Abstract
Purpose
Osteosarcoma is the most common primary bone cancer in children and young adults. Recent experimental evidence has indicated that Runx2/OPN axis play important roles in the metastasis of osteosarcoma cells. The present study aimed to explore their relationship and prognostic significance in surgically resected osteosarcoma.
Methods
The expression of runt‐related transcription factor2(Runx2) and osteopontin (OPN) in clinical specimens from 105 osteosarcoma patients were detected by immunohistochemistry. The correlations between Runx2, OPN, and clinicopathologic data were analyzed by Chi-square (χ2) tests. The prognostic values were determined by univariate and multivariate survival analysis. The accuracy of oncologic outcome prediction was evaluated by receiver-operating characteristics curves.
Results
The results showed there is a significant positive correlation between Runx2 and OPN expression at protein levels (P = 0.015). Runx2 and OPN were both independent predictors for overall survival and metastasis-free survival. When Runx2 and OPN were taken into consideration together, the predictive range was extended and the sensitivity was improved, and more significant and better biomarkers for osteosarcoma metastasis and survival.
Conclusions
These results suggest that a combined Runx2/OPN expression could be a valuable independent predictor of tumor metastasis and survival in osteosarcoma patients.
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Data availability
The data used in this study are available from the corresponding author on reasonable request.
References
Ritter J, Bielack SS (2010) Osteosarcoma. Ann Oncol 21(7):vii320-325. https://doi.org/10.1093/annonc/mdq276
Maugg D, Rothenaigner I, Schorpp K et al (2015) New small molecules targeting apoptosis and cell viability in osteosarcoma. PLoS One 10(6):e0129058. https://doi.org/10.1371/journal.pone.0129058
Ferguson WS, Goorin AM (2001) Current treatment of osteosarcoma. Cancer Invest 19(3):292–315. https://doi.org/10.1081/cnv-100102557
Ducy P, Zhang R, Geoffroy V et al (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89(5):747–754. https://doi.org/10.1016/s0092-8674(00)80257-3
Villanueva F, Araya H, Briceño P et al (2019) The cancer-related transcription factor RUNX2 modulates expression and secretion of the matricellular protein osteopontin in osteosarcoma cells to promote adhesion to endothelial pulmonary cells and lung metastasis. J Cell Physiol 234(8):13659–13679. https://doi.org/10.1002/jcp.28046
Wai PY, Mi Z, Gao C et al (2006) Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. J Biol Chem 281(28):18973–18982. https://doi.org/10.1074/jbc.M511962200
Onodera Y, Miki Y, Suzuki T et al (2010) Runx2 in human breast carcinoma: its potential roles in cancer progression. Cancer Sci 101(12):2670–2675. https://doi.org/10.1111/j.1349-7006.2010.01742.x
Sase T, Suzuki T, Miura K et al (2012) Runt-related transcription factor 2 in human colon carcinoma: a potent prognostic factor associated with estrogen receptor. Int J Cancer 131(10):2284–2293. https://doi.org/10.1002/ijc.27525
Yang J, Zhao L, Tian W et al (2013) Correlation of WWOX, RUNX2 and VEGFA protein expression in human osteosarcoma. BMC Med Genomics 6:56. https://doi.org/10.1186/1755-8794-6-56
Gupta S, Ito T, Alex D et al (2019) RUNX2 (6p21.1) amplification in osteosarcoma. Hum Pathol 94:23–28. https://doi.org/10.1016/j.humpath.2019.09.010
Lucero CM, Vega OA, Osorio MM et al (2013) The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines. J Cell Physiol 228(4):714–723. https://doi.org/10.1002/jcp.24218
Wei R, Wong JPC, Kwok HF (2017) Osteopontin–a promising biomarker for cancer therapy. J Cancer 8(12):2173–2183. https://doi.org/10.7150/jca.20480
Han X, Wang W, He J et al (2019) Osteopontin as a biomarker for osteosarcoma therapy and prognosis. Oncol Lett 17(3):2592–2598. https://doi.org/10.3892/ol.2019.9905
Liu SJ, Hu GF, Liu YJ et al (2004) Effect of human osteopontin on proliferation, transmigration and expression of MMP-2 and MMP-9 in osteosarcoma cells. Chin Med J (Engl) 117(2):235–240
Meyers PA, Heller G, Healey J et al (1992) Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 10(1):5–15. https://doi.org/10.1200/jco.1992.10.1.5
Bacci G, Bertoni F, Longhi A et al (2003) Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer 97(12):3068–3075. https://doi.org/10.1002/cncr.11456
Enneking WF, Spanier SS, Goodman MA (1980) A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 153:106–120
Ren Z, Liang S, Yang J et al (2016) Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma. Tumour Biol 37(4):5089–5096. https://doi.org/10.1007/s13277-015-4352-8
Stein GS, Lian JB, van Wijnen AJ et al (2004) Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene 23(24):4315–4329. https://doi.org/10.1038/sj.onc.1207676
Lengner CJ, Steinman HA, Gagnon J et al (2006) Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. J Cell Biol 172(6):909–921. https://doi.org/10.1083/jcb.200508130
Martin JW, Zielenska M, Stein GS et al (2011) The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma 2011:282745. https://doi.org/10.1155/2011/282745
Sadikovic B, Yoshimoto M, Chilton-MacNeill S et al (2009) Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling. Hum Mol Genet 18(11):1962–1975. https://doi.org/10.1093/hmg/ddp117
Won KY, Park HR, Park YK (2009) Prognostic implication of immunohistochemical Runx2 expression in osteosarcoma. Tumori 95(3):311–316
Senger DR, Wirth DF, Hynes RO (1979) Transformed mammalian cells secrete specific proteins and phosphoproteins. Cell 16(4):885–893. https://doi.org/10.1016/0092-8674(79)90103-x
Luo X, Chen J, Song WX et al (2008) Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects. Lab Invest 88(12):1264–1277. https://doi.org/10.1038/labinvest.2008.98
Velupillai P, Sung CK, Tian Y et al (2010) Polyoma virus-induced osteosarcomas in inbred strains of mice: host determinants of metastasis. PLoS Pathog 6(1):e1000733. https://doi.org/10.1371/journal.ppat.1000733
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Liang, S., Li, Y. & Wang, B. The cancer‐related transcription factor Runx2 combined with osteopontin: a novel prognostic biomarker in resected osteosarcoma. Int J Clin Oncol 26, 2347–2354 (2021). https://doi.org/10.1007/s10147-021-02025-4
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DOI: https://doi.org/10.1007/s10147-021-02025-4