Abstract
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.
Highlights
Radiotherapy is the primary and most important treatment modality for nasopharyngeal carcinoma (NPC) [1]
NPC recurrence and metastasis often result in treatment failure due to radioresistance [30]
The poor prognosis of advanced NPC likely results from the failure to target Cancer stem-like cells (CSCs)
Summary
Radiotherapy is the primary and most important treatment modality for NPC [1]. The loco-regional control rate of NPC has significantly improved in the past decade. Even though there have been significant improvements in the loco-regional control rates of NPC, local recurrence still contributes to concerning levels of mortality and morbidity. The management of local failure in advanced stages of NPC still presents a difficult www.impactjournals.com/oncotarget challenge [2]. Radiobiological research over the past decades has provided evidence that the number of cancer stem-like cells (CSCs) and the intrinsic radiosensitivity of CSCs affect radiocurability [3]. Recurrence and metastasis may arise from residual disease resulting from the ability of CSCs to resistant radiation, which has been demonstrated both experimentally and clinically [4]
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