icg-001 and Nasopharyngeal-Carcinoma

The Wnt signaling pathway is known to serve an important role in the control of cell migration. The present study analyzed the mechanisms underlying the in vitro modulation of the migration of nasopharyngeal carcinoma (NPC) cells by the CREB‑binding protein/catenin antagonist and Wnt modulator ICG‑001. The results revealed that ICG‑001‑mediated inhibition of tumor cell migration involved downregulated mRNA and protein expression of the Wnt target gene cluster of differentiation (CD)44. It was also demonstrated that ICG‑001 downregulated the expression of CD44, and this effect was accompanied by restored expression of microRNA (miRNA)‑150 in various NPC cell lines. Using a CD44 3'‑untranslated region luciferase reporter assay, miR‑150 was confirmed to be a novel CD44‑targeting miRNA, which could directly target CD44 and subsequently regulate the migration of NPC cells. The present study provides further insight into the inhibition of tumor cell migration through the modulation of miRNA expression by the Wnt modulator ICG‑001.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Mice; MicroRNAs; Nasopharyngeal Carcinoma; Pyrimidinones; RNA, Messenger; RNA, Small Interfering; Wnt Signaling Pathway

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy prevalent in southern China. Presence of treatment-resistant cancer stem cells (CSC) may associate with tumor relapse and metastasis in NPC. ICG-001 is a specific CBP/β-catenin antagonist that can block CBP/β-catenin-mediated transcription of stem cell associated genes and enhance p300/β-catenin-mediated transcription, thereby reducing the CSC-like population via forced differentiation. In this study, we aimed to evaluate the effect of ICG-001 on the CSC-like population, and the combination effect of ICG-001 with cisplatin in the C666-1 EBV-positive NPC cells. Results showed that ICG-001 inhibited C666-1 cell growth and reduced expression of CSC-associated proteins with altered expression of epithelial-mesenchymal transition (EMT) markers. ICG-001 also inhibited C666-1 tumor sphere formation, accompanied with reduced SOX2(hi)/CD44(hi) CSC-like population. ICG-001 was also found to restore the expression of a tumor suppressive microRNA-145 (miR-145). Ectopic expression of miR-145 effectively repressed SOX2 protein expression and inhibited tumor sphere formation. Combination of ICG-001 with cisplatin synergistically suppressed in vitro growth of C666-1 cells and significantly suppressed growth of NPC xenografts. These results suggested that therapeutically targeting of the CBP/β-catenin signaling pathway with ICG-001 can effectively reduce the CSC-like population and combination with cisplatin can effectively suppress the growth of NPC.

Topics: Animals; Antineoplastic Agents; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Synergism; Epithelial-Mesenchymal Transition; Herpesvirus 4, Human; Humans; Hyaluronan Receptors; Mice; Mice, Nude; MicroRNAs; Microscopy, Confocal; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplastic Stem Cells; p300-CBP Transcription Factors; Pyrimidinones; RNA Interference; RNA, Small Interfering; Signal Transduction; SOXB1 Transcription Factors; Transplantation, Heterologous