TOP2Ahigh is the phenotype of recurrence and metastasis whereas TOP2Aneg cells represent cancer stem cells in prostate cancer

Abstract

// Xuefeng Li 1 , Yunying Liu 2 , Wenqi Chen 3 , Yuxiang Fang 1 , Huiming Xu 1 , Helen He Zhu 1 , Mingliang Chu 1 , Wang Li 1 , Guanglei Zhuang 1 , Wei-Qiang Gao 1, 2 1 State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China 2 School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China 3 Department of Neurology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200240, China Correspondence to: Dr. Wei-Qiang Gao e-mail: gao.weiqiang@sjtu.edu.cn Dr. Guanglei Zhuang e-mail: zhuangguanglei@gmail.com Key words: prostate cancer, cancer stem cells, TOP2A, recurrence and metastasis Received: June 18, 2014      Accepted: August 28, 2014      Published: September 08, 2014 ABSTRACT Recurrence and metastasis are the main causes of death for prostate cancer patients and cancer stem cells (CSCs) are proposed to play important roles in cancer recurrence and metastasis. It is generally thought that genes upregulated in recurrent/metastatic disease are likely biomarkers of CSCs. Hence we analyzed multiple microarray datasets on prostate tumor tissues to identify upregulated genes associated with cancer recurrence/metastasis, and tried to explore whether those genes were true biomarkers of prostate CSCs. Our results indicated that TOP2A was the most highly upregulated gene in recurrent/metastatic prostate cancer, and its high expression was positively correlated with poor prognosis in patients. Using a promoter reporter system, we unexpectedly discovered enrichment of CSCs in TOP2A neg cells. Compared to TOP2A high cells, TOP2A neg cells formed spheres and tumors more efficiently, and became enriched in the presence of stresses. Analysis of cell divisions by time lapse imaging indicated that more slow-cycling cells were observed in TOP2A neg cells while the proportion of abnormal divisions was higher in TOP2A high cells. Our studies demonstrate that TOP2A high is the phenotype of recurrence/metastasis but TOP2A neg cells show slow cycling and have CSCs properties in prostate cancer, which has significant implications for prostate cancer therapy.