Inhibition of STAT3 Reduces Astrocytoma Cell Invasion and Constitutive Activation of STAT3 Predicts Poor Prognosis in Human Astrocytoma

Jie Ma,Tao Jiang,Chenkai Ma,Yang Zhao,Qinchuan Liang,Guodong Gao

doi:10.1371/journal.pone.0084723

Abstract

Astrocytoma cells characteristically possess high invasion potentials. Recent studies have revealed that knockdown of signal transducers and activators of transcription 3 (STAT3) expression by RNAi induces apoptosis in astrocytoma cell. Nevertheless, the distinct roles of STAT3 in astrocytoma’s invasion and recurrence have not been elucidated. In this study, we silenced STAT3 using Small interfering RNAs in two human glioblastoma multiforme (GBM) cell lines (U251 and U87), and investigated the effect on GBM cell adhesion and invasion. Our results demonstrate that disruption of STAT3 inhibits GBM cell’s adhesion and invasion. Knockdown of STAT3 significantly increased E-cadherin but decreased N-cadherin, vascular endothelial growth factor, matrix metalloproteinase 2 and matrix metalloproteinase 9. Additionally, expression of pSTAT3Tyr705 correlates with astrocytoma WHO classification, Karnofsky performance status scale score, tumor recurrence and survival. Furthmore, pSTAT3Tyr705 is a significant prognostic factor in astrocytoma. In conclusion, STAT3 may affect astrocytoma invasion, expression of pSTAT3Tyr705 is a significant prognostic factor in tumor recurrence and overall survival in astrocytoma patients. Therefore, STAT3 may provide a potential target for molecular therapy in human astrocytoma, and pSTAT3Tyr705could be an important biomarker for astrocytoma prognosis.

Highlights

Astrocytoma is the most common primary tumors of the brain
signal transducers and activators of transcription 3 (STAT3) may provide a potential target for molecular therapy in human astrocytoma, and pSTAT3Tyr705could be an important biomarker for astrocytoma prognosis
48 hours after transfection with 50 nM of STAT3 siRNA, the number of U251 and U87 cells able to migrated through the filter decreased to 65.3% and 59.5%, respectively, when compared to cells transfected with nonspecific siRNA (Figure 1B)

Summary

Introduction

Astrocytoma is the most common primary tumors of the brain. Based on degree of malignancy, astrocytoma is graded into grade ii (diffuse astrocytoma), grade iii (anaplastic astrocytoma), and grade iv (glioblastoma multiforme, GBM) [1,2,3,4,5]. GBM is the most common type with the worst prognosis, and average post-operative survival is less than 2 years [6]. Astrocytoma cells characteristically possess high proliferation and invasion potentials, which explain their aggressive phenotype [7]. In this regard, elucidating the molecular mechanism of cell motility and invasion in astrocytoma is important for the development of more effective treatment options in the future. Signal transducers and activators of transcription (STAT) is a family of transcription factors and is involved in a wide variety of cellular physiological processes, including differentiation, survival, or cell growth [8]. Far, the distinct roles of STAT3 in astrocytoma’s invasion and recurrence have not been elucidated, nor have the downstream targets been evaluated

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