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TrkBT1 Induces Liver Metastasis of Pancreatic Cancer Cells by Sequestering Rho GDP Dissociation Inhibitor and Promoting RhoA Activation

Departments of ¹ Surgical Oncology and ² Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center; ³ Program of Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas; ⁴ The University of Texas at Austin, Austin, Texas; and ⁵ Medical College of Wisconsin, Milwaukee, Wisconsin

Requests for reprints: Paul J. Chiao, Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 107, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1030; Fax: 713-794-4830; E-mail: pjchiao{at}mdanderson.org.

Key Words: Tropomyosin-related kinase B (TrkB) • Rho GDP dissociation inhibitor (GDI) • pancreatic cancer • metastasis

Many genetic and molecular alterations, such as K-ras mutation and NF-B activation, have been identified in pancreatic cancer. However, the mechanisms by which pancreatic cancer metastasizes still remain to be determined. Although we previously showed that the tropomyosin-related kinase B (TrkB) was significantly correlated with the development of liver metastasis, its function in pancreatic cancer metastasis remained unresolved. In the present study, we showed that overexpressed TrkB is an alternatively spliced transcript variant of TrkB (TrkBT1) with a unique COOH-terminal 12–amino acid sequence and is mainly localized in the cytoplasm. Our results showed that overexpression of Flag-tagged TrkBT1 but not a Flag-tagged TrkBT1 COOH-terminal deletion mutant (Flag-TrkBT1C) in nonmetastatic pancreatic cancer cells enhanced cell proliferation, promoted formation of colonies in soft agar, stimulated tumor cell invasion, and induced liver metastasis in an orthotopic xenograft mouse model of pancreatic cancer. TrkBT1 interacted with Rho GDP dissociation inhibitor (GDI) in vivo, but Flag-TrkBT1C did not. Furthermore, overexpression of Flag-TrkBT1 and knockdown of RhoGDI expression by RhoGDI short hairpin RNAs promoted RhoA activation, but Flag-TrkBT1C overexpression did not. Therefore, our results showed that TrkBT1 overexpression induces liver metastasis of pancreatic cancer and uncovered a unique signaling mechanism by which TrkBT1 sequesters GDI and activates RhoA signaling. [Cancer Res 2009;69(19):7851–9]