Radiation-resistant cancer stem-like cell properties are regulated by PTEN through the activity of nuclear β-catenin in nasopharyngeal carcinoma
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Gong Zhang1, Wenjun Wang2, Chunxiao Yao1, Shuping Zhang1, Lili Liang3, Muyuan Han4, Jinjin Ren1, Xiurong Qi1, Xiaofeng Zhang1, Shuye Wang1 and Lei Li1
1Department of Radiotherapy of People’s Hospital of Shanxi Province, Taiyuan 030012, PR China
2Research Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, PR China
3Department of Dermatology of People’s Hospital of Shanxi Province, Taiyuan 030012, PR China
4Department of Ophthalmology of People’s Hospital of Shanxi Province, Taiyuan 030012, PR China
Gong Zhang, email: firstname.lastname@example.org
Keywords: PTEN, nuclear β-catenin, cancer stem-like cells, radioresistance, nasopharyngeal carcinoma
Received: January 12, 2017 Accepted: July 26, 2017 Published: August 18, 2017
Radiotherapy is the primary and most important treatment for nasopharyngeal carcinoma (NPC). Cancer stem-like cells (CSCs) have been shown to be resistant to radiation. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene has been suggested to play a role in stem cell self-renewal. In the present study, we sorted PTEN−/+ cells using a flow cytometer. The clone formation assay showed that PTEN− cells were more radioresistant than PTEN+ NPC cells. We found that PTEN− cells demonstrated a significant increase in tumorsphere formation and CSCs markers compared with PTEN+ cells. Silencing the expression of PTEN with siRNA resulted in increased expression of p-AKT, active β-catenin and Nanog. siPTEN cells irradiated showed more radioresistant and DNA damage than parental cells. We also confirmed that down-regulation of β-catenin expression with shRNA resulted in a reduced percentage of side population cells and expression of Nanog. shβ-catenin cells significantly decreased survivin expression at 4 Gy irradiation in PTEN− cells compared with PTEN+ cells. In siPTEN cells, β-catenin staining shifted from the cytoplasmic membrane to the nucleus. Furthermore, immunofluorescence showed that following irradiation of PTEN− cells, at 4 Gy, active β-catenin was mainly found in the nucleus. Immunohistochemistry analysis also demonstrated that the PTEN−/p-AKT+/β-catenin+/Nanog+ axis may indicate poor prognosis and radioresistance in clinical NPC specimens. Thus, our findings strongly suggest that PTEN− cells have CSCs properties that are resistant to radiation in NPC. PTEN exerts these effects through the downstream effector PI3K/AKT/β-catenin/Nanog axis which depends on nuclear β-catenin accumulation.
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