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

Abstract

The biological function of p27Kip1 largely depends on its subcellular localization and phosphorylation status. Different subcellular localizations and phosphorylation statuses of p27Kip1 may represent distinct clinical values, which are unclear in ovarian cancer. This study aimed to elucidate different subcellular localizations of p27Kip1 and pSer10p27 in predicting prognosis and chemotherapy response in ovarian cancer. Methods. Meta-analyses were executed to evaluate the association of p27Kip1 and phosphorylated p27Kip1 with the prognosis of ovarian cancer patients. The expression levels and patterns of p27Kip1 and pSer10p27 were evaluated by immunohistochemistry. The correlations between different p27Kip1 states, clinicopathological features, and prognosis were analyzed. p27Kip1 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 p27Kip1 was involved. Results Meta-analyses showed that p27Kip1 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 p27Kip1 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 p27Kip1/ pSer10p27 and low nuclear p27Kip1 had worse chemotherapy responses, while patients with low cytoplasmic pSer10p27 expression had better chemotherapy responses. The protein levels of p27Kip1 and pSer10p27 were significantly reduced in the cisplatin-resistant cell lines SKOV3-cDDP and A2780-cDDP, and the level of p27Kip1/pSer10p27 was subjective to Akt activation. Conclusions The present study demonstrates that p27Kip1 and cytoplasmic pSer10p27 are promising biomarkers for predicting prognosis and chemotherapy response in ovarian cancer.