miR-9 targets CXCR4 and functions as a potential tumor suppressor in nasopharyngeal carcinoma

Abstract

MicroRNA deregulation and pathway alterations have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer widely prevalent in Southern China. In this study, we report that miR-9 is commonly downregulated in NPC specimens and NPC cell lines with important functional consequences. The reduced expression of miR-9 was inversely correlated with clinical stages and marked the progression from locoregional to metastatic tumors. The CpG island hypermethylation contributed to miR-9 silencing in NPC cell lines and tissues. Ectopic expression of miR-9 dramatically inhibited the proliferative, migratory and invasive capacities of NPC cells in vitro and in vivo. We found that miR-9 strongly reduced the expression of CXCR4 in NPC cells. Luciferase assay demonstrated that miR-9 could directly bind to the 3' untranslated region of CXCR4. Similar to the restoring miR-9 expression, CXCR4 downregulation inhibited cell growth, migration and invasion, whereas CXCR4 overexpression rescued the suppressive effect of miR-9. Mechanistic investigations revealed that CXCR4 functionally mediated the SDF-1-stimulated activation of p38 mitogen-activated protein kinase pathway in NPC cells with miR-9 downregulation or CXCR4 overexpression. In clinical specimens, CXCR4 and phospho-p38 were widely overexpressed, and the levels increased with the progression from locoregional to metastatic tumors in NPC tissues. The levels of CXCR4 were inversely correlated with miR-9 or phospho-p38 expression. Taken together, our results indicate that miR-9 functions as a tumor-suppressive microRNA in NPC, and that its suppressive effects are mediated chiefly by repressing CXCR4 expression.

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

“…Several direct targets of miR-9 such as cyclin D1, Ets1 (Zheng et al, 2013), and CXCR4 (Lu et al, 2013) have currently been identified. Repression of cyclin D1 and Ets1 is involved in miR-9-mediated suppression of the proliferation, invasion and metastasis of gastric cancer cells (Zheng et al, 2013).…”

“…Repression of cyclin D1 and Ets1 is involved in miR-9-mediated suppression of the proliferation, invasion and metastasis of gastric cancer cells (Zheng et al, 2013). Targeting CXCR4 was found to mediate the suppressive effects of miR-9 in nasopharyngeal carcinoma (Lu et al, 2013). Identification of specific target genes is of great importance in clarifying the functions of miR-9 in curcumin-mediated cytotoxicity.…”

Screening for Metastatic Osteosarcoma Biomarkers with a DNA Microarray

“…MiR-202 may be a potential key regulator resulting in the metastasis of OS, and CALD1 may be the possible therapeutic target. MiR-9 is also a widely studied tumor suppressor miRNA in acute myelocytic leukemia, nasopharyngeal carcinoma and ovarian cancer, even an essential oncogenic miRNA specifically over-expressed in mixed lineage leukemia-rearranged leukemia (Emmrich et al, 2013;Lu et al, 2013;Sun et al, 2013). Furthermore, miR-9 is reported to be up-regulated in breast cancer cells, influencing the expression of E-cadherin, and further leading to increased cell motility and invasiveness and even cancer metastasis (Khew-Goodalland Goodall, 2010;Ma et al, 2010).…”

MicroRNAs in nasopharyngeal carcinoma

“…Not only has miR-9 been identified as a potential circulating biomarker of advanced NPC [31] , several potential targets and functions of miR-9 have also been reported. Recently, two studies describing putative tumor suppressive mechanisms for miR-9 in NPC have been published [32,33] . Lu et al [32] reported that hypermethylation and subsequent underexpression of miR-9 led to up-regulation of its putative target C-X-C chemokine receptor type 4 (CXCR4), resulting in increased cell growth, migration, and invasion through activation of the Mitogen-activated protein kinase (MAPK) pathway.…”

“…Recently, two studies describing putative tumor suppressive mechanisms for miR-9 in NPC have been published [32,33] . Lu et al [32] reported that hypermethylation and subsequent underexpression of miR-9 led to up-regulation of its putative target C-X-C chemokine receptor type 4 (CXCR4), resulting in increased cell growth, migration, and invasion through activation of the Mitogen-activated protein kinase (MAPK) pathway. In contrast, Gao et al [33] postulated a role for miR-9 in modulating the immune response to NPC by targeting several interferon (IFN)-induced genes, multiple members of the major histocompatibility complex (MHC) class I molecule, and a number of interleukins and related genes.…”