The tumor suppressor gene ARHI (DIRAS3) inhibits ovarian cancer cell migration through multiple mechanisms

Abstract

ARHI is an imprinted tumor suppressor gene that is downregulated in > 60% of ovarian cancers, associated with decreased progression-free survival. ARHI encodes a 26 kDa GTPase with homology to Ras. Re-expression of ARHI inhibits ovarian cancer growth, initiates autophagy and induces tumor dormancy. Recent studies have demonstrated that ARHI also plays a particularly important role in ovarian cancer cell migration. Re-expression of ARHI decreases motility of IL-6- and EGF-stimulated SKOv3 and Hey ovarian cancer cells, inhibiting both chemotaxis and haptotaxis. ARHI inhibits cell migration by binding and sequestering STAT3 in the cytoplasm, and preventing STAT3 translocation to the nucleus and localization in focal adhesion complexes. Re-expression of ARHI inhibits FAKY397 phosphorylation, disrupts focal adhesions and blocks FAK-mediated RhoA signaling, resulting in decreased levels of GTP-RhoA. Re-expression of ARHI disrupts formation of actin stress fibers in a FAK- and RhoA-dependent manner. Recent studies indicate that re-expression of ARHI inhibits expression of β-1 integrin which may also contribute to inhibition of migration, adhesion and invasion. © 2013 Landes Bioscience.