Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer

Abstract

Sprouty proteins are evolutionary-conserved modulators of receptor tyrosine kinase signaling, deregulation of which has been implicated in the pathophysiology of cancer. In the present study, the expression status of Spry2 and Spry4 proteins and its clinical relevance in human epithelial ovarian cancer (EOC) were investigated retrospectively. We examined the immunohistochemical expression of Spry2 and Spry4 in matched tumor and normal tissue samples from 99 patients. The expression of ERK, p-ERK, Ki67, fibroblast growth factor-2, vascular endothelial growth factor and interleukin-6 and their correlation with Sprouty homologs were also evaluated. Moreover, the correlation between Spry2 and Spry4 and the clinicopathological characteristics were analyzed along with their predictive value for overall survival (OS) and disease-free survival (DFS). Our data indicated significant downregulation of Spry2 and Spry4 in tumor tissues (p < 0.0001). A significant inverse correlation was evident between Spry2 and p-ERK/ERK (p 5 0.048), Ki67 (p 5 0.011), disease stage (p 5 0.013), tumor grade (p 5 0.003), recurrence (p < 0.001) and post-treatment ascites (p 5 0.001), individually. It was found that Spry2 low-expressing patients had significantly poorer OS (p 5 0.002) and DFS (p 5 0.004) than those with high expression of Spry2. Multivariate analysis showed that high Spry2 (p 5 0.018), low stage (p 5 0.049) and no residual tumor (p =0.006) were independent prognostic factors for a better OS. With regard to DFS, high Spry2 (p 5 0.044) and low stage (p 5 0.046) remained as independent predictors. In conclusion, we report for the first time significant downregulation of Spry2 and Spry4 proteins in human EOC. Spry2 expression was revealed to significantly impact tumor behavior with predictive value as an independent prognostic factor for survival and recurrence.Epithelial ovarian cancer (EOC) is the second most common cause of gynecological cancer-related deaths worldwide. In Australia, it is the second most commonly diagnosed and the most lethal gynecological cancer, comprising 4.8% of all cancer deaths in women.1 Most patients with EOC have the advanced disease at diagnosis. The late presentation and widespread abdominal metastasis account for the high death rate. 2 Despite invasive surgery and platinum-based cytotoxic chemotherapy as the standard of care for the advanced disease, episodes of recurrent disease, progressively shorter disease-free intervals and resistance to chemotherapy will develop in most cases. 3 Since discovery in 1998, 4 Sprouty proteins have been increasingly implicated in the multilayered, complex regulation of MAPK/ERK pathway and receptor tyrosine kinase (RTK) signaling.5 As such, this protein family has been shown to regulate processes central to the development, progression and dissemination of malignant conditions, including cell proliferation, migration, invasion and survival. 6 For the past decade, deregulation of Sprouty has been investigated in a variety of cancers.7 However, the status and clinico...

Sprouty2 inhibits amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells

“…A recent study shows that SPRY2 is down-regulated in human ovarian cancer and that SPRY2 expression levels are negatively correlated with cell proliferation. Importantly, patients with lower tumor SPRY2 expression have significantly poorer overall survival and disease-free survival than those with high SPRY2 expression [28]. These results are consistent with our analyses of the TCGA dataset in the present study.…”

“…SPRY2 expression levels are down-regulated in human ovarian cancer, and patients with low SPRY2 expression have significantly poorer survival than those with high SPRY2 expression [25–28]. In the present study, we provide new evidence that SPRY2 can antagonize the AREG-induced down-regulation of E-cadherin and invasion of human ovarian cancer cells.…”

“…In ovarian cancer, SPRY4 expression levels are also down-regulated, while the changes in SPRY1 expression remain controversial [25, 27, 28, 61]. Our recent study demonstrates that SPRY4 expression is involved in the AREG-induced down-regulation of E-cadherin and invasion of human ovarian cancer cells [20].…”

“…These results indicate that SPRY2 and SPRY4 have opposing effects on the regulation of EGFR-mediated E-cadherin down-regulation and cell invasion in human ovarian cancer. Although SPRY4 down-regulation is detected in ovarian cancer, the expression levels of SPRY4 do not significantly correlate with overall survival or disease-free survival [28]. These results suggest that SPRY2 plays a more important role than SPRY4 in regulating human ovarian cancer progression.…”

“…SPRY is aberrantly expressed in different types of human cancer and is involved in tumorigenesis [24]. Our previous study and others' studies have shown that SPRY2 expression is down-regulated in human ovarian cancer and that patients with low SPRY2 expression have significantly poorer survival than those with high SPRY2 expression [25–28]. These results suggest that SPRY2 acts as a tumor suppressor in ovarian cancer progression.…”