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Role of receptor tyrosine kinase regulator Sprouty in ovarian cancer cells So, Wai Kin

Abstract

Aberrant epidermal growth factor receptor (EGFR) activity contributes to the development of epithelial ovarian cancer (EOC), a common and lethal female malignancy. Elucidating the regulation of EGFR function will improve treatments for EOC and the survival of patients. This study aims to elucidate the role of Sprouty (SPRY) proteins, which are EGFR regulators, in EOC. The investigation began with demonstrating the downregulation of mRNA levels of two SPRY members, SPRY2 and SPRY4, in EOC tissues and/or cell lines. Deletion of the SPRY2 gene was found to cause reduced SPRY2 mRNA. Loss of the SPRY2 gene and thus its expression are particularly common in high-grade serous tumors, suggesting that SPRY2 deficiency may be involved in the pathogenesis of this prevailing subtype of EOC. The regulatory mechanisms of SPRY level are incompletely understood. The EGFR ligand EGF strongly upregulates SPRY4 protein level primarily through the ERK pathway. In addition, the PI3K/AKT pathway and hypoxia-inducible factor-1 (HIF-1α) have been shown to be involved in SPRY4 regulation, allowing the possibility that SPRY4 is regulated by micro-environmental (hypoxia) and genetic (PI3K mutation) abnormalities. Functionally, SPRY2 and SPRY4 counteract various aspects of EGFR activity and generally have tumor suppressor functions. First, in contrast to the EGFR, SPRY2 and SPRY4 prevent loss of cell adhesion by E-cadherin and therefore suppress cancer cell invasion. Second, SPRY4 inhibits PI3K/AKT signalling activated by EGF, as AKT activation is enhanced in the absence of SPRY4. Finally, the HIF-1α oncogene has been identified as a novel SPRY4 target. In ovarian cancer cell lines, SPRY4 suppresses the basal and EGF-stimulated expression of HIF-1α. The negative effects of SPRY4 on HIF-1α are also reflected by modulation of HIF-1 activity and target gene expression. SPRY4 has also been shown to destabilise HIF-1α protein, independent of the classic HIF-1α degradation pathway. The current study investigated the expression, regulation and function of SPRY in ovarian cancer. Understanding the tumor suppressor role of SPRY will not only enhance our knowledge about the pathophysiology of ovarian cancer but also identifies a possible therapeutic intervention against this lethal malignancy.

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