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Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1839-1849. doi: 10.1016/j.bbadis.2018.03.008. Epub 2018 Mar 8.

HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1.

Author information

1
Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China; Department of Orthopedics, Yangpu Hospital, Tongji University, Shanghai, China.
2
Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China.
3
Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
4
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, USA.
5
Department of Orthopedic Surgery David Geffen School of Medicine at UCLA Los Angeles, USA.
6
Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China. Electronic address: czd856@vip.163.com.
7
Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China. Electronic address: yhua@shsmu.edu.cn.

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo-resistance of OS, and could be used as potential therapeutic targets in OS.

KEYWORDS:

Cell growth; Chemotherapy resistance; HER4; NDRG1; Osteosarcoma

PMID:
29524631
DOI:
10.1016/j.bbadis.2018.03.008
[Indexed for MEDLINE]
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