Peptide derived from progranulin of the carcinogenic liver fluke, Opisthorchis viverrini stimulates cell hyperproliferation and proinflammatory cytokine production.

Purpose: Progranulin (PGRN) is a secreted glycoprotein growth factor with roles in wound healing, inflammation, angiogenesis and malignancy. An orthologue of the gene encoding human PGRN was identified in the carcinogenic liver fluke .

Methods: Sequence structure, general characteristics and possible function of PGRN was analyzed using bioinformatics. Expression profiles were investigated with quantitative RT-PCR, western blot and immunolocalization. A specific peptide of -PGRN was used to investigate a role for this molecule in pathogenesis.

Results: The structure of the gene coding for PGRN was 36,463 bp in length, and comprised of 13 exons, 12 introns, and a promoter sequence. The mRNA is 2,768 bp in length and encodes an 846 amino acids with a predicted molecular mass of 91.61 kDa. -PGRN exhibited one half and seven complete granulin domains. Phylogenetic analysis revealed that -PGRN formed its closest relationship with PGRN of liver flukes in the Opisthorchiidae. Transcripts of were detected in several developmental stages, with highest expression in the metacercaria, indicating that -PGRN may participate as a growth factor in the early development of . Western blot analysis revealed the presence of detected -PGRN in both soluble somatic or excretory/secretory products, and immunolocalization indicated high levels of expression in the tegument and parenchyma of the adult fluke. Co-culture of a human cholangiocyte cell line and a peptide fragment of -PGRN stimulated proliferation of cholangiocytes and upregulation of expression of the cytokines IL6 and IL8.

Conclusion: Ov-PGRN is expressed throughout the life cycle of liver fluke, and likely plays a key role in development and growth.