Inhibition of CXCR4 regulates epithelial mesenchymal transition of NSCLC via the Hippo‐YAP signaling pathway

Abstract

CXCR4 has been shown to play a key role in the metastasis of non-small cell lung cancer (NSCLC). And CXCR may be associated with the Hippo-Yes kinase-associated protein (YAP) pathway, thus involving in the occurrence and progression of NSCLC. This study aims to investigate the effect of CXCR4 inhibition on epithelial-mesenchymal transition (EMT), invasion and migration of NSCLC cells via the Hippo-YAP pathway. QRT-PCR and Western blot were employed to detect CXCR4 expression in NSCLC cell lines. A549 and H1299 cells were treated with WZ811 (0, 10, 30, and 50 µM), and A549 cells were also divided into the Control, WZ811, YAP siRNA, and WZ811 + YAP groups. Wound-healing, Transwell assay, immunofluorescent staining, and a luciferase reporter gene assay were performed in this experiment. Compared with human bronchial epithelial (HBE) cells, CXCR4 expression was up-regulated in NSCLC cell lines. WZ811 increased E-cadherin; decreased expression of Twist, vimentin, Snail, p-YAP, CTGF, and BIRC5; blocked GTIIC reporter activity; and reduced migration and invasion of A549 cells, all in a dose-dependent manner. YAP siRNA had a similar effect to WZ811 by inhibiting EMT, invasion and migration of A549 cells. However, compared with A549 cells in the YAP siRNA and WZ811 groups, cells in the WZ811 + YAP group showed a dramatically enhanced EMT phenotype as well as invasion and migration abilities. Inhibition of CXCR4 may reduce EMT, invasion and migration of NSCLC cells, thereby providing a new therapeutic target for NSCLC.

Eva‐1 homolog A promotes papillary thyroid cancer progression and epithelial‐mesenchymal transition via the Hippo signalling pathway

“…Related proteins were detected to explore the mechanism of the EVA1A on EMT and apoptosis progression. Recent studies have provided enormous evidences suggesting that the Hippo signalling pathway can induce EMT 17,27,28 . Results revealed that compared with the control group, the Si‐ EVA1A group showed decreased N‐cadherin, vimentin and Bcl‐xL expression and increased Bax expression (Figure 6B).…”

“…YAP and TAZ are downstream effectors of the Hippo pathway and overexpressed in numerous cancers 16 . In recent years, several studies have found that the Hippo signalling pathway can promote tumour invasion and metastasis via EMT 16‐19 . And the molecular mechanism through which the Hippo pathway activates apoptosis is realized via p73 20‐22 .…”

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…Here, CXCR4 was demonstrated to be heterogeneously expressed and upregulated upon stress, resulting in increased migration, which could be blocked by small molecule inhibitors to the Rho GTPases CDC42 and RAC [225]. Since RAC was shown to activate YAP in response to β-integrin signaling in MSC [63] and CXCR4 was reported to activate YAP in other cancers (i.e., non-small cell lung cancer [226]), it is possible that the metastatic spread of Ewing sarcoma cells with high CXCR4 may be supported by a mechanism involving YAP/TAZ.…”

New CXCR4 Antagonist Peptide R (Pep R) Improves Standard Therapy in Colorectal Cancer

“…Similar results were reported in the RT-CT treated mice ( Figure 5 B Lower). Altogether, the data indicate that ECAD and ZEB-1 are important for HCT116 chemotherapy-induced cellular plasticity, and that these mesenchymal features are modulated by CXCR4 inhibition [ 19 ].…”

“…The chemokine receptor CXCR4 is overexpressed in colon cancer [10], where it represents a poor prognostic factor [11][12][13]. The CXCL12/CXCR4 axis also activates the EMT program in colorectal cancer, targeting the Wnt/β-catenin pathway [7,[14][15][16], and in multiple carcinomas such as pancreatic cancer [17], ovarian cancer [18] and non-small cell lung cancer (NSCLC) [19]. The aim of the study was to improve the efficacy of colon cancer standard therapy targeting CXCR4 with a new CXCR4 antagonistic peptide by reversing the EMT program [20].…”