Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells

Mol Cancer. 2011 May 19;10:59. doi: 10.1186/1476-4598-10-59.

Abstract

Background: Astrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated.

Results: We report that miR-335 acts as a tumor promoter in conferring tumorigenic features such as growth and invasion on malignant astrocytoma. The miR-335 level is highly elevated in C6 astrocytoma cells and human malignant astrocytomas. Ectopic expression of miR-335 in C6 cells dramatically enhances cell viability, colony-forming ability and invasiveness. Conversely, delivery of antagonist specific for miR-335 (antagomir-335) to C6 cells results in growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenografts. Further investigation reveals that miR-335 targets disheveled-associated activator of morphogenesis 1(Daam1) at posttranscriptional level. Moreover, silencing of endogenous Daam1 (siDaam1) could mimic the oncogenic effects of miR-335 and reverse the growth arrest, proapoptotic and invasion repression effects induced by antagomir-335. Notably, the oncogenic effects of miR-335 and siDAAM1 together with anti-tumor effects of antagomir-335 are also confirmed in human astrocytoma U87-MG cells.

Conclusion: These findings suggest an oncogenic role of miR-335 and shed new lights on the therapy of malignant astrocytomas by targeting miR-335.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Animals
  • Apoptosis / genetics
  • Astrocytoma / physiopathology*
  • Cell Line
  • Cell Proliferation
  • Cell Survival / genetics
  • Female
  • Gene Knockdown Techniques
  • Gene Order
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microfilament Proteins
  • Neoplasm Invasiveness / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays
  • Young Adult
  • rho GTP-Binding Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • DAAM1 protein, human
  • MIRN335 microRNA, human
  • MicroRNAs
  • Microfilament Proteins
  • rho GTP-Binding Proteins