SCLU as prognostic biomarker and therapeutic target in osteosarcoma

Weiliang Gao,Jisheng Gao,Jinfeng Ma

doi:10.1080/21655979.2019.1621136

Weiliang Gao, Jisheng Gao + Show 1 more

Open Access

https://doi.org/10.1080/21655979.2019.1621136

Copy DOI

Abstract

ABSTRACT Osteosarcoma (OS) is the most common primary malignant bone tumor. Secretory apolipoprotein J/clusterin (sCLU) is overexpressed in many cancers; however, its role in OS has not been previously investigated. The objectives of this study were to address this question and also to assess the clinical value of sCLU as a prognostic biomarker and therapeutic target by comparing sCLU expression in human OS (n = 106), normal bone (n = 16), fibrous dysplasia (n = 9), and ossifying myositis (n = 11) tissues and by evaluating the effect of sCLU silencing on OS growth, invasion, and chemosensitivity in vitro and in vivo. We found that sCLU was highly expressed in OS tissue specimens, which was positively correlated with metastatic disease and negatively correlated with response to chemotherapy. sCLU knockdown in KHOS cells inhibited proliferation and invasion and increased apoptosis as well as sensitivity to the chemotherapy drug gemcitabine (Gem). In a mouse xenograft model, sCLU depletion suppressed lung metastasis and enhanced the effects of Gem, thereby slowing KHOS tumor growth. These results indicate that sCLU overexpression is a biomarker for malignant transformation of OS and that therapeutic strategies targeting sCLU may be an effective treatment for OS. Highlights ● Secretory apolipoprotein J/clusterin (sCLU) is overexpressed in osteosarcoma (OS). ● sCLU overexpression is associated with metastasis and chemoresistance. ● Silencing sCLU inhibits metastasis and enhances chemosensitivity in OS cells. sCLU is a biomarker for metastatic OS and a potential therapeutic target.

Highlights

Osteosarcoma (OS) is the most common primary malignant bone tumor affecting children and young adults [1]
SCLU immunopositivity was associated with metastasis at initial diagnosis (P = 0.023; Table 1) and poorer overall and disease-free survival (Figure. 2(a,b)), and was correlated with poor histological response after neoadjuvant chemotherapy (Table 1). Secretory apolipoprotein J/clusterin (sCLU) silencing increases apoptosis and decreases proliferation and invasion of KHOS cells
The control siRNA had no effect on sCLU protein expression (Figure 3(a)). sCLU expression was reduced KHOS cells stably transfected with sCLU shRNA (Figure 3(b))

Summary

Introduction

Osteosarcoma (OS) is the most common primary malignant bone tumor affecting children and young adults [1]. 80% of OS patients have metastatic disease at the time of diagnosis, presenting a major challenge for clinical management [2]. Surgical resection with subsequent radio- and chemotherapy can dramatically improve the clinical outcome of OS patients; chemoresistance and pulmonary metastasis are likely to develop later on. Identifying biomarkers of metastatic progression is critical for early diagnosis and timely treatment, which could improve the prognosis of OS. Secretory apolipoprotein J (s)CLU has been extensively investigated in the context of tumor diagnosis and prognosis owing to its antiapoptotic function. Most clinical studies have found that elevated sCLU expression is associated with tumor relapse and metastasis and is an indicator of poor prognosis [5,6,7]. Others have reported contradictory or insignificant results, even for the same type of malignancy [8,9]

Objectives

Methods

Results

Conclusion