PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma
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, t...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-06-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.3066 |
| _version_ | 1828298985418260480 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wenhu Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T12:48:58Z |
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| id | doaj.art-14630367e0b841329edd70c16713e629 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-13T12:48:58Z |
| publishDate | 2020-06-01 |
| publisher | Wiley |
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| series | Cancer Medicine |
| spelling | doaj.art-14630367e0b841329edd70c16713e6292022-12-22T02:46:16ZengWileyCancer Medicine2045-76342020-06-019124371438510.1002/cam4.3066PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcomaWenhu Li0Xianliao Zhang1Xinhua Xi2Yufa Li3Hong Quan4Shifeng Liu5Liqi Wu6Penghuan Wu7Wenxing Lan8Yongjun Shao9Haomiao Li10Kebing Chen11Zhengbo Hu12Department of Orthopedics Shaoguan First People's Hospital Affiliated to Southern Medical University Shaoguan ChinaOrthopedics Center Zhujiang Hospital of Southern Medical University Guangzhou ChinaDepartment of Orthopaedics The Affiliated Yuebei People's Hospital of Shantou University Medical College Shaoguan ChinaThe Second School of Clinical Medicine Southern Medical University Guangzhou ChinaDepartment of Orthopedics Shaoguan First People's Hospital Affiliated to Southern Medical University Shaoguan ChinaOrthopedics Center Dongguan Eighth People's Hospital Dongguan ChinaDepartment of Orthopedics Shaoguan First People's Hospital Affiliated to Southern Medical University Shaoguan ChinaDepartment of Orthopedics Shaoguan First People's Hospital Affiliated to Southern Medical University Shaoguan ChinaDepartment of Orthopedics Shaoguan First People's Hospital Affiliated to Southern Medical University Shaoguan ChinaDepartment of Orthopedics Shaoguan First People's Hospital Affiliated to Southern Medical University Shaoguan ChinaOrthopedics Center The Third Affiliated Hospital of Southern Medical UniversityOrthopedics institute of Guangdong Province Guangzhou ChinaOrthopedics Center The Third Affiliated Hospital of Southern Medical UniversityOrthopedics institute of Guangdong Province Guangzhou ChinaDepartment of Orthopedics Shaoguan First People's Hospital Affiliated to Southern Medical University Shaoguan ChinaAbstract 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.https://doi.org/10.1002/cam4.3066osteogenic differentiationOsteosarcomaPDXPLK2TAp73 |
| spellingShingle | 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 PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma Cancer Medicine osteogenic differentiation Osteosarcoma PDX PLK2 TAp73 |
| title | PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma |
| title_full | PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma |
| title_fullStr | PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma |
| title_full_unstemmed | PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma |
| title_short | PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma |
| title_sort | plk2 modulation of enriched tap73 affects osteogenic differentiation and prognosis in human osteosarcoma |
| topic | osteogenic differentiation Osteosarcoma PDX PLK2 TAp73 |
| url | https://doi.org/10.1002/cam4.3066 |
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