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The development of esophageal cancer is associated with altered expression and regulation of the SnoN oncoprotein. Although it is well established that SnoN exerts its effects by binding to Smad proteins, which are the major effectors of TGFβ signaling, it is not clear if the failure to degrade SnoN in response to TGFβ completely abrogates the TGFβ response. To address this, we compared the genetic and biologic response to TGFβ in an esophageal cancer cell line in which TGFβ induces degradation of SnoN and derivatives of the cell line engineered to express SnoN that cannot be degraded in response to TGFβ. Microarray analysis demonstrated that the non-degradable form of SnoN had profound effects on the ability of TGFβ to both activate and repress gene transcription. Gene responses associated with growth inhibition were almost universally blocked, but regulation of transcription factors associated with migration and invasion was observed. Although the failure to degrade SnoN abrogates TGFβ induced growth arrest in esophageal cancer cell lines, cells that do not degrade SnoN retain the ability to migrate and invade in response to TGFβ. TGFβ induced transcription of transcription factors involved in migration and invasion were shown to be both independent of SnoN degradation and Smad dependent. Thus, these studies demonstrate that SnoN selectively inhibits both biologic and genetic TGFβ responses in esophageal cancer cells. They also have implications for both the mechanism of action of SnoN and its potential as a therapeutic target.

Supported in part by Commonwealth Research Foundation, Philip Morris, USA, Inc., and Philip Morris International

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA