Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

Abstract

Abstract. Spalt-like transcription factor 4 (SALL4) is essential for the maintenance of the self-renewal and pluripotent properties in embryonic stem cells. Although the detailed mechanism remains unclear, dysregulation of SALL4 has been detected in various malignancies. Previously, the authors' of the present study reported that the expression level of SALL4 was associated with the poor prognosis of glioblastoma multiforme (GBM). The present study aimed to investigate the function of SALL4 in U251 human glioblastoma cells, including apoptosis and invasion inhibition. It was revealed that knockdown of SALL4 expression through RNA interference induced cell cycle arrest, enhanced early apoptosis and significantly inhibited invasion. Furthermore, downregulation of SALL4 was associated with a significantly lower expression level of the core transcription factors, including POU class 5 homeobox 1, SRY-box 2 and Nanog homeobox. In addition, inhibition of SALL4 significantly reduced the concentration of chemotherapeutic agent temozolomide required to inhibit cell growth by 50%, which decreased from 113.66±23.07 and 114.93±20.91 µg/ml to 68.34±3.52 and 67.44±4.71 µg/ml in two independent short interfering RNA transfected groups. These results indicate that SALL4 serves an important role in the GBM pathophysiology and targeting SALL4 may be a potential approach to the treatment of GBM. IntroductionGlioma is the most common subgroup type of brain tumor, with an incidence of 5-6/100,000 cases/year in the United States (1). Among all types of glioma, glioblastoma multiforme (GBM) accounts for ~50% of cases and has the most malignant phenotype (2). Despite the extensive developments that have been invested in surgical techniques and therapeutic agents, 88% of patients with GBM succumb to this disease within 3 years (3). GBM remains one of the most challenging malignancies worldwide.Embryonic stem cells (ESCs) are known for their potent pluripotency and are able to differentiate into >220 cell types in the adult body. The human homologue of the drosophila spalt-like transcription factor 4 (SALL4) is a zinc-finger transcription factor, which is responsible for maintaining pluripotency and longevity of ESCs (4-6). Previously, cancer stem cells (CSCs) have been identified in various types of malignancies (7,8) and demonstrate high self-renewal capabilities able to sustain tumor growth (9). Thus far, ESCs and CSCs have been revealed to share numerous biological similarities with the SALL4 expression pattern being one of them. In various types of tumors, high SALL4 expression level has been associated with increased malignancy, including increased metastasis, enhanced proliferation (10-12) and poor differentiation (13,14).In the authors' previous study, it was demonstrated that SALL4 was highly expressed in glioma and significantly associated with poor survival (15). The present study further investigated the biological role of SALL4 in the tumorigenesis of glioma and explored the underlying mechanism of action. It was revealed th...

Norcantharidin inhibits viability and induces cell cycle arrest and apoptosis in osteosarcoma

“…Cell cycle imbalance is an essential mechanism involved in the proliferation of malignant tumor cells (14)(15)(16). Certain studies have supported the hypothesis that the induction of cell cycle arrest may be an effective method for controlling tumor proliferation (17)(18)(19). The current results demonstrated that NCTD induced G2/M cell cycle arrest in both osteosarcoma cell lines in a dose-depen-osteosarcoma cell lines in a dose-depen-cell lines in a dose-dependent manner.…”

Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma

“…Additionally, NANOG might be activated via the aberrant Notch signaling to promote tumor recurrence and invasion in glioma [ 38 ]. More importantly, multiple evidences have confirmed that NANOG could facilitate TMZ resistance in glioma [ 19 , 39 , 40 ]. Here we found circ_0072083 knockdown could decrease NANOG expression.…”

Warburg Effect-Promoted Exosomal Circ_0072083 Releasing Up-Regulates Nango Expression Through Multiple Pathways and Enhances Temozolomide Resistance in Glioma

“…Additionally, NANOG might be activated via the aberrant Notch signaling to promote tumor recurrence and invasion in glioma [38]. More importantly, multiple evidences have con rmed that NANOG could facilitate TMZ resistance in glioma [19,39,40]. Here we found circ_0072083 knockdown could decrease NANOG expression.…”