P,0.01; Figure 1 C)
In Animal experiments, the gga-miR-375 was significantly downregulated in liver tissue from the ALV-J infected chickens from 20 days post infection (Figure 1D), which may serve as a biomarker for diagnostic purposes
Summary
Subgroup J avian leukosis virus (ALV-J), belonging to the family Retroviridae, subfamily Orthoretrovirinae and genus Alpharetrovirus, causes a variety of tumours in chickens. Infection of ALV-J in both commercial and meat-type chickens has caused major economic loss and seriously threatened the prosperity of the poultry industry all over the world [5,6,7]. It was reported, for instance, that ALV-J causes up to 60% morbidity and 20% mortality in some Chinese flocks [8]. Emerging ALV-J infections coarsely induce various tumours in both commercial laying hen flocks as well as native Chinese breeds of chickens [8,9], which results in late onset and acute tumours in the field [10,11]
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