Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma

Yidan Zhang, Yoav S. Zvi, Brian Batko, Nikolas Zaphiros, Edmond F. O’Donnell, Jichuan Wang, Kenji Sato, Rui Yang, David S. Geller, Pratistha Koirala, Wendong Zhang, Xiuquan Du, Sajida Piperdi, Yang Liu, Deyou Zheng, Michael Roth, Jonathan Gill, Jinghang Zhang, Tingting Ren, Richard Gorlick & 2 others Xiaolin Zi, Bang H. Hoang

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Abstract

Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.

Original languageEnglish (US)
Article number14294
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Osteosarcoma
Down-Regulation
Neoplasm Metastasis
Lung
Cell Line
S-Phase Kinase-Associated Proteins
Kava
Chalcone
Bone Neoplasms
Therapeutics
Survival

ASJC Scopus subject areas

  • General

Cite this

Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma. / Zhang, Yidan; Zvi, Yoav S.; Batko, Brian; Zaphiros, Nikolas; O’Donnell, Edmond F.; Wang, Jichuan; Sato, Kenji; Yang, Rui; Geller, David S.; Koirala, Pratistha; Zhang, Wendong; Du, Xiuquan; Piperdi, Sajida; Liu, Yang; Zheng, Deyou; Roth, Michael; Gill, Jonathan; Zhang, Jinghang; Ren, Tingting; Gorlick, Richard; Zi, Xiaolin; Hoang, Bang H.

In: Scientific Reports, Vol. 8, No. 1, 14294, 01.12.2018.

Research output: Contribution to journalArticle

Zhang, Y, Zvi, YS, Batko, B, Zaphiros, N, O’Donnell, EF, Wang, J, Sato, K, Yang, R, Geller, DS, Koirala, P, Zhang, W, Du, X, Piperdi, S, Liu, Y, Zheng, D, Roth, M, Gill, J, Zhang, J, Ren, T, Gorlick, R, Zi, X & Hoang, BH 2018, 'Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma', Scientific Reports, vol. 8, no. 1, 14294. https://doi.org/10.1038/s41598-018-32428-9
Zhang, Yidan ; Zvi, Yoav S. ; Batko, Brian ; Zaphiros, Nikolas ; O’Donnell, Edmond F. ; Wang, Jichuan ; Sato, Kenji ; Yang, Rui ; Geller, David S. ; Koirala, Pratistha ; Zhang, Wendong ; Du, Xiuquan ; Piperdi, Sajida ; Liu, Yang ; Zheng, Deyou ; Roth, Michael ; Gill, Jonathan ; Zhang, Jinghang ; Ren, Tingting ; Gorlick, Richard ; Zi, Xiaolin ; Hoang, Bang H. / Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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abstract = "Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.",
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AU - Zheng, Deyou

AU - Roth, Michael

AU - Gill, Jonathan

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AU - Gorlick, Richard

AU - Zi, Xiaolin

AU - Hoang, Bang H.

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