CXCR4 Promotes Oral Squamous Cell Carcinoma Migration and Invasion through Inducing Expression of MMP-9 and MMP-13 via the ERK Signaling Pathway

Abstract

The increased migration and invasion of oral squamous cell carcinoma cells are key events in the development of metastasis to the lymph nodes and distant organs. Although the chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1a, have been found to play an important role in tumor invasion, its precise role and potential underlying mechanisms remain largely unknown. In this study, we showed that knockdown of CXCR4 significantly decreased Tca8113 cells migration and invasion, accompanied with the reduction of MMP-9 and MMP-13 expression. Inhibition of ligand binding to CXCR4 by a specific antagonist TN14003, also led to reduced cancer cell migration and invasion. Because the degradation of the extracellular matrix and the basement membrane by proteases, such as matrix metalloproteinases (MMP) is critical for migration and invasion of cancer cells, we investigated the expression of several MMPs and found that the expression of functional MMP-9 and MMP-13 was selectively decreased in CXCR4 knockdown cells. More importantly, decreased cell migration and invasion of CXCR4 knockdown cells were completely rescued by exogenous expression of MMP-9 or MMP-13, indicating that the two MMPs are downstream targets of CXCR4-mediated signaling. Furthermore, we found the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in CXCR4-silenced cells, suggesting that ERK may be a potential mediator of CXCR4-regulated MMP-9 and MMP-13 expression in Tca8113 cells. Taken together, our results strongly suggest the underlying mechanism of CXCR4 promoting Tca8113 migration and invasion by regulating MMP-9 and MMP-13 expression perhaps via activation of the ERK signaling pathway. Mol Cancer Res; 9(2); 161-72. Ó2011 AACR.

GPCRs and cancer

“…Increased levels of VEGF, the activation of nuclear factor kappa B (NF-ĸB) and some oncoproteins up-regulate CXCR4 expression, in particular during cancer progression [93,94] and under hypoxic conditions [95] . CXCR4/ SDF-1 contributes to tumor progression also through the activation of tumor-associated integrin and the production of matrix metalloproteases [93] , as observed in human basal carcinoma cells [96] and oral squamous cell carcinomas [97] . Recently, CXCR7/RDC1 has been identified as a novel receptor for CXCL12/SDF-1 and CXCL11 [98] , although its coupling to G-proteins remains controversial.…”

Quantification of Cell Migration and Invasion, and Their Association with Periostin in Anaplastic Thyroid Cancer, Using a Real-time Cell Analyzer

“…MMPs play a role in cancer proliferation and metastasis because of their role in ECM degradation, cellular migration, tissue remodeling, and angiogenesis 9 . In particular, MMP-2 and MMP-9 are closely associated with tumor invasion and metastasis in a variety of human tumors [10][11][12] . MMP-7 also has an important role in the metastasis of ATC 13 .…”

Inhibition of matrix metalloproteinases 9 and 13 affects the degree of lymphocytic infiltration and the expression levels of microRNA miR-21 and miR-let-7b in melanoma cells in vivo

“…Данный механизм передачи сигнала совместно ак-тивируется ММП-9 и ММП-13 при некоторых опухолях [13]. ERK-киназный путь регулирует пролиферацию, жизнеспособность и подвижность клеток и является ком-понентом TGF-β-пути.…”

“…Нельзя исключить, что это связано с компенсаторной ак-тивацией других ММП и, в частности, ММП-13, необхо-димой для совместной активации ERK-киназного пути [13].…”