MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer

Abstract

BackgroundPrimary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy. Platinum resistant cancers progress/recur in approximately 25% of cases within six months. We aimed to identify clinically useful biomarkers of platinum resistance.MethodsA database of ovarian cancer transcriptomic datasets including treatment and response information was set up by mining the GEO and TCGA repositories. Receiver operator characteristics (ROC) analysis was performed in R for each gene and these were then ranked using their achieved area under the curve (AUC) values. The most significant candidates were selected and in vitro functionally evaluated in four epithelial ovarian cancer cell lines (SKOV-3-, CAOV-3, ES-2 and OVCAR-3), using gene silencing combined with drug treatment in viability and apoptosis assays. We collected 94 tumor samples and the strongest candidate was validated by IHC and qRT-PCR in these.ResultsAll together 1,452 eligible patients were identified. Based on the ROC analysis the eight most significant genes were JRK, CNOT8, RTF1, CCT3, NFAT2CIP, MEK1, FUBP1 and CSDE1. Silencing of MEK1, CSDE1, CNOT8 and RTF1, and pharmacological inhibition of MEK1 caused significant sensitization in the cell lines. Of the eight genes, JRK (p = 3.2E-05), MEK1 (p = 0.0078), FUBP1 (p = 0.014) and CNOT8 (p = 0.00022) also correlated to progression free survival. The correlation between the best biomarker candidate MEK1 and survival was validated in two independent cohorts by qRT-PCR (n = 34, HR = 5.8, p = 0.003) and IHC (n = 59, HR = 4.3, p = 0.033).ConclusionWe identified MEK1 as a promising prognostic biomarker candidate correlated to response to platinum based chemotherapy in ovarian cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-837) contains supplementary material, which is available to authorized users.

A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

“…Eight clinically relevant chemotherapeutic agents were tested on their ability to cross the BBB and their cytotoxic effects on glioma cells. The properties of these agents are listed in Supplementary Table 13738394041424344. Among them, only Temozolomide (TMZ) is lipophilic and permeable to BBB, which is used for the treatment of glioblastoma multiforme in clinics.…”

“…Given its solubility, TMZ was dissolved in DMSO, and the other drugs were dissolved in PBS. All eight drugs were prepared at a concentration twice that of their respective IC 50 values3738394041424344. Three groups of experiments were performed: control group (no barrier), BMECs mono-cultured group and BBB group (BMECs co-cultured with astrocytes).…”

Identification of the Key Genes and Pathways in Esophageal Carcinoma

“…Clinically, overexpression of CCT3 predicts poor prognosis in hepatocellular carcinoma patients after hepatectomy [25, 26]. CCT3 is significantly associated with carboplatin resistance in ovarian cancer patients after surgery treatment [27]. The proteomic-based study shows that patients with cholangiocarcinoma (CCA) which are positive for CCT3 and CCT3 might be potential biomarker for the diagnosis of CCA [28].…”

Subcellular localisation of pMEK has a different prognosis in locally advanced head and neck cancer treated with concomitant radiochemotherapy

“…Our results show that high nuclear expression is significantly associated with a higher proliferation rate measured with Ki-67 expression ( p  = 0.04). Although the negative prognostic impact of pMEK has been described in other tumours [6], to our knowledge there are no studies in the literature that investigate the prognostic role of pMEK in head and neck cancer.…”

“…Within this pathway, MEK1 (MAP2K1) and MEK2 (MAP2K2) are closely related dual-specificity protein kinases that are activated by different growth factors and cytokines which function by phosphorylating both serine/threonine and tyrosine residues of their substrates ERK1 and ERK2, controlling fundamental cellular processes that include cell growth and proliferation [4, 5]. There are data that support the overexpression of MEK1 as an independent biomarker of survival in other tumours such as ovarian cancer [6]. However, there are no published investigations that study the value of pMEK as a prognostic factor in head and neck cancer.…”