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

Luo Chen; Yiu Chun Chiang; Lai Sheung Chan; Wai Yin Chau; Maria Li Lung; Michael Kahn; Kwok Wai Lo; Nai Ki Mak; Hong Lok Lung

doi:10.3390/cancers14133125

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

Cancers (Basel). 2022 Jun 25;14(13):3125. doi: 10.3390/cancers14133125.

Authors

Luo Chen¹, Yiu Chun Chiang¹, Lai Sheung Chan², Wai Yin Chau², Maria Li Lung³, Michael Kahn⁴, Kwok Wai Lo^{5

6}, Nai Ki Mak¹, Hong Lok Lung²

Affiliations

¹ Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR, China.
² Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR, China.
³ Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong SAR, China.
⁴ Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA 91010-3000, USA.
⁵ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁶ State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.

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.

Keywords: ICG-001; ITGB1; NPC; Wnt; miR-134.

Abstract

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