RBMS3 at 3p24 inhibits nasopharyngeal carcinoma development via inhibiting cell proliferation, angiogenesis, and inducing apoptosis

PLoS One. 2012;7(9):e44636. doi: 10.1371/journal.pone.0044636. Epub 2012 Sep 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis
  • Carcinoma
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Chromosomes, Human, Pair 3*
  • Down-Regulation
  • Female
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Silencing
  • Genes, Tumor Suppressor
  • Humans
  • Male
  • Microcirculation
  • Middle Aged
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / metabolism*
  • Nasopharyngeal Neoplasms / pathology
  • Neovascularization, Pathologic
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*

Substances

  • RBMS3 protein, human
  • RNA-Binding Proteins
  • Trans-Activators

Grant support

This work was supported by grants from the National Natural Science Foundation of China (30700820, 30772475 and 30971606), the National Key Sci-Tech Special Project of China (2008ZX10002-022), and the Hong Kong UGC Area of Excellent Scheme (AoE/M-06/08). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.