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RRIG1 Mediates Effects of Retinoic Acid Receptor ß₂ on Tumor Cell Growth and Gene Expression through Binding to and Inhibition of RhoA

Departments of ¹ Clinical Cancer Prevention, ² Pathology, and ³ Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Xiao-Chun Xu, Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2940; Fax: 713-563-5747; E-mail: xxu{at}mdanderson.org.

The expression of retinoic acid receptor ß₂ (RAR-ß₂) is frequently lost in various cancers and their premalignant lesions. However, the restoration of RAR-ß₂ expression inhibits tumor cell growth and suppresses cancer development. To understand the molecular mechanisms responsible for this RAR-ß₂-mediated antitumor activity, we did restriction fragment differential display-PCR and cloned a novel retinoid receptor–induced gene 1 (RRIG1), which is differentially expressed in RAR-ß₂-positive and RAR-ß₂-negative tumor cells. RRIG1 cDNA contains 2,851 bp and encodes a protein with 276 amino acids; the gene is localized at chromosome 9q34. Expressed in a broad range of normal tissues, RRIG1 is also lost in various cancer specimens. RRIG1 mediates the effect of RAR-ß₂ on cell growth and gene expression (e.g., extracellular signal–regulated kinase 1/2 and cyclooxygenase-2). The RRIG1 protein is expressed in the cell membrane and binds to and inhibits the activity of a small GTPase RhoA. Whereas induction of RRIG1 expression inhibits RhoA activation and f-actin formation and consequently reduces colony formation, invasion, and proliferation of esophageal cancer cells, antisense RRIG1 increases RhoA activity and f-actin formation and thus induces the colony formation, invasion, and proliferation of these cells. Our findings therefore show a novel molecular pathway involving RAR-ß₂ regulation of RRIG1 expression and RRIG1-RhoA interaction. An understanding of this pathway may translate into better control of human cancer. (Cancer Res 2006; 66(14): 7111-8)

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