Gene Silencing Reduces Metastatic Potential of Melanoma Tumors

Cancer researchers used small hairpin RNA (shRNA) to silence the gene in melanoma cells that encodes the transcription factor E2F1 and found that this treatment reduced the potential for metastasis without modifying the tumor's ability to grow.

E2F1 is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of the cell cycle and the action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA-binding domain, a dimerization domain that determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor-suppressor protein association domain which is embedded within the transactivation domain. E2F1 protein binds preferentially to retinoblastoma protein pRB in a cell-cycle dependent manner. It can mediate both cell proliferation and p53-dependent/independent apoptosis.

Investigators from the University of Rostock (Germany) worked with genetically engineered mice that expressed shRNA that specifically blocked the E2F1 gene. They reported in the December 21, 2009, issue of the Journal of the National Cancer Institute that when implanted with melanoma, these animals developed a smaller area of metastases per lung than did control mice. Tumors in the animals with reduced E2F1 expression grew at similar rates, but formed fewer and smaller metastatic lesions than did tumors in the control mice.

Epidermal growth factor receptor (EGFR) was identified as a direct target of E2F1, and the investigators demonstrated that inhibition of receptor signaling abolished E2F1-induced invasiveness. This finding emphasized the importance of E2F1–EGFR interaction as a driving force in melanoma progression.

The results presented in this study prompted the authors to state that, "Because elevated expression of E2F1 and EGFR has been observed in other tumor types, the established mechanistic link may also be important in other human cancers. This association should be explored in future studies.”

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University of Rostock