p27Kip1 and cytoplasmic pSer10p27 are promising biomarkers for predicting prognosis and chemotherapy response in ovarian cancer.

Abstract

Purpose: The biological function of p27^Kip1 largely depends on its subcellular localization and phosphorylation status. Different subcellular localizations and phosphorylation statuses of p27^Kip1 may represent distinct clinical values, which are unclear in ovarian cancer. This study aimed to elucidate different subcellular localizations of p27^Kip1 and pSer10p27 in predicting prognosis and chemotherapy response in ovarian cancer.

Methods: Meta-analyses were executed to evaluate the association of p27^Kip1 and phosphorylated p27^Kip1 with the prognosis of ovarian cancer patients. The expression levels and patterns of p27^Kip1 and pSer10p27 were evaluated by immunohistochemistry. The correlations between different p27^Kip1 states, clinicopathological features, and prognosis were analyzed. p27^Kip1 and pSer10p27 expression levels in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines were detected using WB. KEGG analysis and WB were performed to evaluate the pathways in which p27^Kip1 was involved.

Results: Meta-analyses showed that p27^Kip1 was associated with significantly better overall survival (OS) in ovarian cancer (HR=2.14; 95% CI [1.71-2.68]) and pSer10p27 was associated with significantly poor OS in mixed solid tumors (HR=2.56; 95% CI [1.76-3.73]). In our cohort of ovarian cancer patients, low total p27^Kip1 remained independent risk factors of OS (HR=2.097; 95% CI [1.121-3.922], P=0.021) and PFS (HR=2.483; 95% CI [1.364-4.518], P=0.003), while low cytoplasmic pSer10p27 had independent protective effects in terms of OS (HR=0.472; 95% CI [0.248-0.898], P=0.022) and PFS (HR=0.488; 95% CI [0.261-0.910], P=0.024). Patients with low total p27^Kip1/pSer10p27 and low nuclear p27^Kip1 had worse chemotherapy responses, while patients with low cytoplasmic pSer10p27 expression had better chemotherapy responses. The protein levels of p27^Kip1 and pSer10p27 were significantly reduced in the cisplatin-resistant cell lines SKOV3-cDDP and A2780-cDDP, and the level of p27^Kip1/pSer10p27 was subjective to Akt activation.

Conclusions: The present study demonstrates that p27^Kip1 and cytoplasmic pSer10p27 are promising biomarkers for predicting prognosis and chemotherapy response in ovarian cancer.