Oncotarget

Research Papers:

Manganese superoxide dismutase mediates anoikis resistance and tumor metastasis in nasopharyngeal carcinoma

Shuai Li, Yuling Mao, Ti Zhou, Chuanghua Luo, Jinye Xie, Weiwei Qi, Zhonghan Yang, JianXing Ma, Guoquan Gao and Xia Yang _

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Oncotarget. 2016; 7:32408-32420. https://doi.org/10.18632/oncotarget.8717

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Abstract

Shuai Li1,2,*, Yuling Mao1,*, Ti Zhou1, Chuanghua Luo1, Jinye Xie1, Weiwei Qi1, Zhonghan Yang1, JianXing Ma3, Guoquan Gao1,4, Xia Yang1,5

1Program of Molecular Medicine, Affiliated Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

2Department of Biochemistry, Guangzhou Medical University, Guangzhou, China

3Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, USA

4China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China

5Key Laboratory of Functional Molecules from Marine Microorganisms (Sun Yat-Sen University), Department of Education of Guangdong Province, Guangzhou, China

*These authors contributed equally to this work

Correspondence to:

Xia Yang, email: yangxia@mail.sysu.edu.cn

Guoquan Gao, email: gaogq@mail.sysu.edu.cn

Keywords: MnSOD, nasopharyngeal carcinoma, anoikis, reactive oxygen species, β-catenin

Received: October 31, 2015     Accepted: March 28, 2016     Published: April 13, 2016

ABSTRACT

Metastatic cancer cells are able to survive the loss of attachment to the extracellular matrix (ECM) by developing resistance to anoikis, a specialized form of apoptosis. Here we investigated resistance to anoikis in nasopharyngeal carcinoma cells (NPC). When detached in culture, the highly metastatic S18 NPC cell line exhibited strong resistance to anoikis, as compared to the poorly metastatic S26 NPC cell line. With loss of attachment, S18 cells had lower levels of reactive oxygen species (ROS) and higher levels of manganese superoxide dismutase (MnSOD), an essential mitochondrial antioxidant enzyme. MnSOD knockdown increased the levels of ROS and diminished resistance to anoikis in S18 cells. Conversely, removal of reactive oxygen species (ROS) using NAC or overexpression of MnSOD in S26 cells induced resistance to anoikis. Blocking β-catenin through RNA interference down-regulated MnSOD expression and enhanced anoikis in S18 cells, while β-catenin overexpression enhanced MnSOD expression and suppressed anoikis in S26 cells. In addition, knockdown of MnSOD in S18 cells reduced colony formation in vitro and ameliorated lung metastasis in vivo. In patients with NPC, MnSOD expression was positively correlated with pathologic tumor stages and negatively correlated with overall survival. These results establish MnSOD as a key mediator of anoikis resistance and tumor metastasis and suggest that β-catenin/MnSOD could be a therapeutic target in NPC.


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