RBMS3 at 3p24 Inhibits Nasopharyngeal Carcinoma Development via Inhibiting Cell Proliferation, Angiogenesis, and Inducing Apoptosis

Abstract

Deletion of the short arm of chromosome 3 is one of the most frequent genetic alterations in many solid tumors including nasopharyngeal carcinoma (NPC), suggesting the existence of one or more tumor suppressor genes (TSGs) within the frequently deleted region. A putative TSG RBMS3 (RNA binding motif, single stranded interacting protein 3), located at 3p24-p23, has been identified in our previous study. Here, we reported that downregulation of RBMS3 was detected in 3/3 NPC cell lines and 13/15 (86.7%) primary NPC tissues. Functional studies using both overexpression and suppression systems demonstrated that RBMS3 has a strong tumor suppressive role in NPC. The tumor suppressive mechanism of RBMS3 was associated with its role in cell cycle arrest at the G1/S checkpoint by upregulating p53 and p21, downregulating cyclin E and CDK2, and the subsequent inhibition of Rb-ser780. Further analysis demonstrated that RBMS3 had a pro-apoptotic role in a mitochondrial-dependent manner via activation of caspase-9 and PARP. Finally, RBMS3 inhibited microvessel formation, which may be mediated by down-regulation of MMP2 and β-catenin and inactivation of its downstream targets, including cyclin-D1, c-Myc, MMP7, and MMP9. Taken together, our findings define a function for RBMS3 as an important tumor suppressor gene in NPC.

β-Catenin is important for cancer stem cell generation and tumorigenic activity in nasopharyngeal carcinoma

“…However, whether the high expression level of β-catenin is necessarily required for stemness maintenance of CSC is still not clear. Some studies have suggested that the CSC characteristics in NPC cells with high level of β-catenin are attenuated when the Wnt/β-catenin signaling pathway is blocked by inhibitors targeting β-catenin [16,25]. In addition, the antineoplastic activities of some microRNAs like miR-200a were reported to be mediated by their inhibitory effect on β-catenin pathway [26][27][28].…”

“…Our xenograft experiment results showed that the growth of tumors was indeed limited. In addition, prevention of Wnt/β-catenin transduction pathway can also inhibit the expressions of angiogenesis-related genes, such as MMP9, MMP2, and VEGF [25,38], which were very important in solid tumor growth. Some studies have already proved that suppressing the function or expression of β-catenin by corresponding inhibitors and microRNA ultimately leads to the limited growth of tumors in mice.…”

Comparative analyses of histone H3K9 trimethylations in the heart and spleen of normal humans

“…Further analysis demonstrated that RBMS3 played a pro-apoptotic role in a mitochondrial-dependent manner via activation of caspase-9 and poly-ADP ribose polymerase. Finally, RBMS3 inhibited microvessel formation, which might be mediated by the down-regulation of matrix metalloproteinase (MMP)-2 and β-catenin and inactivation of its downstream targets, including cyclin-D1, c-Myc, MMP-7, and MMP-9 (Chen et al, 2012).…”

Cytogenetic characterization of HB2 epithelial cells from the human breast

“…The breakpoints of the jumping translocation identified in HB2 cells are located in 3p24-p23 and 7q31-q36 regions and in 6q25 band. This could lead to a deregulation of RNA binding motif , single-stranded interacting protein, and transcript variant 3 (RBMS3) gene, present in 3p24 band, whose product is an RNA-binding protein that belongs to the c-myc gene single-strand binding protein family and is involved in the regulation of cell cycle and apoptosis (Chen et al 2012). On the other hand, 6q25 band contains the F-box protein 5 gene that encodes an homologue of a X. laevis protein, named EMI1, acting as a mitotic regulator via interaction with Cdc20 and inhibition of the anaphase-promoting complex (Reimann et al 2001), as well as other cell division regulatory genes such as gravin (AKAP12) and AT-rich interactive domain 1B variant 1 (Nagl et al 2005;Canton et al 2012).…”