The CBP/β-Catenin Antagonist, ICG-001, Inhibits Tumor Metastasis via Blocking of the miR-134/ITGB1 Axis-Mediated Cell Adhesion in Nasopharyngeal Carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy ranking as the 23rd most common cancer globally, while its incidence rate ranked the 9th in southeast Asia. Tumor metastasis is the dominant cause for treatment failure in NPC and metastatic NPC is yet incurable. The Wnt/β-catenin signaling pathway plays an important role in many processes such as cell proliferation, differentiation, epithelial–mesenchymal transition (EMT), and self-renewal of stem cells and cancer stem cells (CSCs). Both the EMT process and CSCs are believed to play a critical role in cancer metastasis. We here investigated whether the specific CBP/β-catenin Wnt antagonist, IGC-001, affects the metastasis of NPC cells. We found that ICG-001 treatment could reduce the adhesion capability of NPC cells to extracellular matrix and to capillary endothelial cells and reduce the tumor cell migration and invasion, events which are closely associated with distant metastasis. Through a screening of EMT and CSC-related microRNAs, it was found that miR-134 was consistently upregulated by ICG-001 treatment in NPC cells. Very few reports have mentioned the functional role of miR-134 in NPC, except that the expression was found to be downregulated in NPC. Transient transfection of miR-134 into NPC cells reduced their cell adhesion, migration, and invasion capability, but did not affect the growth of CSC-enriched tumor spheres. Subsequently, we found that the ICG-001-induced miR-134 expression resulting in downregulation of integrin β1 (ITGB1). Such downregulation reduced cell adhesion and migration capability, as demonstrated by siRNA-mediated knockdown of ITGB1. Direct targeting of ITGB1 by miR-134 was confirmed by the 3′-UTR luciferase assay. Lastly, using an in vivo lung metastasis assay, we showed that ICG-001 transient overexpression of miR-134 or stable overexpression of miR-134 could significantly reduce the lung metastasis of NPC cells. Taken together, we present here evidence that modulation of Wnt/β-catenin signaling pathway could inhibit the metastasis of NPC through the miR-134/ITGB1 axis.

Targeting Wnt signaling for improved glioma immunotherapy

“…Wnt/β-catenin pathway signaling is also correlated with immunotherapy resistance in melanoma ( 15 , 56 , 57 ) and across other tumor types ( 12 ). Tumor-intrinsic Wnt/β-catenin signaling mediates cancer immune evasion by preventing T-cell and/or dendritic cell infiltration, migration, and function, and thereby resistance to immunotherapies ( 12 , 13 , 16 , 58 ).…”

“…The Wnt/b-catenin signaling pathway, which is a critical regulator of both somatic stem cells and cancer stem/tumor initiating cells, has been correlated with resistance to radiation and cytotoxic and targeted Wnt/b-catenin pathway signaling is also correlated with resistance in melanoma (15, 56, 57) and across other tumor types (12). Tumor-intrinsic Wnt/b-catenin signaling mediates cancer immune evasion by preventing T-cell and/or dendritic cell infiltration, migration, and function, and thereby resistance to immunotherapies (12,13,16,58).…”

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/β-Catenin signaling

“…ICG-001, a novel small molecule selective inhibitor of the Wnt/β-Catenin pathway, exhibits an exquisite affinity for the transcriptional coactivator CBP, engaging in a specific and potent binding interaction [ 48 ]. Through this extraordinary affinity, ICG-001 disrupts the delicate interplay between CBP and β-Catenin, leading to the suppression of Wnt/β-Catenin-mediated gene transcription [ 49 ].…”

THY1 (CD90) Maintains the Adherens Junctions in Nasopharyngeal Carcinoma via Inhibition of SRC Activation

“…WB analysis was performed as previously described [ 22 ]. For the total lysate, cells were lysed in lysis buffer containing 1% of NP40, 250 mM of Tris, 150 mM of NaCl, 0.25% of protease inhibitor, and 1% of phosphatase inhibitor.…”

“…Transfection was then conducted in a similar way for THY1 expression, as described in 4.2. For SRC and PTPN22 knockdown, siRNAs (siTHY1, Dharmacon, Lafayette, CO, USA, #L-015337-00-0005; siSRC, ThermoFisher, Waltham, MA, USA, #s13414; siPTPN22, ThermoFisher #s25225; siCTL, Dharmacon #D-001810-10-20) were transfected into NPC cells with Lipofectamine ® 2000 (Invitrogen, Thermo Fisher Scientific, Waltham, MA, USA) as previously described [ 22 ].…”