Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing and Potentially Promotes Neoplasia.
Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated with wound healing and cancer pathways. Given the notable but seemingly paradoxical properties of liver fluke granulin in promoting not only wound healing but also a carcinogenic microenvironment, Ov-GRN-1 likely holds marked potential as a therapeutic wound-healing agent and as a vaccine against an infection-induced cancer of major public health significance in the developing world.
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
Michael J
MJ
Smout
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
Javier
J
Sotillo
Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Thewarach
T
Laha
Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Atiroch
A
Papatpremsiri
Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, George Washington University, Washington, D.C., United States of America.
Gabriel
G
Rinaldi
Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, George Washington University, Washington, D.C., United States of America.
Rafael N
RN
Pimenta
The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Lai Yue
LY
Chan
Microbial Imaging Facility, The iThree institute, University of Technology Sydney, Ultimo, New South Wales, Australia.
Michael S
MS
Johnson
Microbial Imaging Facility, The iThree institute, University of Technology Sydney, Ultimo, New South Wales, Australia.
Lynne
L
Turnbull
Microbial Imaging Facility, The iThree institute, University of Technology Sydney, Ultimo, New South Wales, Australia.
Cynthia B
CB
Whitchurch
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
Paul R
PR
Giacomin
Queensland Research Centre for Peripheral Vascular Disease, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
Corey S
CS
Moran
Queensland Research Centre for Peripheral Vascular Disease, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia; Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia.
Jonathan
J
Golledge
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
Norelle
N
Daly
Department of Pathology, Khon Kaen University, Khon Kaen, Thailand.
Banchob
B
Sripa
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Jason P
JP
Mulvenna
Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, George Washington University, Washington, D.C., United States of America.
Paul J
PJ
Brindley
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
Alex
A
Loukas
D000595:Amino Acid Sequence; D000818:Animals; D001650:Bile Duct Neoplasms / Q000469:parasitology; D063646:Carcinogenesis / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000469:parasitology; D015801:Helminth Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D009889:Opisthorchiasis / Q000150:complications* / Q000378:metabolism; D009891:Opisthorchis / Q000378:metabolism*; D000077153:Progranulins; D034622:RNA Interference; D014945:Wound Healing / Q000502:physiology*
D015801:Helminth Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins