EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

PURPOSE: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.

EXPERIMENTAL DESIGN: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.

RESULTS: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.

CONCLUSIONS: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230-42. ©2015 AACR.

Commentary on the Licensing Act 1662

Legislation prohibiting the publication of any literary work without prior licence.
Drawing upon both the Star Chamber Decree 1637 (uk_1637) and the Acts Regulating Printing during the Interregnum (see: uk_1643 and associated documents), the Licensing Act set out a comprehensive set of provisions concerning both the licensing of the press and the regulation and management of the book trade. In addition, it confirmed the rights of those holding printing privileges (or patents) granted in accordance with the royal prerogative (see for example: Day's privilege for The Cosmographical Glass (uk_1559b)) as well as those who had registered works with the Stationers' Company (uk_1557). It also introduced the first legal library deposit requirement. In force between 1662 and 1679, and then again between 1685 and 1695, the Act represents the last occasion on which the censorship of the press was formally and strategically linked to the protection of the economic interests of the Stationers' Company. Its lapse led the Stationers' Company to lobby parliament for renewed protection, ultimately resulting in the passing of the Statute of Anne 1710 (uk_1710).