FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients

Abstract

BackgroundEpithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. Forkhead box M1 (FOXM1) is an oncogene aberrantly expressed in many solid cancers including serous EOC, but its role in non-serous EOCs remains undefined. We examined FOXM1 expression and its correlation to prognosis across the three major EOC subtypes, and its role in tumorigenesis and chemo-resistance in vitro.MethodsGene signatures were generated by microarray for 14 clear-cell and 26 endometrioid EOCs, and 15 normal endometrium snap-frozen biopsies. Validation of FOXM1 expression was performed by RT–qPCR and immunohistochemistry in the same samples and additionally in 50 high-grade serous EOCs and in their most adequate normal controls (10 luminal fallopian tube and 20 ovarian surface epithelial brushings). Correlations of FOXM1 expression to clinic-pathological parameters and patients’ prognosis were evaluated by Kaplan-Meier and Cox proportional-hazards analyses. OVCAR-3 and two novel deeply characterized EOC cell lines (EOC-CC1 and OSPC2, with clear-cell and serous subtype, respectively) were employed for in vitro studies. Effects of FOXM1 inhibition by transient siRNA transfection were evaluated on cell-proliferation, cell-cycle, colony formation, invasion, and response to conventional first- and second-line anticancer agents, and to the PARP-inhibitor olaparib. Gene signatures of FOXM1-silenced cell lines were generated by microarray and confirmed by RT-qPCR.ResultsA significant FOXM1 mRNA up-regulation was found in EOCs compared to normal controls. FOXM1 protein overexpression significantly correlated to serous histology (p = 0.001) and advanced FIGO stage (p = 0.004). Multivariate analyses confirmed FOXM1 protein overexpression as an independent indicator of worse disease specific survival in non-serous EOCs, and of shorter time to progression in platinum-resistant cases. FOXM1 downregulation in EOC cell lines inhibited cell growth and clonogenicity, and promoted the cytotoxic effects of platinum compounds, doxorubicin hydrochloride and olaparib. Upon FOXM1 knock-down in EOC-CC1 and OSPC2 cells, microarray and RT-qPCR analyses revealed the deregulation of several common and other unique subtype-specific FOXM1 putative targets involved in cell cycle, metastasis, DNA repair and drug response.ConclusionsFOXM1 is up-regulated in all three major EOCs subtypes, and is a prognostic biomarker and a potential combinatorial therapeutic target in platinum resistant disease, irrespective of tumor histology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0536-y) contains supplementary material, which is available to authorized users.

Regulation of the master regulator FOXM1 in cancer

“…As a classic proliferation-associated transcription factor, FOXM1 directly or indirectly activates the expression of target genes at the transcriptional level and exhibits a spatiotemporal pattern whose dysregulation is involved in almost all hallmarks of tumor cells [ 3 , 12 ]. Increased expression of FOXM1 is observed in a variety of human cancers, such as ovarian cancer, breast cancer, prostate cancer, hepatoma, angiosarcoma, colorectal cancer, melanoma, lung cancer, and gastric cancer [ 13 – 21 ], which is consistent with the results obtained from the TCGA database (Fig. 2 ).…”

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

“…expression is coordinately upregulated in a sizable proportion of patients with chemoresistant recurrent HGSC (the front line therapy for these patients is carboplatin + paclitaxel). FOXM1 is reported to promote resistance to carboplatin and taxol, and we speculate that RHNO1, which promotes the DDR, might have an additional impact on this phenotype (Carr et al, 2010;Kwok et al, 2010;Nestal de Moraes et al, 2015;Tassi et al, 2017;Wang et al, 2013). In addition, ATR and CHK1 kinases have been shown to have cancer-specific synthetic lethality, suggesting that RHNO1 loss might synergize with a CHK1 inhibitor (Sanjiv et al, 2016).…”

“…The most common oncogenic function assigned to FOXM1 is deregulation of the G2/M checkpoint to promote cellular proliferation (Costa, 2005;Laoukili et al, 2005;Wonsey and Follettie, 2005). FOXM1 also promotes HR (Khongkow et al, 2014;Maachani et al, 2016;Monteiro et al, 2013;Park et al, 2012) and chemoresistance (Carr et al, 2010;Fang et al, 2018;Kwok et al, 2010;Tassi et al, 2017;Zhao et al, 2014). Pan-cancer analyses have demonstrated increased FOXM1 expression across a variety of cancers and a robust connection to genomic instability and poor prognosis (Barger et al, 2019;Carter et al, 2006;Gentles et al, 2015;Jiang et al, 2015;Li et al, 2017).…”

Identification of Hub Genes Associated with Melanoma Development by Comprehensive Bioinformatics Analysis

“…It has been shown that the positive feedback of FOXM1 promotes the growth and invasion of gastric cancer and that FOXM1 promotes gastric cancer progression by interacting with PVT1 [26]. FOXM1 has also been reported in non-serious epithelial ovarian carcinoma: FOXM1 was upregulated in all epithelial ovarian cancers [27]. In addition, it has been shown that the FOXM1-PSMB4 axis can play a catalytic role in the proliferation and development of cervical cancer [28].…”