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IMPDH2 and HPRT expression and a prognostic significance in preoperative and postoperative patients with osteosarcoma
Parunya Chaiyawat1,2, Areerak Phanphaisarn1, Nutnicha Sirikaew1
1Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Abstract:
Osteosarcoma is one of the most aggressive bone tumors in children and adolescents. Development of effective therapeutic options is still lacking due to the complexity of the genomic background. In previous work, we applied a proteomics-guided drug repurposing to explore potential treatments for osteosarcoma. Our follow-up study revealed an FDA-approved immunosuppressant drug, mycophenolate mofetil (MMF) targeting inosine-5'-phosphate dehydrogenase (IMPDH) enzymes, has an anti-tumor effect that appeared promising for further investigation and clinical trials. Profiling of IMPDH2 and hypoxanthine-guanine phosphoribosyltransferase (HPRT), key purine-metabolizing enzymes, could deepen understanding of the importance of purine metabolism in osteosarcoma and provide evidence for expanded use of MMF in the clinic. In the present study, we investigated levels of IMPDH2, and HPRT in biopsy of 127 cases and post-chemotherapy tissues in 20 cases of high-grade osteosarcoma patients using immunohistochemical (IHC) analysis. Cox regression analyses were performed to determine prognostic significance of all enzymes. The results indicated that low levels of HPRT were significantly associated with a high Enneking stage (P = 0.023) and metastatic status (P = 0.024). Univariate and multivariate analyses revealed that patients with low HPRT expression have shorter overall survival times [HR 1.70 (1.01-2.84), P = 0.044]. Furthermore, high IMPDH2/HPRT ratios were similarly associated with shorter overall survival times [HR 1.67 (1.02-2.72), P = 0.039]. Levels of the enzymes were also examined in post-chemotherapy tissues. The results showed that high IMPDH2 expression was associated with shorter metastasis-free survival [HR 7.42 (1.22-45.06), P = 0.030]. These results suggest a prognostic value of expression patterns of purine-metabolizing enzymes for the pre- and post-chemotherapy period of osteosarcoma treatment.
Insights
Low expression of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and high IMPDH2/HPRT ratios indicate poor prognosis in osteosarcoma patients. These purine-metabolizing enzyme profiles offer prognostic value for treatment strategies.
Area of Science:
- Oncology
- Biochemistry
- Genetics
Background:
- Osteosarcoma is an aggressive pediatric bone tumor with limited therapeutic options due to complex genomics.
- Mycophenolate mofetil (MMF), an immunosuppressant targeting inosine-5'-phosphate dehydrogenase (IMPDH) enzymes, shows potential anti-tumor effects.
- Understanding purine metabolism, involving IMPDH2 and hypoxanthine-guanine phosphoribosyltransferase (HPRT), is crucial for osteosarcoma treatment.
Purpose of the Study:
- To investigate the prognostic significance of IMPDH2 and HPRT expression in osteosarcoma.
- To correlate enzyme levels with clinical parameters like tumor stage and metastasis.
- To evaluate the prognostic value of these enzymes in pre- and post-chemotherapy settings.
Main Methods:
- Immunohistochemical (IHC) analysis of IMPDH2 and HPRT in 127 osteosarcoma biopsies and 20 post-chemotherapy tissues.
- Cox regression analyses (univariate and multivariate) to assess prognostic significance.
- Correlation of enzyme expression patterns with clinical outcomes and tumor characteristics.
Main Results:
- Low HPRT expression correlated with high Enneking stage and metastatic status (P=0.023, P=0.024).
- Patients with low HPRT expression had significantly shorter overall survival (HR 1.70, P=0.044).
- High IMPDH2/HPRT ratios were associated with shorter overall survival (HR 1.67, P=0.039).
- High IMPDH2 expression in post-chemotherapy tissues predicted shorter metastasis-free survival (HR 7.42, P=0.030).
Conclusions:
- Expression patterns of IMPDH2 and HPRT possess prognostic value in osteosarcoma.
- These findings support the potential for expanded use of MMF in osteosarcoma treatment.
- Enzyme profiling offers insights into purine metabolism's role and can guide therapeutic strategies.
