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Published on: September 9, 2020
c-Jun Is critical for the progression of osteosarcoma: proof in an orthotopic spontaneously metastasizing model
Crispin R Dass1, Levon M Khachigian, Peter F M Choong
1Department of Orthopaedics, St. Vincent's Hospital, Fitzroy, Melbourne, Victoria 3065, Australia. cris.dass@yahoo.com
Abstract:
The oncogene c-Jun has been found to be up-regulated in a variety of cancers including osteosarcoma. DNA enzymes (DNAzymes) are oligonucleotides capable of specific catalysis of target mRNA. A c-Jun DNAzyme inhibited the growth and metastasis of osteosarcoma in an orthotopic spontaneously metastasizing model of the disease. c-Jun down-regulation-mediated apoptosis in osteosarcoma cells involved caspase-1, caspase-2, and caspase-8, but not the Fas/FasL pathway. Clinically, knockdown of c-Jun with DNAzymes may proffer an improved treatment outcome for these tumors originating in bone.
Insights
A novel DNA enzyme targeting the oncogene c-Jun effectively inhibited osteosarcoma growth and metastasis. This c-Jun down-regulation induced cancer cell death via specific caspases, suggesting a potential new bone cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The oncogene c-Jun is frequently upregulated in various cancers, including osteosarcoma.
- Osteosarcoma is a primary bone cancer with a high risk of metastasis.
- Targeting oncogenic pathways offers a strategy for cancer treatment.
Purpose of the Study:
- To investigate the therapeutic potential of a c-Jun DNAzyme in osteosarcoma.
- To elucidate the mechanisms by which c-Jun downregulation affects osteosarcoma progression.
- To evaluate the efficacy of DNAzymes as a treatment for bone tumors.
Main Methods:
- Utilized an orthotopic, spontaneously metastasizing osteosarcoma mouse model.
- Administered a specific DNAzyme designed to target and cleave c-Jun mRNA.
- Assessed tumor growth, metastasis, and apoptosis markers in treated and control groups.
- Analyzed the involvement of caspase pathways and the Fas/FasL system.
Main Results:
- The c-Jun DNAzyme significantly inhibited both primary tumor growth and metastasis in the osteosarcoma model.
- Downregulation of c-Jun by the DNAzyme induced apoptosis in osteosarcoma cells.
- The apoptotic process involved caspase-1, caspase-2, and caspase-8 activation.
- The Fas/FasL pathway was not implicated in the observed c-Jun-mediated apoptosis.
Conclusions:
- DNAzymes targeting c-Jun demonstrate potent anti-tumor and anti-metastatic effects in osteosarcoma.
- c-Jun inhibition triggers apoptosis through the caspase cascade, independent of the Fas/FasL pathway.
- Targeting c-Jun with DNAzymes represents a promising therapeutic strategy for osteosarcoma, potentially improving patient outcomes.
