PLK2 Modulation of Enriched TAp73 Affects Osteogenic Differentiation and Prognosis in Human Osteosarcoma

Overview

Journal Cancer Med

Specialty Oncology

Date 2020 Apr 30

PMID 32349184

Citations 8

Authors

Wenhu Li

Xianliao Zhang

Xinhua Xi

Yufa Li

Hong Quan

Shifeng Liu

Liqi Wu

Penghuan Wu

Wenxing Lan

Yongjun Shao

Haomiao Li

Kebing Chen

Zhengbo Hu

Affiliations

Soon will be listed here.

Abstract

There are three subtypes of undifferentiated human conventional osteosarcoma (HCOS): osteoblastic osteosarcoma (OOS), chondroblastic osteosarcoma (COS), and fibroblastic osteosarcoma (FOS). HCOS also exhibits heterogeneous pathological maldifferentiation in individual patients. Currently, the mechanism regulating HCOS differentiation remains unclear, and therapies are ineffective. Osteopontin (OPN) and osteocalcin (OCN) are markers of osteoblast maturation, and their expression is inhibited in HCOS. A previous study found that PLK2 inhibited TAp73 phosphorylation and consequent anti-OS function of TAp73 in OS cells with enriched TAp73. TAp73 was also reported to regulate bone cell calcification. Here, OOS was found to have higher TAp73 levels and PLK2 expression than those in COS, which is correlated with HCOS maldifferentiation according to Spearman analysis and affects patient prognosis according to Kaplan-Meier survival analysis. In the conventional OS cell-line Saos2 and in patient-derived xenograft OS (PDX-OS) cells, increased PLK2 expression owing to abundant TAp73 levels affected OPN and OCN content as measured by RT-PCR and Western blotting, and alizarin red staining showed that PLK2 affected calcium deposition in OS cells. In addition, PLK2 inhibition in PDX-OS cells prohibited clone formation, as indicated by a clonogenic assay, and sensitized OS cells to cisplatin (CDDP) (which consequently limited proliferation), as shown by the CCK-8 assay. In an established PDX animal model with abundant TAp73 levels, PLK2 inhibition or CDDP treatment prevented tumor growth and prolonged median survival. The combined therapeutic effect of PLK2 inhibition with CDDP treatment was better than that of either monotherapy. These results indicate that increased PLK2 levels due to enriched TAp73 affect osteogenic differentiation and maturation and OS prognosis. In conclusion, PLK2 is a potential target for differentiation therapy of OS with enriched TAp73.

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References

Zenmyo M, Komiya S, Hamada T, Hiraoka K, Kato S, Fujii T . Transcriptional activation of p21 by vitamin D(3) or vitamin K(2) leads to differentiation of p53-deficient MG-63 osteosarcoma cells. Hum Pathol. 2001; 32(4):410-6. DOI: 10.1053/hupa.2001.23524. View

Ma S, Charron J, Erikson R . Role of Plk2 (Snk) in mouse development and cell proliferation. Mol Cell Biol. 2003; 23(19):6936-43. PMC: 193943. DOI: 10.1128/MCB.23.19.6936-6943.2003. View

Niklison-Chirou M, Steinert J, Agostini M, Knight R, Dinsdale D, Cattaneo A . TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor. Proc Natl Acad Sci U S A. 2013; 110(47):18952-7. PMC: 3839698. DOI: 10.1073/pnas.1221172110. View

Arfaoui Toumi A, El Amine El Hadj O, Ben Mahmoud L, Ben Hmida A, Chaar I, Gharbi L . The prognostic value of p73 overexpression in colorectal carcinoma: a clinicopathologic, immunohistochemical, and statistical study of 204 patients. Appl Immunohistochem Mol Morphol. 2009; 18(2):128-36. DOI: 10.1097/PAI.0b013e3181bcb2da. View

Finch J, Dusso A, Pavlopoulos T, Slatopolsky E . Relative potencies of 1,25-(OH)(2)D(3) and 19-Nor-1,25-(OH)(2)D(2) on inducing differentiation and markers of bone formation in MG-63 cells. J Am Soc Nephrol. 2001; 12(7):1468-1474. DOI: 10.1681/ASN.V1271468. View

He B, Chen L, Zuo G, Zhang W, Bi Y, Huang J . Synergistic antitumor effect of the activated PPARgamma and retinoid receptors on human osteosarcoma. Clin Cancer Res. 2010; 16(8):2235-45. DOI: 10.1158/1078-0432.CCR-09-2499. View

de The H . Differentiation therapy revisited. Nat Rev Cancer. 2017; 18(2):117-127. DOI: 10.1038/nrc.2017.103. View

Liu W, Zha Z, Wang H . Upregulation of microRNA-27a inhibits synovial angiogenesis and chondrocyte apoptosis in knee osteoarthritis rats through the inhibition of PLK2. J Cell Physiol. 2019; 234(12):22972-22984. DOI: 10.1002/jcp.28858. View

Ye H, Guo X . TP73 is a credible biomarker for predicting clinical progression and prognosis in cervical cancer patients. Biosci Rep. 2019; 39(8). PMC: 6682548. DOI: 10.1042/BSR20190095. View

10.

Vassilev L . p53 Activation by small molecules: application in oncology. J Med Chem. 2005; 48(14):4491-9. DOI: 10.1021/jm058174k. View

11.

Lu H, Yan C, Quan X, Yang X, Zhang J, Bian Y . CK2 phosphorylates and inhibits TAp73 tumor suppressor function to promote expression of cancer stem cell genes and phenotype in head and neck cancer. Neoplasia. 2014; 16(10):789-800. PMC: 4212254. DOI: 10.1016/j.neo.2014.08.014. View

12.

Ferrari S, Serra M . An update on chemotherapy for osteosarcoma. Expert Opin Pharmacother. 2015; 16(18):2727-36. DOI: 10.1517/14656566.2015.1102226. View

13.

Jo V, Fletcher C . WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition. Pathology. 2014; 46(2):95-104. DOI: 10.1097/PAT.0000000000000050. View

14.

Isakoff M, Bielack S, Meltzer P, Gorlick R . Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. J Clin Oncol. 2015; 33(27):3029-35. PMC: 4979196. DOI: 10.1200/JCO.2014.59.4895. View

15.

Fletcher C . The evolving classification of soft tissue tumours - an update based on the new 2013 WHO classification. Histopathology. 2013; 64(1):2-11. DOI: 10.1111/his.12267. View

16.

Han D, Rodriguez-Bravo V, Izadmehr S, Domingo-Domenech J, Cordon-Cardo C . Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts. J Vis Exp. 2019; (148). PMC: 7247278. DOI: 10.3791/57011. View

17.

Haydon R, Luu H, He T . Osteosarcoma and osteoblastic differentiation: a new perspective on oncogenesis. Clin Orthop Relat Res. 2006; 454:237-46. DOI: 10.1097/BLO.0b013e31802b683c. View

18.

Symon A, Harley V . SOX9: A genomic view of tissue specific expression and action. Int J Biochem Cell Biol. 2017; 87:18-22. DOI: 10.1016/j.biocel.2017.03.005. View

19.

Carpio L, Gladu J, Goltzman D, Rabbani S . Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. Am J Physiol Endocrinol Metab. 2001; 281(3):E489-99. DOI: 10.1152/ajpendo.2001.281.3.E489. View

20.

Moll U, Slade N . p63 and p73: roles in development and tumor formation. Mol Cancer Res. 2004; 2(7):371-86. View