title: An unexpected role for caspase-2 in neuroblastoma.
abstract: Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene-mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the Eμ-Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH-MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2(-/-) mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2(+/+) counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2(-/-) tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis.
authors.affiliation: 1] Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia [2] Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Dorstyn
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Puccini
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Nikolic
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Shalini
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: C H
authors.initials: CH
authors.lastname: Wilson
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Haber
authors.affiliation: 1] Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia [2] Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000818:Animals; D053143:Caspase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D020928:Mitogen-Activated Protein Kinases; D053143:Caspase 2; D018631:ras Proteins